CN113941002B - Slow-release drug delivery system for small-molecule drugs - Google Patents

Abstract

The invention relates to a pharmaceutical composition, which comprises a pharmaceutically active ingredient, glycerol, a slow-release carrier and a pharmaceutically acceptable solvent. The pharmaceutical composition has small irritation, good slow release performance, medication safety and tolerance, is a high-viscosity liquid at normal temperature, and is particularly favorable for perfusion administration.

Description

Slow-release drug delivery system for small-molecule drugs

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a slow-release drug delivery system for a small-molecule drug.

Background

The injectable sustained-release preparation is one of the research hotspots of the current pharmaceutical preparation, and aims to provide a drug storage, which can be used for subcutaneous injection, intramuscular injection, local injection and other administration modes. Wherein, the local injection refers to an administration mode that the medicine is locally administered, such as injected in the vertebral cavity, the joint cavity, the wound, the eye and other parts, and the medicine can be locally acted after being slowly released.

Injectable sustained release formulations have various advantages, such as: the preparation can be directly injected into expected administration parts for slow release, so as to reduce system toxicity and increase treatment effect; secondly, the preparation can also reduce the administration times and improve the compliance of patients; in addition, the preparation can also significantly reduce the treatment cost. However, such formulations also present some disadvantages, such as: since the drug is released over a long period of time and is not generally withdrawn after administration, good formulation stability is required. Furthermore, attention needs to be paid to whether sustained release preparations cause burst effect or cause other adverse effects such as dispersion, toxicity, etc. at the injection site.

In recent years, studies on injectable sustained-release techniques have mainly included oil sustained-release systems, sustained-release systems using polymers and lipids as matrices, and the like.

The oil slow release system mainly comprises injectable vegetable oil and organic solvent, and patent 201310022657.3 discloses an analgesic slow release drug delivery system composed of analgesic, drug solvent and drug slow release agent, wherein the drug slow release agent is liquid oil. The oil slow release system has low viscosity and simultaneously the organic solvent diffuses in vivo, so that the burst release phenomenon can be caused, potential safety hazards exist, and in addition, the release is fast, so that the release requirements of some medicines cannot be met.

The polymer slow release system mainly comprises polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polyorthoester (POE) and the like. Patent document US200303156A1 provides a sustained release microsphere composition and a preparation method thereof, wherein the composition comprises PLGA polymer, risperidone or 9-hydroxy risperidone as an active substance, and other excipients. In 2003, the FDA approved risperidone long-acting microspheres developed by Janssen Pharmaceuticals and using PLGA as a slow release carrier, and the product is called RISPERDAL

The sustained release microspheres can provide 14-day sustained release. A composition containing amide local anesthetics, enol NSAIDs and polyorthoesters and a preparation method thereof are disclosed in patent CN106535886A of Heron Therapeutics Inc, wherein polyorthoesters are used as sustained release carriers. Currently approved by the European Union under the trade name of

Since the polymeric material degrades slowly at the site of administration, there is a safety risk.

The slow release system with lipid as matrix mainly comprises lipid complex and liposome. PACIRA develops a long-acting bupivacaine multivesicular liposome suspension injection with the trade name of

Can be used for treating postoperative pain and nerve block, and has analgesic effect lasting for 24 hr. The liposome mainly contains two synthetic phospholipids, namely dicamba lecithin (DEPC) and dipalmitoyl phosphatidyl glycerol (DPPG), and bupivacaine is wrapped in the multivesicular liposome to play a slow-release role. However, multivesicular liposomes are complex in preparation process and have high requirements for storage conditions. Furthermore, patent CN103705442 discloses an in situ lipid gel formulation characterized in that said formulation comprises a phospholipid, a therapeutically effective amount of an active substance and a solvent; the phospholipid is preferably one or more of soybean phospholipid and egg yolk lecithin, and more preferably soybean phospholipid; the solvent contains organic solvent, preferably one or more of absolute ethyl alcohol, benzyl alcohol, tertiary butanol and glycerol, and simultaneously contains water or physiological aqueous medium. Patent CN103705439 discloses a lipid gel formulation characterized in that said formulation comprises pegylated phospholipids, non-pegylated phospholipids, a therapeutically effective amount of an active substance and a solvent, wherein said lipid gel formulation is free of cholesterol as solvent in water or physiological aqueous medium. CN102933200 discloses a single phase gel composition comprising: 20-80% by weight of one or more phospholipids; 0.1% to 70% by weight water, wherein the phospholipid has a particle size of less than 100nm and the gel composition is capable of being extruded from a 1cc syringe through a 25GX1/2 inch long needle at an extrusion rate of 2cc/min and with a force of no more than 12 pounds using a high shear, high energy or high pressure homogenizer, and the composition further optionally comprises a pharmacologically active agent. Patents CN103705442, CN103705439 and CN102933200 all contain water in different proportions, and may have stability problems such as easy oxidation, and at the same time, the viscosity is low, and only subcutaneous injection administration is possible.

The existing approved or researched sustained-release system has the problems of complex preparation process, difficult degradation of a sustained-release carrier, safety caused by burst release and the like. Furthermore, the lipid-based sustained release systems that have been developed or marketed all have a problem that they have a low viscosity and cannot satisfy the incision administration. Accordingly, there is a need to develop a sustained-release formulation system suitable for pharmaceutical use, improved in stability, safety, tolerability and/or sustained-release property, and high in viscosity.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a liquid pharmaceutical composition, which comprises the following components:

a. a pharmaceutically active ingredient;

b. glycerol;

c. the sustained-release carrier is selected from one or more compounds of formula I or formula II, and the compound of formula I is

Wherein, rs is selected from H,

each R ₁ 、R ₂ Identical or different, independently from each other, from saturated or unsaturated aliphatic hydrocarbon radicals; each R ₃ 、R ₄ 、R ₅ Identical or different, independently of one another, from H or alkyl; l is selected from alkylene; the compound of formula II is

Wherein R is selected from alkyl;

d. at least one pharmaceutically acceptable solvent.

According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable release modifier.

According to an embodiment of the invention, in said formula I, each R ₁ 、R ₂ Identical or different, independently of one another, from C _10-30 Saturated or unsaturated aliphatic hydrocarbon radicals, e.g. C _13-21 An alkyl group; each R ₃ 、R ₄ 、R ₅ Identical or different, independently of one another, from H or C _1-10 Alkyl, for example independently of one another selected from H, methyl, ethyl; l is selected from C _1-10 Alkylene, preferably, L is selected from C _1-6 Alkylene, for example methylene, ethylene;

according to an embodiment of the invention, in the compound of formula II, R is selected from C _1-10 Alkyl radicals, e.g. C _8-10 An alkyl group.

According to an embodiment of the invention, the c-component slow release carrier is selected from the group consisting of HSPC (hydrogenated soybean lecithin), DMPC (dimyristoyl phosphatidylcholine), DPPC (dipalmitoyl phosphatidylcholine), DSPC (distearoyl phosphatidylcholine), DLPC (dilauroyl phosphatidylcholine), SPC soybean phosphatidylcholine (soybean phospholipid), EPC (egg yolk phospholipid), rapeseed phospholipid, sunflower phospholipid, DEPC (dicaprylyl lecithin), DOPC (dioleoyl lecithin), one or more of POPC (palmitoyl oleoyl lecithin), sphingomyelin, distearoyl phosphatidic acid (DSPA), dioleoyl phosphatidylethanolamine (DOPE), dipalmitoyl phosphatidic acid (DPPA), myristoyl lysophospholipid (M-lysoPC), palmitoyl lysophospholipid (P-lysoPC), 1-stearoyl-lysophosphatidylcholine (S-lysoPC), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl phosphatidylethanolamine (DSPE), dioleoyl phosphatidylglycerol (DOPG), dimyristoyl phosphatidylethanolamine (DMPE), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), distearoyl phosphatidylglycerol (DSPG), dipalmitoyl phosphatidylserine (DPPS), phosphatidylinositol (PI), cholesterol (CHO).

Preferably, the c-component slow release carrier is one or more of SPC soybean phosphatidylcholine (soybean phospholipid), EPC (egg yolk phospholipid), DEPC (dicapryl lecithin), DOPC (dioleoyl lecithin), POPC (palmitoyl oleoyl lecithin).

According to an embodiment of the present invention, the pharmaceutically active ingredient is not limited to the type of treatment, and may be an anti-inflammatory drug, a local anesthetic, an analgesic, an anti-psychotic drug, an anxiolytic drug, a sedative hypnotic drug, an antidepressant, an antihypertensive drug, a steroid hormone, an antiepileptic drug, an antiseptic, an anticonvulsant, an anti-parkinson's disease drug, a central nervous stimulant, an antipsychotic, an anti-arrhythmic drug, an anti-angina drug, an antithyroid drug, an antidote, an antiemetic, a hypoglycemic drug, an anti-tuberculotic drug, an anti-aids drug, an anti-hepatitis b drug, an antineoplastic drug, an anti-rejection drug, and mixtures thereof.

According to an embodiment of the invention, suitable pharmaceutically active ingredients may be selected from the group of one or more of the following compounds: aspirin, acetaminophen, benorilate, indomethacin, sulindac, diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, loxoprofen, nabumetone, ketorolac, phenylbutazone, bufexamac, fenoprofen, celecoxib, rofecoxib, polmacoxib, nimesulide, meloxicam, lornoxicam, piroxicam, etodolac, valdecoxib, parecoxib, ericoxib, lumiracoxib. Bupivacaine, levobupivacaine, ropivacaine, mepivacaine, lidocaine, procaine, benzocaine, tetracaine, dyclonine. Enkephalin, dynorphin, beta-endorphin, naltrexone, buprenorphine, morphine, dimethylmorphine, codeine, dihydrocodeine, oxycodone, hydrocodone, nalbuphine, fentanyl, sufentanil, remifentanil, tramadol, nortramadol, tapentadol, dezocine, pentazocine, methadone, meperidine, ketamine, diazepam, chlordiazepam, lisdexamphetamine, dexpropoxyphene, difelikefatin, olicridine. Chlorpromazine, trifluoropropylazine, mesoridazine, piperazines, thioridazine, chlorprothixene. Diazepam, alprazolam, clonazepam, oxazepam, imipramine, amitriptyline, doxepin, nortriptyline, amoxapine, tranylcypromine, and phenelzine. Procainamide, isoamyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin, phentolamine, mizhiophene, captopril and enalapril. Clonidine, dexmedetomidine, epinephrine, norepinephrine, tizanidine, alpha-methyldopa, glycopyrrolate. Cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone ester, prednisone, prednisolone, methylprednisolone, beclomethasone, clobetasol, progesterone, testosterone heptanoate, testosterone undecanoate, testosterone cypionate, progesterone, fulvestrant, allopregnanolone, ganaxolone, phenytoin, and ethionine. Benzalkonium chloride, benzethonium chloride, mafenide acetate, benzethonium chloride, nitrofural, and nitromersol. Phenobarbital, amobarbital, pentobarbital, secobarbital. Carbidopa, levodopa, aniracetam, oxiracetam, piracetam, doxapram, aripiprazole, olanzapine, haloperidol, quetiapine, risperidone, clozapine, paliperidone, atenolol, bisoprolol, metoprolol. Atenolol, amlodipine, nimodipine, isosorbide mononitrate, epoprostenol, treprostinil, iloprost, beraprost. Methimazole, propylthiouracil, propranolol, naloxone, lofexidine, flumazenil, amphetamine. Granisetron, ondansetron, tropisetron, dolasetron, palonosetron, scopolamine, domperidone, glipizide, glyburide, glimepiride, glibenclamide, gliclazide, tolbutamide, liraglutide, exenatide, dolabrlutide, somaglutethide, and somagluteline. Darunavir, doritavir sodium, emtricitabine, lativavir, ritonavir, stavudine, nevirapine, zidovudine, stavudine, etravirine, adefovir dipivoxil, entecavir, telbivudine, lamivudine, tenofovir dipivoxil, foscarnofovir, thiosemicarbazide, pyrazinamide, prothionamide, cyclophosphamide, 5-fluorouracil, carmustine, lomustine, melphalan, chlorambucil, methotrexate, vincristine, bleomycin, doxorubicin, tamoxifen, cyclosporine, tacrolimus, everolimus, sirolimus and pharmaceutically acceptable salts, stereoisomers, and derivatives of said compounds.

According to an embodiment of the invention, the pharmaceutically active ingredient is selected from amide local anesthetics, for example selected from bupivacaine, ropivacaine, levobupivacaine, mepivacaine, lidocaine in salt form. The salt of the amide local anesthetic can be selected from fatty acid salts and water-soluble salts thereof, and the acid for forming the salt comprises lauric acid, myristic acid, stearic acid, palmitic acid, behenic acid, arachidic acid, methanesulfonic acid, hydrochloric acid, sulfonic acid, phosphoric acid, acetic acid, citric acid, maleic acid and the like.

According to an embodiment of the present invention, the pharmaceutically active ingredient may further comprise a second active ingredient in addition to the amide-based local anesthetic, and the pharmaceutically active ingredient may be one selected from a COX receptor inhibitor, an adrenoceptor agonist, and a glucocorticoid. The COX receptor inhibitory drugs include non-selective COX inhibitory drugs and selective COX-2 inhibitory drugs. Non-steroidal anti-inflammatory drugs represented in these classes include, but are not limited to, the following non-selective COX inhibitors: aspirin, acetaminophen, benorilate, indomethacin, sulindac, diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, loxoprofen, nabumetone, piroxicam, ketorolac, phenylbutazone, bufexamac, fenoprofen; the following selective COX-2 inhibitors: celecoxib, rofecoxib, nimesulide, meloxicam, lornoxicam, etodolac, valdecoxib, parecoxib, erexib, lumixib. And pharmaceutically acceptable salts, stereoisomers, derivatives of said compounds. The adrenoceptor agonist is mainly alpha 2-adrenoceptor agonist, and includes but is not limited to clonidine, dexmedetomidine, epinephrine, norepinephrine, tizanidine and alpha-methyldopa. The glucocorticoid drugs include, but are not limited to, cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, prednisone, prednisolone, methylprednisolone, beclomethasone, and clobetasol.

In some embodiments, the pharmaceutically active ingredient is selected from one or a combination of several of ropivacaine hydrochloride, ropivacaine mesylate, bupivacaine hydrochloride, levobupivacaine hydrochloride, meloxicam, celecoxib, ketorolac, and triamcinolone acetonide.

In some embodiments, the pharmaceutically active ingredient is selected from the group consisting of amide local anesthetics in combination with non-steroidal anti-inflammatory drugs, such as ropivacaine hydrochloride and meloxicam compositions, levobupivacaine hydrochloride and meloxicam compositions, bupivacaine hydrochloride and meloxicam compositions, ropivacaine mesylate and celecoxib hydrochloride compositions, levobupivacaine hydrochloride and celecoxib compositions, bupivacaine hydrochloride and celecoxib compositions, and the like. According to an embodiment of the invention, the pharmaceutically acceptable release modifier is selected from one or more of sterols, saturated phospholipids and other surfactants. The saturated phospholipid is used to adjust the viscosity of the sustained release drug delivery system and thus the drug diffusion rate, and the sterol and surfactant are used to adjust the hydrophilicity of the sustained release drug delivery system in order to achieve the desired drug release rate.

In some embodiments, the sterol comprises cholesterol.

In some embodiments, the saturated phospholipids include Hydrogenated Soybean Phospholipids (HSPC), dilauroyl Lecithin (DLPC), dimyristoyl lecithin (DMPC), distearoyl phosphatidylcholine (DSPC), dipalmitoyl lecithin, and the like (DPPC), and the like.

In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the surfactant comprises polyoxyl 40 stearate, macrogol caprylate caprate, polyoxyethylene lauryl glyceride, polyoxyethylene stearyl glyceride, polyoxyethylene oleyl glyceride, polyethylene glycol E succinate, poloxamer, polysorbate, polyethylene glycol-12-hydroxystearate, propylene glycol monocaprylate, glycerol dioleate, glycerol monooleate, and the like. The poloxamer may be selected from poloxamer 407, poloxamer 188, for example, and the polysorbate may be selected from polysorbate 80, for example.

According to an embodiment of the invention, the composition may further comprise one or more antioxidants. Antioxidants may be used to prevent or reduce oxidation of phospholipids in the sustained release drug delivery systems described in the present invention. Antioxidants provided by the present invention include, but are not limited to, vitamin C (ascorbic acid), cysteine hydrochloride, vitamin E (tocopherol), ascorbyl palmitate, glutathione, alpha lipoic acid, thioglycerol.

According to an embodiment of the invention, the composition may further comprise other Excipients conventional In the pharmaceutical field, examples of suitable pharmaceutical Excipients are described In Excipients and the use In injectable products PDA J Pharm Sci technol. Vol.51, p.7-8, 1997, p.166-171 and Excipient Selection In particulate formation Development, pharma Times, vol.45, p.3, p.2013, p.65-77, which are incorporated herein by reference In their entirety.

According to an embodiment of the present invention, the mass ratio of glycerol to slow-release carrier/pharmaceutically acceptable solvent is 1. In some embodiments, the ratio by mass of glycerol to slow release carrier/pharmaceutically acceptable solvent is from 1. In some embodiments, the ratio by mass of glycerol to slow release carrier/pharmaceutically acceptable solvent is from 1.

According to an embodiment of the present invention, the mass ratio of the sustained-release carrier to the pharmaceutically acceptable solvent is 1. In some embodiments, the sustained release carrier to pharmaceutically acceptable solvent mass ratio is 1. In some embodiments, the sustained release carrier to pharmaceutically acceptable solvent mass ratio is 1.

According to an embodiment of the invention, the glycerol comprises about 1% to about 95% (w/w) of the total amount of the composition, such as about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%. In some embodiments, the glycerol ratio is about 2% to 60% (w/w). In some embodiments, the glycerol ratio is about 3% to 30% (w/w).

According to an embodiment of the invention, the slow release carrier constitutes 3% to 90% (w/w) of the total composition, such as 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%. In some embodiments, the sustained release carrier comprises 20% to 60% (w/w) of the total composition.

According to an embodiment of the invention, the pharmaceutically active ingredient is present in an amount of 0.1% to 50.0% (w/w) of the total composition. According to some embodiments, the pharmaceutically active ingredient comprises 0.1% to 15% (w/w) of the total amount of the composition, e.g. 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%. According to some embodiments, the pharmaceutically active ingredient is present in an amount of 3% (w/w) to 10% (w/w). According to some embodiments, when the pharmaceutically active ingredient is selected from two or more, each pharmaceutically active ingredient may constitute 0.1% to 15% (w/w) of the total amount of the composition, for example, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%.

According to an embodiment of the present invention, the total amount of the pharmaceutically acceptable solvent is 5% to 50% (w/w) of the total amount of the composition, and in some embodiments, the total amount of the pharmaceutically acceptable solvent may be 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% of the total amount of the composition. In some embodiments, the total amount of the pharmaceutically acceptable solvent is 10% -50% (w/w) of the total composition, and in some embodiments, the total amount of the pharmaceutically acceptable solvent is 5% to 30% (w/w) of the total composition.

According to an embodiment of the invention, the pharmaceutically acceptable solvent is a non-aqueous solvent selected from one or more combinations of ethanol, N-methylpyrrolidone, benzyl alcohol, N-propanol, isopropanol, N-butanol, isobutanol, tert-butanol.

According to embodiments of the present invention, the release modifier may be 0% to 40% (w/w), preferably 0.1% to 40% (w/w) of the total composition, and in some embodiments, the release modifier may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40% of the total composition, and in some embodiments, the release modifier may be 1 to 30% (w/w) when the release modifier is selected from a saturated phospholipid; in some embodiments, when the release modifier is selected from surfactants, the release modifier is used in an amount of 0.1% to 5% (w/w).

According to an embodiment of the present invention, the pharmaceutical composition provided by the present invention is a high viscosity liquid formulation. The viscosity of the liquid preparation is more than or equal to 500 mPa.s at normal temperature (about 25 ℃). In some embodiments, the composition has a viscosity of 500 to 100000 mPa-s at 25 ℃. In some embodiments, the viscosity of the composition is in the range of 500 to 50000 mPa-s at 25 ℃. In some embodiments, the composition has a viscosity in the range of 500 to 30000 mPa-s at 25 ℃. In some embodiments, the viscosity of the composition is in the range of 500 to 15000 mPa-s at 25 ℃. In some embodiments, the composition has a viscosity in the range of 500 to 10000 mPa-s at 25 ℃.

In the pharmaceutical composition of the present invention, the pharmaceutically acceptable solvent and the release modifier may serve as a viscosity modifier, rendering the composition suitable for injection. The invention provides a preparation method of the pharmaceutical composition, which comprises the following steps:

(a1) Mixing the slow release carrier and a pharmaceutically acceptable solvent, and stirring or shearing under a heating condition to obtain a clear and uniform mixed solution;

(a2) Adding at least one pharmaceutically active ingredient into the mixed solution, and stirring or shearing under heating to form a uniform mixture;

(a3) Adding glycerol into the mixed solution, and stirring or shearing under heating condition to form uniform solution.

According to an embodiment of the present invention, the mixing of step (a 1) further comprises adding at least one pharmaceutically acceptable release modifier, for example, the step (a 1) may be mixing a sustained release carrier, a pharmaceutically acceptable solvent, glycerin and a release modifier.

In some embodiments, the method comprises:

1. mixing the slow release carrier, the pharmaceutically acceptable solvent, the pharmaceutically acceptable active ingredients and the glycerol at 50-70 ℃ until a clear and transparent solution is obtained.

2. The hot solution was sterilized through a 0.22 μm filter.

3. The filtered mixed solution was cooled to room temperature.

The invention provides a sustained release formulation comprising the pharmaceutical composition, the formulation being administered as a depot formulation, in one aspect the formulation is injectable. In another aspect, the formulation may be administered topically.

In another aspect, the formulation may be injected subcutaneously, injected peripherally, injected intramuscularly, or administered by infusion (direct application to wound, arterial infusion, rectal infusion).

In another aspect, the formulation is suitable for topical or mucosal administration to the skin.

The preparation provided by the invention is applied in a single dose, and the contained dose can achieve the effects of relieving pain and blocking nerves, and can be used for preventing or relieving local pain.

According to some embodiments, the preparation provided by the invention can form a stable-shape storage at an administration position, can slowly and continuously release the medicine, prolongs the medicine release time and improves the treatment effect.

In some embodiments, the formulation is administered for at least 24 hours after effective treatment. In some embodiments, the formulation continues to be effective for at least 24 to 48 hours after administration. In some embodiments, the formulation continues to be effective for at least 48 to 72 hours after administration. In some embodiments, the formulation is administered for at least 72 hours after effective treatment is continued. According to an embodiment of the invention, the formulation further comprises a packaging filled with the formulation, the packaging being selected from one or more of the following: penicillin bottles, pre-filled and sealed injectors and clamping bottles.

Terms and abbreviations

Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.

Where a range of numerical values is recited in the specification and claims of this application, and where the range of numerical values is defined or can only be "integers," it is to be understood that both endpoints of the range are recited and each integer within the range is also recited. For example, "an integer of 0 to 10" should be understood to describe each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

When a range of values is defined as "a number" or can include "an integer" or "a non-integer," it should be understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "a number of 0 to 10" should be understood to not only recite each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also to recite at least the sum of each integer with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

The term "aliphatic hydrocarbon group" includes saturated or unsaturated, straight-chain or branched-chain hydrocarbon groups, the type of which may be selected from alkyl groups (saturated aliphatic hydrocarbon groups), unsaturated aliphatic hydrocarbon groups (containing at least one double bond and/or triple bond, such as alkenyl, alkynyl), and the like, the number of carbon atoms of the aliphatic hydrocarbon group is preferably 1 to 40, and more preferably 1 to 30 (for example, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30), and specifically may include, but are not limited to, the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylethenyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl and 1-hexynyl; the "aliphatic hydrocarbon group" moiety contained in the other groups is as explained above.

The term "alkyl" is a saturated aliphatic hydrocarbon group, conforming to the relevant definition in the above aliphatic hydrocarbon group, for example the alkyl group preferably has 1 to 40, more preferably 1 to 30, or 1 to 10 carbon atoms (e.g. being C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C30, C40, i.e. methyl, ethyl, propyl, and so on). And it will be understood by those skilled in the art that in some specific structures, when an alkyl group is explicitly indicated as a linking group, then that alkyl group represents the linked alkylene group, and thus, "alkylene" may also be defined in relation to the aliphatic hydrocarbon group described above, for example, the alkylene group may have a number of carbon atoms of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 (i.e., the alkylene group may be methylene, ethylene, and so on).

The term "biocompatible" refers to the interaction between the components of a composition and the body.

The term "active ingredient" refers to a drug used to treat a disease. Therefore, the active ingredients and the medicaments can be used alternatively. The term "active ingredient" or "drug" as used herein includes, but is not limited to, pharmaceutically active substances that act locally or systemically, which can be administered by local administration or by injection, such as subcutaneous, intradermal, intramuscular, and intraarticular injection. At least one active ingredient is present in the sustained release delivery system of the present invention.

The term "amide type" as used herein refers to an amide or a local anesthetic of the caine type, such as bupivacaine, levobupivacaine, ropivacaine, mepivacaine, lidocaine and the like. The amide local anesthetics generally consist of lipophilic parts and hydrophilic parts, wherein the lipophilic parts can be aromatic hydrocarbons or aromatic heterocycles, and the benzene rings have the strongest effect. The introduction of an electron-donating group such as an amino group or the like to the benzene ring can enhance the activity. The hydrophilic moiety is typically a secondary amine, a tertiary amine or pyrrolidine, piperidine, morpholine, and the like, with tertiary amines being most common. The pKa is generally between 7.5 and 7.9 and is ionic under physiological conditions.

The abbreviations used in the present invention have the following definitions: SPC is soybean phosphatidylcholine (soybean phospholipid), EPC is egg yolk phosphatidylcholine (egg yolk phospholipid), HSPC is hydrogenated soybean phosphatidylcholine, DLPC is dilauroyl phosphatidylcholine, DMPC is dimyristoyl phosphatidylcholine, DPPC is dipalmitoyl phosphatidylcholine, DSPC is distearoyl phosphatidylcholine, DEPC is dicaprylyl lecithin, DOPC is dioleoyl phosphatidylcholine (dioleoyl lecithin), POPC is palmitoyl oleoyl lecithin, BA represents benzyl alcohol, NMP represents N-methylpyrrolidone, DMSO represents dimethyl sulfoxide, BUP represents bupivacaine, ROMLP represents ropivacaine, ROMX represents meloxicam, CHO represents cholesterol, PRX represents piroxicam, LBUP represents levobupivacaine, TAC represents triamcinolone, KTL represents ketorolac, CLD represents clonidine, etOH represents absolute ethanol, BA represents benzyl alcohol, PEG200 represents polyethylene glycol 200, PEG400 represents polyethylene glycol 400, PEG600 represents polyethylene glycol 600.

Advantageous effects

1) The invention provides a sustained-release preparation composition, which is a high-viscosity liquid at normal temperature and can generate phase change at the administration part. The auxiliary material components selected by the invention have good biocompatibility. The invention unexpectedly discovers that the viscosity of the composition preparation can be obviously improved by controlling the proportion of the glycerol, the sustained-release carrier and the solvent system, so that the pharmaceutical composition is easier to infuse and administer, and stays in vivo for a longer time, and the sustained-release effect of the medicine is improved.

2) The invention further discovers that the addition of a proper release regulator into a preparation system can further improve the viscosity of the system, improve the release performance of the active ingredients and the like;

3) The composition has small irritation and good medication safety and tolerance.

4) The sustained-release preparation system provided by the invention can realize good release performance of the active pharmaceutical ingredient and reduce the possibility of burst release.

5) The composition is particularly suitable for developing pharmaceutical preparations with anesthesia and analgesic activities, has more advantages compared with other sustained-release analgesic systems, for example, the composition has sustained and stable release of analgesic active ingredients, can be injected for administration, is suitable for stable and convenient local administration, and has good tolerance and less side effect for patients.

Drawings

Fig. 1-1 through 1-4 are the rheological results of compositions 3058, 3061, 3062, 3064, respectively.

FIGS. 1-5 are viscosity-shear rate curves for compositions 3058, 3061, 3062, 3064.

FIG. 2-1 shows the site of administration of compositions 3075 and 3076 in rats for 24h, 48h, 72 h.

Fig. 3-1 through 3-2 are ropivacaine and bupivacaine plasma concentration-time curves, and meloxicam plasma concentration-time curves for compositions 3077 and 3078, respectively.

Fig. 4-1 to 4-2 are ropivacaine plasma concentration-time curves and meloxicam plasma concentration-time curves for compositions 3079 and 3080, respectively.

Fig. 5-1 to 5-2 show plasma ropivacaine and meloxicam concentration-time curves of composition 3082, respectively.

Fig. 6-1 to 6-2 show plasma ropivacaine concentration-time curves and plasma meloxicam concentration-time curves of compositions 3079, 3080 and 3081, respectively.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

The experimental animal source is as follows:

example 1

Investigation of viscosity of composition with different kinds of alcohols

The compositions were prepared as in table 1-1, SPC was dissolved in BA under heating, glycerol, propylene glycol, PEG200, PEG400, PEG600 were added separately, heated and stirred to form a homogeneous solution, left at room temperature, and the influence of different alcohols on the system viscosity was examined. The viscosity of the composition was measured using a 14-rotor at 50rpm and the results are shown in tables 1-2.

TABLE 1-1 composition active ingredients

TABLE 1-2 composition solution State and viscosity

The invention unexpectedly discovers that the viscosity of the composition can be obviously increased by adding glycerol into the phospholipid solution, and the viscosity of the composition is not obviously increased by propylene glycol and polyethylene glycol with different molecular weights.

Example 2

Study of Glycerol/organic solvent/sustained Release vehicle ratio on viscosity of composition

Preparing the compositions according to tables 2-1 and 2-2, dissolving SPC in solvents of different types and proportions under a heating state, adding glycerol, heating and stirring to form a uniform solution, standing at room temperature, and inspecting the influence of the proportion of auxiliary materials of the compositions on the viscosity of the system.

TABLE 2-1 measurement of viscosity of compositions containing different solvents

TABLE 2-2 viscosity test results for compositions containing different solvents

Example 3

Study of composition homogeneity

The compositions of tables 2-1 and 2-2 having different viscosities were centrifuged at 9000rpm for 15min in a PE tube, and the state of the solution after centrifugation was observed. The results are shown in tables 3-1 and 3-2.

TABLE 3-1 results for homogeneity of the composition of different solvents (benzyl alcohol)

TABLE 3-2 composition homogeneity results for different solvents (absolute ethanol)

From the results, it was found that the samples with different viscosities were in a uniform state without separation after high-speed centrifugation, indicating that the physical stability was good.

Example 4

Rheology study

Compositions were prepared and subjected to rheological studies as per Table 4-1. Rheometer type: TA DHR-1, sample size: 1mL. Measurement mode: oscillation mode: time scanning, fixing 0.5 percent of string and 1Hz in frequency; oscillation mode: frequency sweep, fixed Strain0.5%, frequency sweep range 0.1-100rad/s.

TABLE 4-1 composition Components

The sample exhibits gel behavior when the storage modulus (G ') is greater than the loss modulus (G') and solution behavior when the storage modulus (G ') is less than the loss modulus (G'). As shown in FIGS. 1-1 to 1-4, the compositions of the present invention all exhibited solution characteristics.

FIGS. 1-5 are the viscosity-shear rate curves for the compositions of Table 4-1, showing that the viscosity of the compositions increases with increasing amounts of glycerin and that the viscosity of the compositions can be adjusted by the addition of modifiers. In addition, as the shear rate increases, the composition exhibits a shear thinning phenomenon.

Example 5

Pharmaceutical composition containing different glycerin ratios

The compositions were prepared as shown in Table 5-1, and the SPC and active ingredients were dissolved in an organic solvent under heating, glycerin was added in different proportions, and the mixture was heated and stirred to form a homogeneous solution.

TABLE 5-1 composition Components

Example 6

Drug release from pharmaceutical compositions of varying glycerol ratios

100mg of the pharmaceutical composition from example 5 was added to a dialysis bag and placed in a tube containing 200mL of phosphate buffer to determine the release of ropivacaine from the composition of example 5. After shaking at 37 ℃ 1mL of phosphate buffer was removed from the tube at 24h, 48h, and 72h, respectively. The concentrations of ropivacaine mesylate and meloxicam in each sample were determined by HPLC. The results are shown in Table 6-1 below.

TABLE 6-1 Release of ropivacaine mesylate and meloxicam from the composition

Example 7

Pharmaceutical composition containing different release regulator ratios

The compositions were prepared as shown in Table 7-1, and SPC, DPPC and the active ingredient were dissolved in an organic solvent under heating, glycerin was added, and a homogeneous solution was formed by heating and stirring.

TABLE 7-1 composition Components

Example 8

Drug release from pharmaceutical compositions of different release modifier ratios

100mg of the pharmaceutical composition from example 7 was added to a dialysis bag and placed in a tube containing 200mL of phosphate buffer to determine the release of ropivacaine from the composition of example 7. After shaking at 37 ℃ 1mL of phosphate buffer was removed from the tube at 24h, 48h, and 72h, respectively. The concentrations of ropivacaine mesylate and meloxicam in each sample were determined by HPLC. The results are shown in the following Table 8-1.

TABLE 8-1 Release of ropivacaine mesylate and meloxicam from the composition

Example 9

Pharmaceutical composition containing different active ingredients

The compositions were prepared as shown in Table 9-1, and the SPC and the active ingredient were dissolved in the organic solvent under heating, glycerin was added, and the mixture was stirred under heating to form a homogeneous solution.

TABLE 9-1 composition Components

Example 10

Pharmaceutical composition containing different active ingredients

The compositions were prepared as shown in Table 10-1, and the SPC and the active ingredient were dissolved in the organic solvent under heating, and the mixture was heated and stirred to form a homogeneous solution.

TABLE 10-1 composition Components

Example 11

Pharmaceutical composition containing different antioxidants

The compositions were prepared as shown in Table 11-1, and the SPC and the active ingredient were dissolved in the organic solvent under heating, glycerin was added, and the mixture was stirred under heating to form a homogeneous solution.

TABLE 11-1 compositions containing different antioxidants

Example 12

Stability of pharmaceutical compositions

The compositions were prepared as shown in Table 12-1, and the SPC and the active ingredient were dissolved in the organic solvent under heating, and the mixture was heated and stirred to form a homogeneous solution. The samples were left at 60 ℃ and 40 ℃ to examine the changes of the substances concerned, and the results are shown in Table 12-2.

TABLE 12-1 compositions containing different antioxidants

TABLE 12-2 stability of the compositions

As can be seen from the results in Table 12-2, the pharmaceutical composition shows no significant increase in the related substances at 60 ℃ and 40 ℃ and has good chemical stability.

Example 13

In vivo administration of pharmaceutical compositions

The compositions were prepared as shown in Table 13-1, the lateral hair of the right hind leg of the rat was removed, 0.2mL of the composition (administration dose: 100mg/kg, drug content: 20mg in terms of ROP) was subcutaneously administered to each rat, the administration site was opened by dislocation at 24h, 48h and 72h, and the form of the preparation at the administration site was observed. The results are shown in FIG. 2-1. Composition 3075 and composition 3076 were still visible as a depot after 72 h.

TABLE 13-1 composition Components

Example 14

In vivo administration of pharmaceutical compositions

In vivo pharmacokinetic studies in dogs were as follows. Beagle dogs weighing about 10kg were fasted for over 12 hours (with the feeding tray removed) prior to the experiment, allowed free access to water and fed 4 hours after dosing. Each group was administered by subcutaneous injection, and the information on the samples is shown in Table 14-1. Each beagle dog received two injections, 50mg each, and each group of animals was bled 0 hours before dosing, approximately 0.5mL each at 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hours after dosing into EDTA-2K + anticoagulated blood collection tubes, and whole blood was centrifuged at 8000rpm for 5min before plasma was collected, followed by detection of drug concentration in plasma samples by LC-MS/MS.

TABLE 14-1 composition Components

The blood concentration-time curves of compositions 3077, 3078 are shown in fig. 3-1 and fig. 3-2.

Example 15

In vivo administration of pharmaceutical compositions

In vivo pharmacokinetic studies in dogs were as follows. The beagle dogs weighing about 10kg were fasted for over 12 hours (with the feeding box removed) before the experiment, allowed free access to water and were fed 4 hours after dosing. Each group was administered by subcutaneous injection, and the sample information is shown in Table 15-1. Each beagle dog received two injections, 50mg each, and each group of animals was bled 0 hours before dosing, approximately 0.5mL each at 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hours after dosing into EDTA-2K + anticoagulated blood collection tubes, and whole blood was centrifuged at 8000rpm for 5min before plasma was collected, followed by detection of drug concentration in plasma samples by LC-MS/MS.

TABLE 15-1 composition Components

The plasma concentration-time curves of compositions 3079, 3080 are shown in fig. 4-1 and fig. 4-2.

Example 16

In vivo administration of pharmaceutical compositions

In vivo pharmacokinetic studies in dogs were as follows. The beagle dogs weighing about 10kg were fasted for over 12 hours (with the feeding box removed) before the experiment, allowed free access to water and were fed 4 hours after dosing. Each group was administered by subcutaneous injection, and the information on the samples is shown in Table 16-1. Each beagle dog received two injections, 50mg each, and each group of animals was bled 0 hours before dosing, approximately 0.5mL each at 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hours after dosing into EDTA-2K + anticoagulated blood collection tubes, and whole blood was centrifuged at 8000rpm for 5min before plasma was collected, followed by detection of drug concentration in plasma samples by LC-MS/MS.

TABLE 16-1 composition Components

The plasma concentration-time curve of composition 3082 is shown in fig. 5-1 and fig. 5-2.

Example 17

In vivo administration of pharmaceutical compositions

The pharmacokinetics in rats were studied as follows. Animals weighing about 180-200 g are randomly grouped and uniquely identified by tail numbers. The administration was performed by subcutaneous injection at the back of the neck of the rat, and the administration volume was fixed to 0.2 mL/animal. Blood samples were collected 0h before dosing, approximately 0.5, 1, 2, 3, 6, 8, 10, 24, 34, 48, 72 and 96h after dosing into K2EDTA anticoagulation tubes and stored temporarily on ice until centrifugation. Centrifuging to obtain plasma within 60min (centrifuging at 2-8 deg.C and 8000rpm for 5 min), transferring into 96-well plate or centrifuge tube, transferring in wet ice-box, and storing at-15 deg.C or below for LC-MS/MS detection.

TABLE 17-1 composition Components

The plasma concentration-time curves of compositions 3079, 3080, 3081 are shown in fig. 6-1 and fig. 6-2.

The above description is directed to exemplary embodiments of the present invention. However, the scope of the present invention is not limited to the above embodiments. Any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.

Claims (21)

1. A pharmaceutical composition comprising the following components:

a. a pharmaceutically active ingredient;

b. glycerol;

c. a slow release carrier;

d. at least one pharmaceutically acceptable solvent;

the pharmaceutically active component is selected from ropivacaine hydrochloride, ropivacaine mesylate, bupivacaine hydrochloride, levobupivacaine hydrochloride

One or a combination of more of caine, meloxicam, celecoxib, ketorolac and triamcinolone acetonide;

the pharmaceutically acceptable solvent is a non-aqueous solvent, and the non-aqueous solvent is selected from one or more of ethanol, N-methylpyrrolidone, benzyl alcohol, N-propanol, isopropanol, N-butanol, isobutanol and tert-butanol;

the c component slow release carrier is selected from SPC soybean phosphatidylcholine;

the glycerol comprises 3% to 10% (w/w) of the total composition;

the slow release carrier accounts for 50-70% (w/w) of the total composition;

the pharmaceutically active ingredient accounts for 3% to 15% (w/w) of the total composition;

the total amount of the pharmaceutically acceptable solvent accounts for 10-20% (w/w) of the total composition.

2. The pharmaceutical composition according to claim 1, wherein the mass ratio of the sustained-release carrier to the pharmaceutically acceptable solvent is 1.

3. The pharmaceutical composition according to claim 1, wherein the glycerol is present in an amount of 4% to 10% (w/w) of the total composition.

4. The pharmaceutical composition according to claim 1, wherein the glycerol is present in an amount of 5% to 8% (w/w) of the total composition.

5. The pharmaceutical composition of claim 1, wherein the sustained release carrier comprises 55% to 70% (w/w) of the total composition.

6. The pharmaceutical composition of claim 1, wherein the sustained release carrier comprises 55% to 66% (w/w) of the total composition.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutically active ingredient is 8% to 15% (w/w) of the total composition.

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutically active ingredient is 10% to 15% (w/w) of the total composition.

9. The pharmaceutical composition according to claim 1, wherein the total amount of solvent is 15% to 20% (w/w) of the total composition.

10. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable release modifier.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutically acceptable release modifier is selected from one or more of sterols, saturated phospholipids, and surfactants;

the sterol is cholesterol;

the saturated phospholipid is selected from hydrogenated soybean phospholipid, dilauroyl lecithin, dimyristoyl lecithin, distearoyl phosphatidylcholine or dipalmitoyl lecithin;

the surfactant is selected from polyoxyl 40 stearate, caprylic/capric macrogol glyceride, lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, vitamin E polyethylene glycol succinate, poloxamer, polysorbate, polyethylene glycol-12-hydroxystearate, propylene glycol monocaprylate, glyceryl dioleate or glyceryl monooleate.

12. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises one or more antioxidants.

13. The pharmaceutical composition of claim 12, wherein the antioxidant is selected from the group consisting of vitamin C, cysteine hydrochloride, vitamin E, ascorbyl palmitate, glutathione, alpha lipoic acid and thioglycerol.

14. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 13, comprising the steps of:

(a1) Mixing the slow release carrier and a pharmaceutically acceptable solvent, and stirring or shearing under a heating condition to obtain a clear and uniform mixed solution;

(a2) Adding at least one pharmaceutically active ingredient into the mixed solution, and stirring or shearing under heating condition to form a uniform mixture;

(a3) Adding glycerol into the mixed solution, and stirring or shearing under heating condition to form a uniform solution.

15. The method of claim 14, wherein the mixing of step (a 1) further comprises adding at least one pharmaceutically acceptable release modifier.

16. A sustained release formulation comprising the pharmaceutical composition of any one of claims 1-13, wherein the formulation is administered as a depot formulation.

17. The extended release formulation of claim 16, wherein the formulation is injectable or the formulation can be administered topically.

18. The sustained release formulation of claim 16, wherein the formulation is administered subcutaneously, peri-neurally, intramuscularly or by infusion.

19. The sustained release formulation of claim 18, wherein the perfusion administration is direct application to a wound, arterial perfusion, or rectal perfusion.

20. The sustained-release formulation according to claim 16, wherein the formulation is administered by external application to the skin or mucosal administration.

21. The sustained-release formulation according to claim 16, further comprising a packing material filled with the formulation, wherein the packing material is selected from one or more of the following: penicillin bottles, pre-filled syringes or snap-on bottles.

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