CN101467959A - Sustained release composition and method for preparing the same - Google Patents

Abstract

The present invention provides sustained release compositions and methods of making the same. The sustained release composition of the present invention comprises a polymer, a bioactive agent, and a release rate controlling agent, wherein the release rate controlling agent is dispersed in the sustained release composition to control the release of the bioactive agent. The method of preparing the sustained release composition of the present invention comprises providing an oil phase comprising a bioactive agent, a polymer, and a release rate controlling agent; providing an aqueous phase comprising a surfactant; the oil phase and the aqueous phase are mixed to form a sustained-release composition having a controlled-release effect.

Description

Sustained release composition and preparation method thereof

technical field

The present invention relates to a drug release system, and in particular to a sustained release composition without lag time and a method for its preparation.

Background technique

At present, drug delivery systems have been widely used in many places, for example, surgical transplantation, tissue regeneration or bandaging of affected areas. In general, drug delivery systems allow a drug or bioactive substance to treat a disease in a specific area. For example, the drug delivery system can directly provide antibiotics in a certain area to avoid infection at the site, or it can be combined with tissue regeneration engineering to provide necessary growth factors, etc.

Therefore, it is necessary to develop a safe and good drug delivery system. For example, biodegradable materials that can produce maximum drug activity with minimum side effects, have a stable release rate, and are non-toxic. Biodegradable materials have been widely used in drug delivery systems, and are mainly used in situations where continuous drug delivery is required. Usually, the drug is a compound, peptide or protein.

However, the general traditional drug release curve includes three periods, which are the initial release period, the lag period and the second release period, and the drug is released only in the initial release period and the second release period. Therefore, during the lag phase, patients must combine other oral or topical medications to enhance the therapeutic effect, but this additional medication will lead to increased treatment costs and inconvenience. In order to overcome the above shortcomings, the industry urgently needs a novel drug release system and its preparation method.

Contents of the invention

The present invention provides a sustained release composition without lag time, which comprises a polymer, a bioactive agent and a release rate controlling agent, wherein the bioactive agent and the release rate controlling agent are dispersed in the sustained release composition, and the release rate controlling agent The rate of release of the bioactive agent can be controlled.

The present invention also provides a method for preparing a sustained release composition, comprising providing an oil phase comprising a bioactive agent, a polymer, and a release rate controlling agent; providing an aqueous phase comprising a surfactant; mixing the oil phase and the aqueous phase to form a sustained release release composition; and recovering the sustained release composition.

The present invention further provides a composition for treating animals, which comprises an effective amount of the above-mentioned sustained release composition.

In order to make the above-mentioned and other purposes, features and advantages of the present invention more obvious and understandable, the preferred embodiments are specifically cited below, and in conjunction with the accompanying drawings, the detailed description is as follows:

Description of drawings

Figure 1 shows the drug release profile of the sustained release composition of the present invention.

Implementation

The present invention provides a sustained release composition comprising a polymer, a bioactive agent and a release rate controlling agent, wherein the bioactive agent and the release rate controlling agent are dispersed in the sustained release composition, and the release rate controlling agent can control the release rate of the bioactive agent release rate.

One or more bioactive agents are included in the sustained release compositions of the present invention. Bioactive agents include, but are not limited to, proteins, nucleic acids, carbohydrates, peptides, immunogens or hormones. Nucleic acids include, but are not limited to, DNAs, RNAs, chemically modified DNAs, chemically modified RNAs, aptamers, antisense oligonucleotides, interfering RNAs, and small interfering RNAs. Carbohydrates include, but are not limited to, heparin, small molecule heparins, and their analogs. Peptides include, but are not limited to, LHRH analogs and synthetic analogs, leuprolide, somatostatin analogs, hormones, octreotide, glucagon-like peptide, oxytocin, or analogs thereof. Proteins include, but are not limited to, antibodies, therapeutic proteins, human growth hormone (e.g., bone morphogenetic protein, TGF-β1, fibroblast growth factor, platelet growth factor, or insulin-like growth factor, etc.), octreotide, gonadotropins Release hormones, interferons, insulin, calcitonin, cytokines, or their analogs. Small molecule drugs include, but are not limited to, anti-infectives (eg, amphotericin B), cytostatics, antihypertensives, antifungals (eg, fluconazole, sporanox, ketoconazole), Antipsychotics (eg, clopine, olanzapine, rispritole, sertindole, aripiprazole, ziprasidone, or quetiapine), antidiabetic agents, immunostimulators (eg, , beta-1,3/1,6-glycans), immunosuppressants (eg, cyclosporine or prednisone), antibiotics (eg, penicillins, cephalosporins, vancomycin hydrochloride, or lincomycin) , antiviral drugs, antispasmodics, antihistamines, cardiovascular drugs, anticoagulants, antimalarials, analgesics, anesthetics, antineoplastic agents, antiulcer agents, anticancer agents, bronchodilators, vasodilators agents, central nervous system agents, steroids, nonsteroidal anti-inflammatory drugs, and antiemetics. Hormones include, but are not limited to, growth factors, melatonin, serotonin, thyroxine, triiodothyronine, epinephrine, norepinephrine, dopamine, adipohormones, angiotensin, cholecystokinin, erythropoietin , gastrin, glucagon, insulin, secretin, thrombopoietin or aldosterone, etc.

The polymers of the present invention are biodegradable polymers, for example, phospholipids, lecithin, glycolate, polylactic acid, polyglycolic acid, polylactic-glycolic acid (PLGA), polyglutamic acid, polycaprolactone Alcohol (PCL), polyamino acid, polydioxanone, polyhydroxybutyrate, polyphospholipid, polyester polyurethane, polycarboxyphenoxypropane-sebacic acid, polyorthoester, polycarbonate resin, Polyesteramides, polyanhydrides, polyacetals, polycyanoacrylates, polyetheresters, poly(alkylenealkyl), or combinations thereof. The biodegradable polymer of the present invention can be decomposed in a living body without causing harm to the living body.

A "release rate controlling agent" of the present invention refers to a surfactant, which controls the release of a bioactive agent.

 80)、山梨糖醇酐三油酸酯(例如，Span

 85)、油酸、PEG-PCL二嵌段共聚物、甘油三辛酸酯、泊洛沙姆(例如，Pluronic

(F68))、聚山梨酯80(例如，Tween

80)或维生素E-TPGS。Release rate controlling agents of the present invention include, but are not limited to, sorbitan monooleate (e.g., Span

80), sorbitan trioleate (for example, Span

85), oleic acid, PEG-PCL diblock copolymer, tricaprylycerin, poloxamers (e.g., Pluronic

(F68)), polysorbate 80 (for example, Tween

80) or Vitamin E-TPGS.

TPGS (D-α-tocopheryl polyethylene glycol succinate) is a commercial product, also known as "vitamin E-TPGS". Vitamin E-TPGS is a water-soluble vitamin E derivative, similar to amphiphilic molecules. In the present invention, vitamin E-TPGS includes various chemical derivatives of vitamin E-TPGS, such as ester or ether linkages of various chemical groups. In the present invention, the release rate control agent is dispersed in the sustained-release composition to control the release of the bioactive agent, so that the release curve of the sustained-release composition of the present invention has no lag time (lag phase), and the bioactive agent can be continuously released. dose to avoid additional oral administration. In the present invention, the release rate controlling agent accounts for 1-50%, preferably 4-15%, of the whole weight of the sustained release composition.

In one embodiment, the sustained release composition of the present invention can be microspheres, microsomes or microcapsules. Microcapsules consist of a central part and an outer membrane part. The microspheres, microsomes or microcapsules of the present invention can be used interchangeably. In another embodiment, the sustained release composition of the present invention has a drug coverage rate of 69% or more, preferably 69% to 99.9%, and a diameter of 5 μm or more, preferably 5 μm-200 μm, most preferably 30 μm-100 μm, And it can continuously release the drug (bioactive agent) in the living body without lag time.

The sustained release compositions of the present invention may be administered topically or systemically. For example, sustained release compositions may be administered by intramuscular, intraperitoneal, intravenous or subcutaneous injection. In addition, the sustained-release composition can also be prepared in any dosage form, such as paint, ointment, cream, gel, drop, suspension, spray, water or powder, and can be used in combination with traditional pharmaceutical carriers .

The present invention further provides a method of preparing a sustained release composition, the method comprising providing an oil phase comprising a bioactive agent, a polymer, and a release rate controlling agent; providing an aqueous phase comprising a surfactant; mixing the oil phase and the water phase to form a sustained release composition, wherein the bioactive agent may constitute 0.1-10% by weight of the oily phase, preferably 2% by weight.

The "oil phase" in the present invention refers to a solution comprising solvent, polymer, bioactive agent and release rate controlling agent, which can be emulsified with the aqueous phase to produce the sustained release composition of the present invention. Solvents in the oil phase include, but are not limited to, dichloromethane, ethyl acetate, benzyl alcohol, acetone, acetic acid, propylene carbonate, chloroform, 1,4-dioxane, dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), toluene or tetrahydrofuran (THF).

(F68))、聚山梨酯80或维生素E-TPGS。在本发明中，释放速率控制剂占油相中生物活性剂、聚合物和释放速率控制剂总重量的1-50％重量，优选为4-15％重量。As mentioned above, release rate controlling agents of the present invention include, but are not limited to, sorbitan monooleate, sorbitan trioleate, oleic acid, PEG-PCL diblock copolymer, tricaprylycerin esters, poloxamers (Pluronic

(F68)), polysorbate 80 or vitamin E-TPGS. In the present invention, the release rate control agent accounts for 1-50% by weight, preferably 4-15% by weight, of the total weight of the bioactive agent, polymer and release rate control agent in the oil phase.

The "water phase" in the present invention refers to a solution of water and surfactant, which can be reacted with the oil phase to produce a sustained release composition through emulsification.

Surfactants of the present invention include, but are not limited to, polyvinyl alcohol (PVA), NP-5, polyethylene glycol octylphenyl ether (Triton x-100), polysorbate 80, PEG 200-800 (polyethylene glycol Glycol 200-300), sodium dodecyl sulfate (SDS), alcohol ethoxylates, alkylphenol hydroxyethyl salts, secondary alcohol ethoxylates, fatty acid esters or alkyl polyglycosides. The surfactant of the present invention accounts for 0.1%-10% by weight of the aqueous phase, for example, it may be 0.1%-5% by weight.

In one embodiment, the oil phase is mixed with the water phase to form an emulsion, and the emulsion compound comprises droplets of the oil phase dispersed in the water phase, and then the solvent is removed from the emulsion to form microsomes. Methods for solvent removal include vacuum, filtration, or extraction into the extract. For example, the extract can be water. Microsomes can be recovered from the aqueous phase and dried.

Emulsions can be produced by stirring the oil phase and the water phase. In one embodiment, an agitator, such as a static agitator, can be used to create the emulsion. In another embodiment, vigorous agitation may be used to create the emulsion.

The emulsion preparation procedure can be carried out at any temperature between the boiling point and the freezing point. In one embodiment, the temperature may be between 0°C and 100°C, or between about 5°C and 75°C, or between about 15°C and 60°C.

In addition, a cosolvent can also be additionally added to the oil phase, and the cosolvent can promote the dissolution of the bioactive agent in the oil phase. In one embodiment, co-solvents include, but are not limited to, dimethylsulfoxide, dimethylformamide, n-methylpyrrolidone, PEG 200, PEG 400, methanol, ethanol, isopropanol, and benzyl alcohol. The co-solvent may comprise from 0 to 90% by weight of the oil phase solvent, or from 0 to 50% by weight of the oil phase solvent. The bioactive agent can be first dissolved in an appropriate volume of co-solvent, which is then added to the solvent of the oil phase and re-dissolved in the biodegradable polymer to form the oil phase. It should be noted that those skilled in the art can arbitrarily adjust the amount and order of addition to obtain an ideal oil phase solution. In one embodiment, the bioactive agent may comprise from 0.1 to 10% by weight of the oil phase. In another embodiment, the biodegradable polymer may comprise 0.1 to 20% by weight of the oil phase, eg, 1 to 10% by weight.

The present invention further provides a composition for treating an animal comprising an effective amount of the sustained release composition of the present invention. Since the sustained-release composition of the present invention releases the bioactive agent continuously, it is not necessary to combine other oral and topical administrations to promote the therapeutic effect.

The sustained release composition of the present invention can be dispersed in any solution or diluent for injection into human or animal body. The diluent can be selected from a viscosity promoter, and the viscosity promoter can be sodium carboxymethylcellulose, sucrose, mannitol, glucose, sucrose and other bioacceptable viscosity promoters.

"Animal" in the present invention refers to any mammal. Mammals of the present invention include human or non-human animals such as dogs, cats, mice, rats, cows, sheep, pigs, goats or primates as well as laboratory animals or livestock. In one embodiment, the animal can be a human. In another embodiment, the animal may be a rodent, eg, a mouse or a rat.

Example

Example 1. 50/50 PLGA Containing 0, 7, 26 and 42% Vitamin-E TPGS

Mix 80 mg of olanzapine, 200 mg of PLGA (LA/GA (lactic acid/glycolic acid) ratio = 50/50, M.W. = 43000) and different amounts of vitamin E-TPGS (accounting for olanzapine, PLGA and vitamin 0, 7, 26, 42% by weight of the total weight of E-TPGS) were dissolved together in 5 mL of dichloromethane to form an oil phase. The oil phase was added dropwise into 1000 mL of ice-water phase, the water phase contained 0.1% polyvinyl alcohol (PVA); and emulsified at 1000 rpm. The obtained oil/water (o/w) emulsion was continuously stirred at room temperature for 3 hours, the microspheres were collected by centrifugation, washed with F68 and water, and freeze-dried. The particle size and drug coating rate of the microspheres were analyzed by Multisizer and high performance liquid chromatography (HPLC), respectively. The results showed that the particle diameters of microspheres containing 0, 7, 26 and 42% (weight/weight) vitamin E-TPGS were 68.4±28.3, 71.6±27.3, 91.0±35.8, 101.9±42.8μm, and their drug-coated The rates are 77.7, 83.5, 85.9, 85.2% respectively.

Example 2. 85/15 PLGA Microspheres Containing 0, 4, 15 and 26% Vitamin E-TPGS

320mg of olanzapine, 800mg of PLGA (LA/GA ratio=85/15, M.W.=53000) and different amounts of vitamin E-TPGS (accounting for 0, 4, 15, 26% by weight) were dissolved together in 15 mL of dichloromethane to form an oil phase. The oil phase was added dropwise into 2000 mL of ice-water phase, wherein the water phase contained 0.1% polyvinyl alcohol (PVA), and emulsified at 1000 rpm. The stirring, collection and analysis methods of this embodiment are the same as those of Example 1. The results showed that the particle diameters of microspheres containing 0, 4, 15 and 26% (weight/weight) vitamin E-TPGS were 40.0 ± 21.3, 58.8 ± 28.4, 47.4 ± 21.4 and 62.9 ± 25.9 μm, and the drug coating rate They are 77.2, 74.7, 87.6 and 83.7% respectively.

Example 3. 50/50 PLGA Microspheres Containing Different Aqueous Phases

80mg of olanzapine, 200mg of PLGA (LA/GA ratio=50/50, M.W.=43000) and 42% (w/w) vitamin E-TPGS (to account for olanzapine, PLGA and vitamin E-TPGS total % by weight) were dissolved together in 5 mL of dichloromethane to form an oil phase. The oil phase was added dropwise to 1000 mL of ice-water phase, and emulsified at 1000 rpm; wherein the ice-water phase contained 0.05% PVA or 0.05% PVA containing 0.5% gelatin. The obtained oil/water emulsion was continuously stirred at room temperature for 3 hours, and the microspheres were collected by centrifugation, washed with F68 and water, and freeze-dried. The analysis methods of particle size and drug coverage rate in this embodiment are the same as above. The results showed that the particle diameters of microspheres without gelatin and 0.5% gelatin were 108.7±37.3 and 85.5±31.4 μm, respectively, and their drug coating ratios were 74.1 and 73.1%, respectively.

Example 4. 85/15 PLGA Microspheres Containing Different Oil Phases

320 mg of olanzapine, 800 mg of PLGA (LA/GA ratio=85/15, M.W.=53000) and 15 wt/wt % vitamin E-TPGS (accounted for total weight of olanzapine, PLGA and vitamin E-TPGS % by weight) were dissolved together in 15 mL of dichloromethane to form an oil phase. In this example, dichloromethane was pure dichloromethane (recipe #1), dichloromethane with ethanol (DCM:ethanol = 2:1, recipe #2), and dichloromethane with acetone (DCM :acetone=2:1, recipe #3). The oil phase was added dropwise to 2000 mL ice-water phase, wherein the water phase contained 0.1% PVA, and emulsified at 1000 rpm. The analysis methods of particle size and drug coverage rate in this embodiment are the same as above. The results showed that the particle sizes of the microspheres containing formulations #1, #2, and #3 were 76.2±31.4, 70.6±31.8, and 70.6±31.8 μm, respectively, and their drug coverage rates were 86.8, 89.7, and 88.5%, respectively.

Example 5. 85/15 PLGA Microspheres Containing Different LA/GA Ratio

The olanzapine of 320mg, the PLGA of 800mg and 15% (weight/weight) vitamin E-TPGS (accounting for the weight percentage of total weight of olanzapine, PLGA and vitamin E-TPGS) are dissolved together in the methylene chloride of 15mL An oil phase was formed in which PLGA had different ratios of LA/GA which were 85/15:50/50=3:1 (recipe #4), 85/15:50/50=1:3 (recipe #5) And 75/25:50/50 = 4:1 (Recipe #6). The above oil phase was added dropwise into 2000 mL of ice-water phase, wherein the water phase contained 0.1% PVA, and emulsified at 1000 rpm. The analysis methods of particle size and drug coverage rate in this embodiment are the same as above. The results showed that the particle diameters of the microspheres containing formulations #4, #5 and #6 were 62.2±32.0, 59.1±24.9 and 41.1±19.1 μm, respectively, and their drug coverage rates were 84.9, 84.2 and 83.2%, respectively.

Example 6.75/25 PLGA microspheres

320mg of olanzapine, 800mg of PLGA (LA/GA ratio=75/25) and 4% (weight/weight) of vitamin E-TPGS (accounting for the weight percentage of the total weight of olanzapine, PLGA and vitamin E-TPGS ) were dissolved together in 15 mL of dichloromethane to form an oil phase. In this example, the molecular weights of PLGA are 30000Da and 21000Da, respectively. The oil phase was added dropwise to 2000 mL of ice-water phase, wherein the water phase contained 0.1% PVA, and emulsified at 1000 rpm. The analysis methods of particle size and drug coverage rate in this embodiment are the same as above. The results showed that the particle diameters of the 30000Da and 21000Da PLGA microspheres were 43.5±18.8 and 37.4±20.2μm, respectively, and the drug coating rates were 80.8 and 77.6%, respectively.

Example 7.85/15 PLGA microspheres

320mg of olanzapine, 800mg of PLGA (LA/GA ratio=85/15) and 4% (weight/weight) of vitamin E-TPGS (accounting for the weight percentage of the total weight of olanzapine, PLGA and vitamin E-TPGS ) were dissolved together in 15 mL of dichloromethane to form an oil phase. In this example, the molecular weights of PLGA are 53000 and 27000 Da, respectively. The oil phase was added dropwise to 2000 mL of ice-water phase, wherein the water phase contained 0.1% PVA, and emulsified at 1000 rpm. The analysis methods of particle size and drug coverage rate in this embodiment are the same as above. The results showed that the particle diameters of microspheres with 53000 and 27000 Da were 58.8±28.4 and 43.9±20.6 μm, respectively, and their drug coating ratios were 74.7 and 77.0%, respectively.

Example 8. Formulations of different release rate controlling agents

 80、

 85、油酸、PEG-PCL二嵌段共聚物、甘油三辛酸酯(glyceryltricaprylate)、

及 80)一起溶于15mL的二氯甲烷以形成油相。将油相滴加至2000mL的冰水相，其中水相含有0.1％PVA，并于1000rpm下进行乳化。本实施例的粒径及药物包覆率的分析方法与上述相同。结果显示含

 80、

 85、油酸、PEG-PCL二嵌段共聚物、甘油三辛酸酯、

及

 80的微球体的粒径分别为46.7±18.6、40.3±15.5、46.3±22.6、55.7±27.3、49.5±22.0、68.1±30.9、30.1±14.9μm，且其药物包覆率分别为86.9、78.2、79.4、87.2、69.5、85.2及75.5％。320mg of olanzapine, 800mg of PLGA (LA/GA ratio=85/15, MW=53000) and different release rate controlling agents (

80、

85. Oleic acid, PEG-PCL diblock copolymer, glyceryltriccaprylate,

and 80) were dissolved together in 15 mL of dichloromethane to form an oil phase. The oil phase was added dropwise to 2000 mL of ice-water phase, wherein the water phase contained 0.1% PVA, and emulsified at 1000 rpm. The analysis methods of particle size and drug coverage rate in this embodiment are the same as above. The results showed that the

80、

85. Oleic acid, PEG-PCL diblock copolymer, glyceryl tricaprylate,

and

The particle diameters of 80 microspheres were 46.7±18.6, 40.3±15.5, 46.3±22.6, 55.7±27.3, 49.5±22.0, 68.1±30.9, 30.1±14.9μm, and their drug coating ratios were 86.9, 78.2, 79.4, 87.2, 69.5, 85.2 and 75.5%.

Example 9. Drug release in vivo

Evaluate and screen suitable Sprague-Dawley rats for subsequent experiments. Sprague-Dawley rats of 250 to 300 g were injected with a 20- or 21-gauge needle into the biceps femoris. The dose of injection varies according to the concentration of different formulations, but in principle, the dose of each injection should not exceed 1mL. Each rat was given 40 mg of olanzapine/kg body weight.

At each different time point, 0.1 mL blood samples were drawn from the tail vein into heparinized collection tubes. Blood samples were drawn once prior to the drug injection and several times over a 50-day period after the injection. The extraction time points were 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 1 day, 2 days, 4 days, 7 days, 10 days, 14 days, 17 days after injection , 21 days, 24 days, 28 days, 31 days, 35 days, 38 days, 42 days, 45 days and 50 days, and the plasma was further obtained, and the concentration of olanzapine in the plasma was analyzed by HPLC/MS-MS.

 80取代TPGS(PLGA/Tween

 80)作为实验组。参照附图1，含TPGS的微球体可在大鼠体内持续地释放奥氮平，且其药物释放曲线没有迟滞期(lag phase)。The microspheres of Example 2 containing 15% (w/w) vitamin E-TPGS were injected intramuscularly into rats. With microspheres without TPGS (only PLGA), or with Tween

80 replaces TPGS (PLGA/Tween

80) as the experimental group. Referring to Figure 1, microspheres containing TPGS can continuously release olanzapine in rats, and the drug release curve has no lag phase.

Although the present invention has disclosed the above content through preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the present invention The scope of protection required by the invention shall be subject to what is defined in the appended claims.

Claims (29)

1. A sustained release composition without lag time, comprising a polymer, a bioactive agent and a release rate controlling agent, wherein the bioactive agent and the release rate controlling agent are dispersed in the sustained release composition, and the release rate controls The agent controls the release rate of the bioactive agent. 2. The sustained release composition without lag time according to claim 1, wherein the bioactive agent is selected from the group consisting of proteins, nucleic acids, carbohydrates, peptides, immunogens, hormones or combinations thereof. 3. The sustained release composition without lag time according to claim 1, wherein the bioactive agent is selected from the group consisting of small molecule drugs, antineoplastic agents, antihistamine agents, antipsychotic agents, antiulcer agents, anticancer agents, Cardiovascular agents, bronchodilators, vasodilators, central nervous system agents, anesthetics, or combinations thereof. 4. The sustained release composition without lag time of claim 1, wherein the polymer is a biodegradable polymer. 5. The sustained release composition without lag time according to claim 1, wherein said polymer is selected from the group consisting of phospholipids, lecithin, glycolate, polylactic acid, polyglycolic acid, polylactic-glycolic acid (PLGA), Polyglutamic acid, polycaprolactone polyol (PCL), polyamino acid, polydioxanone, polyhydroxybutyrate, polyphospholipid, polyester polyurethane, polycarboxyphenoxypropane-sebacic acid, Polyorthoesters, polycarbonate resins, polyesteramides, polyanhydrides, polyacetals, polycyanoacrylates, polyetheresters, poly(alkylenealkyl)s, or combinations thereof. 6. The sustained release composition without lag time as claimed in claim 1, wherein the release rate controlling agent accounts for 1-50% by weight of the sustained release composition. 7. The sustained release composition without lag time as claimed in claim 1, wherein said release rate control agent is selected from the group consisting of sorbitan monooleate, sorbitan trioleate, oleic acid, PEG-PCL Diblock copolymer, tricaprylycerin, poloxamer (F68), polysorbate 80 or vitamin E-TPGS. 8. The sustained release composition without lag time of claim 1, wherein the sustained release composition releases the bioactive agent continuously. 9. The sustained-release composition without lag time according to claim 1, wherein the bioactive agent coating ratio of the sustained-release composition is 69% or more. 10. The sustained release composition without lag time of claim 1, wherein the sustained release composition is microspheres, microsomes or microcapsules. 11. The sustained release composition without lag time according to claim 1, wherein the sustained release composition has a diameter of 5 μm or more. 12. The sustained release composition without lag time according to claim 1, wherein the sustained release composition is for intramuscular injection or subcutaneous injection. 13. A method of preparing a sustained release composition, comprising: providing an oil phase comprising a bioactive agent, a polymer and a release rate controlling agent; providing an aqueous phase comprising a surfactant; mixing the oil phase and the aqueous phase to form a sustained release composition, and The sustained release composition is recovered. 14. The method for preparing a sustained release composition according to claim 13, wherein the oil phase further comprises a solvent. 15. The method for preparing a sustained release composition according to claim 14, wherein the solvent is selected from the group consisting of dichloromethane, ethyl acetate, benzyl alcohol, acetone, acetic acid, propylene carbonate, chloroform, 1,4-dioxane ring, dimethylformamide (DMF), dimethylsulfoxide (DMSO), toluene or tetrahydrofuran (THF). 16. The method for preparing a sustained release composition as claimed in claim 13, wherein the bioactive agent is selected from the group consisting of proteins, nucleic acids, carbohydrates, peptides, immunogens, hormones or combinations thereof. 17. The method for preparing a sustained release composition according to claim 13, wherein the bioactive agent is selected from the group consisting of small molecule drugs, antineoplastic agents, antihistamine agents, antipsychotic agents, antiulcer agents, anticancer agents, cardiac Vascular agents, bronchodilators, vasodilators, central nervous system agents, anesthetics, or combinations thereof. 18. The method for preparing a sustained release composition according to claim 13, wherein the polymer is a biodegradable polymer. 19. The method for preparing a sustained release composition according to claim 13, wherein the polymer is selected from the group consisting of phospholipids, lecithin, glycolate, polylactic acid, polyglycolic acid, polylactic-glycolic acid (PLGA), poly Glutamic acid, polycaprolactone polyol (PCL), polyamino acid, polydioxanone, polyhydroxybutyrate, polyphospholipid, polyester polyurethane, polycarboxyphenoxypropane-sebacic acid, poly Orthoesters, polycarbonate resins, polyesteramides, polyanhydrides, polyacetals, polycyanoacrylates, polyetheresters, poly(alkylenealkyl)s, or combinations thereof. 20. The method for preparing sustained release composition according to claim 13, wherein said surfactant is selected from polyvinyl alcohol (PVA), NP-5, polyethylene glycol octylphenyl ether (Triton x-100) , polysorbate 80, PEG 200-800, sodium dodecyl sulfate (SDS), alcohol ethoxylate, alkylphenol hydroxyethyl salt, secondary alcohol ethoxylate, fatty acid ester or alkyl poly glycosides. 21. The method for preparing sustained-release composition according to claim 13, wherein the release rate control agent is selected from the group consisting of sorbitan monooleate, sorbitan trioleate, oleic acid, PEG-PCL dioleate Block copolymer, tricaprylycerin, poloxamer (F68), polysorbate 80 or vitamin E-TPGS. 22. The method for preparing a sustained release composition as claimed in claim 13, wherein the release rate controlling agent accounts for 1-50% by weight of the total weight of the bioactive agent, the polymer and the release rate controlling agent in the oil phase. 23. The method for preparing a sustained release composition according to claim 13, wherein the sustained release composition is microspheres, microparticles or microcapsules. 24. A composition for treating an animal comprising an effective amount of the sustained release composition of claim 1. 25. The composition for treating an animal according to claim 24, wherein said animal is a mammal. 26. The composition for treating an animal according to claim 24, wherein said animal is a human. 27. Use of the sustained release composition of claim 1 for the manufacture of a pharmaceutical composition for the treatment of animals. 28. The use of claim 27, wherein the animal is a mammal. 29. The use of claim 27, wherein the animal is a human.

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