WO2014190832A1 - Ketorolac implant and method of preparing same - Google Patents

Abstract

The present invention provides a ketorolac implant and a method of preparing same. The implant comprises ketorolac and a degradable carrier, is prepared by adopting a hot melt extrusion method, can release drugs in a manner of zero-order kineics within a preset releasing time period, and can be used to prevent or treat acute and chronic ache and inflammation. The ketorolac implant prepared in the present invention has stable release, does not have a burst release effect, and has significant advantages in clinical use.

Description

 Ketorolac acid implant and preparation method thereof

Technical field

 The present invention belongs to the field of medical technology, and in particular, the present invention relates to a ketorolac implant having a zero-order kinetic release effect and a preparation method thereof. Background technique

 The chemical name of ketorolac is (soil) 5-benzoyl-2,3-dihydro-1H-pyrazine-carboxylic acid with a molecular weight of 225 g/mol. As a non-steroidal anti-inflammatory drug (NSAIDs), ketorolac is widely used in the treatment of rheumatic diseases, inflammatory diseases, pain, soft tissue diseases and sports injuries. Ketorolac has a potent analgesic effect. In the writhing reaction experiment induced by phenylhydrazine, the relative analgesic intensity of ketorolac is 350 times that of aspirin, which is caused by buckling in adjuvanted inflammatory paws in rats. In the pain test, the relative analgesic intensity of ketorolac was 800 times that of aspirin; 30 mg of ketorolac showed an analgesic effect better than morphine 6 mg, meperidine 50 and 100 mg, analgesic new 30 mg, and morphine 12 mg (Zeng Zhaoxian) , ketorolac, a non-steroidal anti-inflammatory drug with strong analgesic effect, West China Pharmaceutical Journal, 1 992, 7 (1) 53-56).

 However, ketorolac is prone to cause serious adverse reactions such as systemic allergies, gastrointestinal perforation, gastric bleeding, asthma, pulmonary edema, and renal failure. These serious side effects limit the dose and duration of ketorolac in pain management. The preparation of ketorolac as an implant can achieve topical administration and reduce systemic dosage, thereby reducing the side effects. At the same time, in order to minimize the amount of drug absorbed into the body, the implant should have zero-order kinetic release and there should be no sudden release. Especially for long-term sustained-release ketorolac implants with large drug loading, the burst effect may have serious adverse reactions.

 The ketorolac implant can relieve pain for a long time and thus greatly alleviate the suffering of the patient. By implanting the ketorolac implant composition into a specific area of the body, such as under surgical wounds, under the skin, joints, and limits, the desired concentration and effect of the target tissue can be maintained. The controlled sustained release drug maintains a stable concentration and sufficient duration in the target tissue, thereby avoiding the concentration fluctuations common to systemic administration.

However, it is very difficult to prepare an implant which is suitable for therapeutic purposes and has a long-term zero-order kinetic release. A method for preparing a ketoprofen implant disclosed in Chinese Patent No. ZL021 601 97.0, The prepared 5% ketoprofen implant was released at about 30% in 0.8 days; the prepared 10% ketoprofen implant was released on the 8th day about 30%; the prepared 15% ketoprofen implant On the second day, about 30% was released, and the burst effect of the implant was obvious, and zero-order release could not be achieved. Hu Lei et al. (Preparation and in vitro release characteristics of triamcinolone acetonide acetate implants, Journal of Third Military Medical University, 2009, 31 (8) 706-709) Preparation of polylactic acid columnar plants with a diameter of 0.8 mm and a length of about 8 mm In the case of the drug, the drug has a burst release phenomenon in the first 3 days, and the entire drug release process conforms to the Higuchi equation rather than the zero-order kinetic release. Wang Qin et al. (Influencing factors of in vitro release of anti-brain glioma sustained-release implants, Chinese Journal of Pharmaceutical Sciences, 201 2,47 (1 9) 1 561 -1 564) Preparation of hydrochloric acid with polylactic acid-glycolic acid Compared with star implants, the release on day 1 is about 10%, and the release process after 35 days is not zero-order release. The ketorolac implant disclosed in U.S. Patent No. 2009/026331, the entire disclosure of which is hereby incorporated herein by reference in its entirety in its in in in in in in in in in in in Significantly released. Chinese Patent No. 200780020639.4 discloses a method for reducing the burst effect of an implant by coating a polymer film on the surface of the implant, but this method is difficult to achieve in industrial production. Summary of the invention

 SUMMARY OF THE INVENTION An object of the present invention is to provide a ketorolac implant which has a large drug loading amount while achieving a zero-order kinetic release effect without causing a burst release phenomenon. Another object of the present invention is to provide a process for the preparation of such a ketorolac implant.

 Specifically, the present invention relates to a ketorolac implant comprising a pharmaceutically active ingredient and a degradable carrier, wherein the pharmaceutically active ingredient is ketorolac, ketorolac, ketorolac tromethamine And one of a ketorolac; the degradable carrier comprises a carboxyl-terminated polylactic acid and a carboxyl-terminated polylactic acid-glycolic acid.

 Specifically, the pharmaceutically active ingredient is ketorolac tromethamine.

 Specifically, the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 30% to 50%.

 Specifically, the present invention relates to a ketorolac drug implant wherein the weight percentage of the carboxyl-terminated polylactic acid in the pharmaceutical composition is 0-50%, and the weight of the carboxyl-terminated polylactic-glycolic acid in the pharmaceutical composition The percentage is from 10% to 65%. The molecular weight of polylactic acid is 1 0000-1 20000; the molecular weight of polylactic acid-glycolic acid is 4000-1 1 5000.

 Specifically, the present invention relates to a ketorolac drug implant, wherein the weight percentage of lactic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 50%-75%, and the carboxyl-terminated polylactic acid-glycolic acid polymer is ethanol. The weight percentage of the acid is 25%-50%.

 Specifically, the ketorolac drug implant of the present invention may further comprise a release rate modifier, and the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate. , one or more of mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, chondroitin, gelatin.

 Specifically, the release rate modifier is from 0% to 10% by weight of the pharmaceutical composition.

 The invention relates to a zero-order release ketorolac implant, the pharmaceutical composition comprising a pharmaceutically active ingredient and a degradable carrier, wherein the pharmaceutically active ingredient is ketorolac, ketorolac, ketorolac tromethamine One of an alcohol and a ketorolac; the degradable carrier comprises a carboxyl terminated polylactic acid and a carboxyl terminated polylactic acid-glycolic acid.

 Specifically, the pharmaceutically active ingredient is ketorolac tromethamine.

 Specifically, the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 30% to 40%.

 Specifically, the weight percentage of the carboxyl-terminated polylactic acid in the pharmaceutical composition is 25% to 30%, and the weight percentage of the carboxyl-terminated polylactic acid-glycolic acid in the pharmaceutical composition is 30% to 35%. The molecular weight of polylactic acid is 1 0000-1 8000; the molecular weight of polylactic acid-glycolic acid is 7000-1 7000.

 Specifically, the weight percentage of lactic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 50%, and the weight percentage of glycolic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 50%.

 Specifically, the pharmaceutical composition further comprises a release rate modifier, wherein the release rate modifier is present in the pharmaceutical composition in an amount of from 0% to 10% by weight.

 Preferably, the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt One or more of sodium salt, hyaluronic acid, collagen, chondroitin, and gelatin.

 Preferably, the release rate modifier is preferably PEG 4000 and the weight percentage in the pharmaceutical composition is 10%.

The invention relates to a 14-day zero-order release ketorolac implant, the pharmaceutical composition comprising a pharmaceutically active ingredient and a degradable carrier, wherein the pharmaceutically active ingredient is ketorolac, ketorolac, ketorolac Triol, One of the ketorolacs; the degradable carrier comprises a carboxyl terminated polylactic acid and a carboxyl terminated polylactic acid-glycolic acid.

 Specifically, the pharmaceutically active ingredient is ketorolac tromethamine.

 Specifically, the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 35% to 45%.

 Specifically, the weight percentage of the carboxyl-terminated polylactic acid in the pharmaceutical composition is from 0% to 10%, and the weight percentage of the carboxyl-terminated polylactic acid-glycolic acid in the pharmaceutical composition is from 37% to 5%. The molecular weight of polylactic acid is 1 0000-1 8000; the molecular weight of polylactic acid-glycolic acid is 4000-1 5000.

 Specifically, the weight percentage of lactic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 75%, and the weight percentage of glycolic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 25%.

 Specifically, the pharmaceutical composition further comprises a release rate modifier wherein the release rate modifier is from 0% to 10% by weight of the pharmaceutical composition.

 Preferably, the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt One or more of sodium salt, hyaluronic acid, collagen, chondroitin, and gelatin.

 Preferably, the release rate modifier is sodium lauryl sulfate in an amount of 8% by weight of the pharmaceutical composition.

 The invention relates to a 60-day zero-order release ketorolac implant, the pharmaceutical composition comprising a pharmaceutically active ingredient and a degradable carrier, wherein the pharmaceutically active ingredient is ketorolac, ketorolac, ketorolac One of a triol, a ketorolac; a degradable carrier comprising a carboxyl terminated polylactic acid and a carboxyl terminated polylactic acid-glycolic acid.

 Specifically, the pharmaceutically active ingredient is ketorolac tromethamine.

 Specifically, the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 35% to 40%.

 Specifically, the weight percentage of the carboxy-terminated polylactic acid in the pharmaceutical composition is 40% to 50%, and the weight percentage of the carboxy-terminated polylactic acid-glycolic acid in the pharmaceutical composition is 10% to 5%. The molecular weight of polylactic acid is 1 0000-1 8000; the molecular weight of polylactic acid-glycolic acid is 27000-43000.

 Specifically, the weight percentage of lactic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 50%, and the weight percentage of glycolic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 50%.

 Specifically, the pharmaceutical composition further comprises a release rate modifier wherein the release rate modifier is from 0% to 10% by weight of the pharmaceutical composition.

 Preferably, the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt One or more of sodium salt, hyaluronic acid, collagen, chondroitin, and gelatin.

 Preferably, the release rate modifier is preferably PEG 4000 and the weight percentage in the pharmaceutical composition is 10%.

 The present invention relates to a 1-20 day zero-order release ketorolac implant, the pharmaceutical composition comprising a pharmaceutically active ingredient and a degradable carrier, wherein the pharmaceutically active ingredient is ketorolac, ketorolac, ketorolac One of butyl triol and ketorolac; the degradable carrier comprises a carboxyl terminated polylactic acid and a carboxyl terminated polylactic acid-glycolic acid.

 Specifically, the pharmaceutically active ingredient is ketorolac tromethamine.

 Specifically, the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 40% to 45%.

Specifically, the weight percentage of the carboxyl-terminated polylactic acid in the pharmaceutical composition is 40% to 45%, carboxy The weight percentage of the base-terminated polylactic acid-glycolic acid in the pharmaceutical composition is from 13% to 15%. The molecular weight of polylactic acid is 75000-1 20000; the molecular weight of polylactic acid-glycolic acid is 75000-1 1 5000.

 Specifically, the weight percentage of lactic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 75%, and the weight percentage of glycolic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 25%.

 Specifically, the pharmaceutical composition further comprises a release rate modifier wherein the release rate modifier is from 0% to 10% by weight of the pharmaceutical composition.

 Preferably, the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt One or more of sodium salt, hyaluronic acid, collagen, chondroitin, and gelatin.

 Preferably, the release rate modifier is preferably PEG6000 and is 2% by weight of the pharmaceutical composition.

 The ketorolac implants of the present invention are useful for the treatment of acute pain, chronic pain, local non-infectious inflammation, and local tissue damage.

 Studies of the present invention have shown that the difference in the blocking groups of the degradable carrier also has an effect on the release behavior of the drug. The effect of ketorolac on the release of ester-based RESOMER® R 203 S (molecular weight 1 8000-28000) and carboxyl-terminated RESOMER® R 203 H (molecular weight 1 8000-28000) (π=4), the results are as follows As shown in Figure 1, it is shown that the ester-terminated polymer helps to delay the release of ketorolac molecules in the initial stage, but at a later release rate; the ketorolac in the implant composition prepared by the carboxyl-terminated polymer. The molecule is released at a constant rate throughout the drug release interval.

 The drug loading of ketorolac has a relatively large effect on the release behavior of the obtained product. Generally, the smaller the drug loading amount, the less likely to cause the sudden release phenomenon, and the burst release effect is obvious after the drug loading is increased. Generally, the ketone chromium The drug loading of more than 30% of acid is very likely to cause sudden release of the drug. The invention overcomes the problem that the bursting effect of the large drug loading is obvious. By using RESOMER RG 755S as the degradable carrier, the ratio of different ketorolacs is investigated (η=4), and the results are shown in Table 1 below:

 Conclusion: The data in Table 1 shows that the preferred ketorolac loading is 30%-50%.

 The invention also relates to a method of preparing a ketorolac implant, the specific steps are as follows:

 (1) thoroughly mixing a prescribed amount of the pharmaceutically active ingredient, the degradable carrier, and the release rate modifier;

(2) The mixture obtained in the step 1) is fed to a hot melt extruder, and the extrusion temperature is set to 00 ° C to 85 ° C. Cutting the extruded material into a desired shape;

 (3) The product obtained in step 2) is sterilized and packaged to obtain the final product.

The sterilization process can be carried out by methods currently used in medical products, including but not limited to gamma ray irradiation (Gamma), plasma sterilization, high frequency irradiation sterilization, electron beam irradiation sterilization (E-beam). , Oxygen ethane steam sterilization (E†〇), ultraviolet light irradiation, heat sterilization, and the like. The ketorolac implant has a rod shape, but can be formed into other shapes such as a cylinder, a disk, a sphere, a microsphere, a pellet, or the like according to clinical needs.

 The ketorolac implant can be implanted into the site of administration, such as the lesion area or adjacent tissue, by a dedicated drug delivery device or surgery. The implant releases the drug at the implantation site at the zero-order time according to the predetermined time. The local drug concentration is high, the action intensity is high, and the curative effect is good, and the drugs entering the systemic system are few, and the drug-related adverse reactions are greatly reduced. The implant is suitable for treating diseases requiring local treatment with ketorolac, such as acute pain, chronic pain, local non-infectious inflammation.

 The ketorolac implant developed by the invention achieves the zero-order kinetic release effect under the condition of large drug loading, and effectively controls the occurrence of drug burst release. The ketorolac implant can control and sustain release of ketorolac over a period of 2 days to 4 months. The ketorolac release is stable, complete and controllable, making it ideal for clinical applications. At the same time, the formulations provided by the present invention are stable under different pH and temperature environments. DRAWINGS

 Figure 1: Effect of different end-capped degradable carriers on drug release

 Figure 2: In vitro release profile of ketorolac implant B shown in Example 3

 Figure 3: In vitro release profile of ketorolac implant H shown in Example 4

 Figure 4: In vitro release profile of the ketorolac implant P shown in Example 8.

 Figure 5: In vitro release profile of the ketorolac implant enthalpy shown in Example 13

 The following examples are presented to illustrate preferred embodiments of the invention. From the following examples, the skilled person of the present invention should be able to understand and understand the technical functions of the present invention and the practice of the invention, which may be considered as a preferred mode of carrying out the invention. However, it will be apparent to those skilled in the art that many variations and modifications can be made in the present disclosure, and such or similar results can still be obtained, and such changes and modifications are still within the scope of the invention. The ketochromate tromethamine involved in the invention is purchased from Jinan Weidu Pharmaceutical Chemical Co., Ltd. Example 1 : Ketorolac acid implant (released for 2 days)

 1) Preparation of ketorolac implant (released for 2 days)

 In terms of weight percent, 30% ketorolac tromethamine and 20% poly D, L-lactic acid (carboxy terminated, molecular weight 18 kDa to 28 kDa) and 40% poly D, L-lactic acid-CO - Glycolic acid (carboxy-terminated, lactic acid to glycolic acid 50:50, molecular weight range 7kDa to 17kDa) and 10% polyethylene glycol

 (PEG4000) After mixing, place the Turbula 3D Mixer (T2F, WAB Machinery) and 4 stainless steel balls to shake twice, each time for 15 minutes. The mixture was then placed in a HAAKE micro twin-screw extruder (MiniLab, Thermo Scientific) with an extruder temperature set at 66 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of test specimens with a length of 2 mm using a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Sample 4 ml every 4 hours for drug concentration analysis and add new buffer for the next release test.

Determination of ketorolac content in buffer using reversed-phase high performance liquid chromatography (HPLC), sample use 〇DS column (Waters Xterra, C18, 5μΓΠ, 4.6X150mm) with methanol/water/acetic acid (58/41/1, V/V/V) as mobile phase and UV detector at 247nm.

 The results showed that the ketorolac implant was released within 2 days. During the period, the cumulative release is basically linear, the release is zero-order kinetics, there is no burst release, and the ketorolac release is almost constant. Example 2: Ketorolac acid implant (released for 5 days)

 1) Preparation of ketorolac implant (released for 5 days)

 50% ketorolac tromethamine and 30% poly D, L-lactic acid (carboxy terminated, molecular weight 18kDa to 28kDa) and 20% poly D, L-lactic acid-CO-ethanol The acid (carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 7kDa to 17kDa) was mixed and placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, each time 15 minute. The mixture was then placed in a HAAKE micro twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 78 ° C and a speed of 25 rpm. The extruded small rod has a diameter of 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Sample 4 ml every 12 hours for drug concentration analysis and add new buffer for the next release test.

 The test method was as described in Example 1. The results showed that the ketorolac implant was completely released within 5 days. During the period, the cumulative release is basically linear, the release amount is zero-order kinetics, there is no burst release, and the release amount of ketorolac is basically constant. Example 3: Ketorolac acid implant (released for 11 days)

 1) Preparation of ketorolac implants (release days)

 Five groups of ketorolac implants with 11-day release were prepared with different levels of ketorolac tromethamine and rate modifier, and different molecular weight, different content of carboxyl-terminated PLA and carboxyl-terminated PLGA. 2 shows:

 Table 2: Release 11-day ketorolac implant

植入剂 B的制备方法如下：

The preparation method of the implant B is as follows:

40% ketorolac tromethamine and 25% poly D, L-lactic acid (carboxy terminated, molecular weight 10kDa to 18kDa) and 35% poly D, L-lactic acid-CO-ethanol by weight percent The acid (carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 7kDa to 17kDa) was mixed and placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, each time. 15 minutes. The mixture was then placed in a HAAKE micro twin screw extruder (MiniLab type, Thermo Scientific), the extruder temperature was set at 82 ° C, and the speed was set at 25 revolutions per minute. The extruded small rod has a diameter of 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 The preparation method of the implant C is as follows:

 30% ketorolac tromethamine and 30% poly D, L-lactic acid (carboxy-terminated, molecular weight l OkDa to 18 kDa) and 30% poly D, L-lactic acid-CO - Glycolic acid (carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 7kDa to 17kDa) and 10% polyethylene glycol (PEG4000) mixed, placed in Turbula three-dimensional mixer (T2F type, WAB The mechanical company) and the four stainless steel balls oscillate twice, each time for 15 minutes. The mixture was then placed in a HAAKE micro-double screw extruder (MiniLab, Thermo Scientific) with the extruder set at 68 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 The ketorolac implant A, the implant D, and the implant E were prepared in the same manner as the implant B.

2) In vitro release test:

 Place the test samples (n=4) of implants A, B, C, D, E in an 8 ml glass tube and add 4 ml of phosphate buffer (pH 7.2 Sigma) to a 37 ° C water bath. , mild vibration

(50 rpm) A sample of 4 liters was taken every 24 hours for drug concentration analysis and a new buffer was added for the next release test.

 The detection method is as described in Example 1. The results are shown in Table 3 below. The in vitro release profile of implant B is shown in Figure 2.

Table 3: Percent release of different ketorolac implants for 24 h.

结论： 结果表明， 酮咯酸植入剂 A、 E突释现象明显， 不呈零级释放； 酮咯 酸植入剂 D释药过慢； 酮咯酸植入剂 B、 C优选处方， 当酮铬酸氨丁三醇重量 百分比含量为 30%-40% , 羧基封端的聚乳酸重量百分比为 25%-30% , 羧基封端 的聚乳酸 -乙醇酸在药物组合物中的重量百分比为 30%-35%时， 植入剂可在 天内酮咯酸释放完毕， 没有突释现象， 酮咯酸释放量基本恒定。植入剂 B为最优 选处方， 即酮铬酸氨丁三醇重量百分比含量为 40% , 羧基封端的聚乳酸重量百 分比为 25% ,羧基封端的聚乳酸 -乙醇酸在药物组合物中的重量百分比为 35%时, 酮铬酸累积释放基本成线性， 释放量呈零级动力学。 实施例 4 : 酮咯酸植入剂 （释药 14天）

Conclusion: The results show that the ketoprofen implants A and E have obvious burst release and do not exhibit zero-order release; the ketorolac implant D is too slow to release; the ketorolac implants B and C are preferred prescriptions. The ketochromate tromethamine weight percentage is 30%-40%, the carboxyl terminated polylactic acid weight percentage is 25%-30%, and the carboxyl terminated polylactic acid-glycolic acid is 30% by weight in the pharmaceutical composition. At -35%, the release of ketorolac is completed within the day of the implant, there is no burst release, and the amount of ketorolac released is substantially constant. Implant B is the most preferred formulation, ie 40% ketochrome tromethamine, 25% by weight of carboxyl-terminated polylactic acid, and weight of carboxyl-terminated polylactic-glycolic acid in the pharmaceutical composition At a percentage of 35%, the cumulative release of keto chromic acid is essentially linear and the release is zero-order kinetics. Example 4: Ketolactoic acid implant (released for 14 days)

 1) Preparation of ketorolac implant (released for 14 days)

Different levels of ketorolac tromethamine and rate modifiers, as well as different molecular weights and contents The carboxy-terminated PLA and carboxyl-terminated PLGA were used to prepare 5 groups of ketorolac implants for 14 days, as shown in Table 4 below:

 Table 4: Release 14-day ketorolac implants

 The preparation method of the implant H is as follows:

 Mixing 35% ketorolac tromethamine and 05% poly D, lactic acid-00-glycolic acid (carboxy-terminated, lactic acid to glycolic acid ratio 75:25, molecular weight range 4kDa to 15kDa) After that, put the Turbula 3D Mixer (T2F, WAB Machinery) and 4 stainless steel balls to oscillate twice, each time for 15 minutes. The mixture was then placed in a HAAKE mini twin-screw extruder (MiniLab type, Thermo Scientific) with an extruder temperature set at 78 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 The preparation method of the implant I is as follows:

 In terms of weight percent, 45% ketorolac tromethamine and 10% poly D, L-lactic acid (carboxy terminated, molecular weight l OkDa to 18 kDa) and 37% poly D, L-lactic acid - CO-glycolic acid (carboxy-terminated, lactic acid to glycolic acid ratio 75:25, molecular weight range 4kDa to 15kDa) and 8% sodium dodecyl sulfate are mixed into the Turbula three-dimensional mixer (T2F type, WAB Machinery Co., Ltd.) ) and 4 stainless steel balls oscillate twice, each time for 15 minutes. The mixture was then placed in a HAAKE micro twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 67 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 The implant F, the implant G, and the implant J are prepared in the same manner as the implant I.

2) In vitro release test:

 Place the test samples (n=4) of the implants F, G, H, I, J in an 8 ml glass tube, and add 4 ml of phosphate buffer (pH 7.2, Sigma) at 37 °C. In the water bath, mild vibration (50 rpm). A sample of 4 ml was taken every 24 hours for drug concentration analysis and a new buffer was added for the next release test.

The detection method is as described in Example 1. The specific results are shown in Table 5. The in vitro release profile of the implant H is shown in FIG. Table 5: 24 h release percentages for different ketochromic implants.

结论： 结果表明， 植入剂 F、 G、 」突释现象明显， 不呈零级释放曲线。 植 入剂 H、 I为优选处方， 当酮铬酸氨丁三醇重量百分比含量为 35%-45%, 羧基封 端的聚乳酸重量百分比为 0%-10%, 羧基封端的聚乳酸-乙醇酸在药物组合物中 的重量百分比为 37%-05%时，植入剂没有突释现象产生，在 14天内酮咯酸释放 完毕， 酮咯酸释放量基本恒定。 植入剂 Η 为最优选处方， 即酮铬酸氨丁三醇重 量百分比含量为 35%, 羧基封端的聚乳酸-乙醇酸在药物组合物中的重量百分比 为 65%时， 酮铬酸累积释放基本成线性， 释放量呈零级动力学。 实施例 5: 酮咯酸植入剂 （释药 20天）

Conclusion: The results show that the implant F, G, and "burst phenomenon" are obvious, and there is no zero-order release curve. Implants H, I are preferred formulations, when the ketochromate tromethamine weight percentage is 35%-45%, the carboxyl-terminated polylactic acid weight percentage is 0%-10%, carboxyl-terminated polylactic acid-glycolic acid When the weight percentage in the pharmaceutical composition was 37% to -05%, no sudden release of the implant occurred, and the release of ketorolac was completed within 14 days, and the amount of ketorolac released was substantially constant. The implant Η is the most preferred prescription, that is, the ketochromate tromethamine weight percentage is 35%, and the carboxy-terminated polylactic acid-glycolic acid is 65% by weight in the pharmaceutical composition, the keto chromic acid cumulative release Basically linear, the release is zero-order kinetics. Example 5: Ketorolac acid implant (released for 20 days)

 1) Preparation of ketorolac implant (released for 20 days)

 40% ketorolac tromethamine and 20% poly D, L-lactic acid (carboxy terminated, molecular weight 18kDa to 28kDa) and 40% poly D, L-lactic acid-CO-ethanol The acid (carboxy-terminated, lactic acid to glycolic acid ratio 75:25, molecular weight range 7kDa to 17kDa) was mixed and placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, each time 15 minute. The mixture was then placed in a HAAKE micro twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 78 ° C and a speed of 25 rpm. The extruded small rod has a diameter of 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Samples were taken once every day on the 1st and 2nd day, and then sampled every 2 days, 4 ml each time, for drug concentration analysis, and a new buffer was added for the next release test.

 The detection method is as described in Example 1. The results showed that the ketorolac implant was released within 20 days of the ketorolac implant. During this period, the cumulative release is essentially linear, the release is zero-order kinetics, and the ketorolac release is essentially constant. Example 6: Ketorolac acid implant (released for 30 days)

 1) Preparation of ketorolac implant (released for 30 days)

In terms of weight percent, 38% ketorolac tromethamine and 22% poly D, L-lactic acid (carboxy terminated, molecular weight 18kDa to 28kDa) and 40% poly D, L-lactic acid-CO-ethanol The acid (carboxy-terminated, lactic acid to glycolic acid ratio 75:25, molecular weight range 4kDa to 15kDa) was mixed and placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, each time 15 minute. The mixture is then placed in a HAAKE micro twin screw extruder (MiniLab type, Thermo Scientific), the extruder temperature is set at 80 ° C, and the speed is set at 25 rpm. The extruded small rod has a diameter of 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Samples were taken once every day on the first and third days, and then sampled once every three days, 4 ml each time, for drug concentration analysis, and a new buffer was added for the next release test.

 The detection method is as described in Example 1. The results showed that the ketorolac implant was released within 30 days of the ketorolac implant. During this period, the cumulative release is essentially linear, the release is zero-order kinetics, and the ketorolac release is essentially constant. Example 7: Ketorolac acid implant (released for 45 days)

 1) Preparation of ketorolac implant (released for 45 days)

 40% ketorolac tromethamine and 35% poly D, L-lactic acid (carboxy-terminated, molecular weight l OkDa to 18 kDa) and 25% poly-D, L-lactic acid-CO - Glycolic acid (carboxy-terminated, lactic acid to glycolic acid ratio 75:25, molecular weight range 7kDa to 17kDa), mixed, placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, 15 minutes each time. The mixture was then placed in a HAAKE mini twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 80 ° C and a speed of 25 rpm. The extruded small rod has a diameter of 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Samples were taken once every day on the first and third days, and then sampled once every three days, 4 ml each time, for drug concentration analysis, and a new buffer was added for the next release test.

 The detection method is as described in Example 1. The results showed that the ketorolac implant was released within 45 days of the ketorolac implant. During the period, the cumulative release is basically linear, the release amount is zero-order kinetics, there is no burst release, and the ketorolac release is almost constant. Example 8: Ketolacric acid implant (released for 60 days)

 1) Preparation of ketorolac implant (released for 60 days)

 Five groups of ketorolac implants with 60-day release were prepared with different levels of ketorolac tromethamine and rate modifier, and different molecular weight, different content of carboxyl-terminated PLA and carboxyl-terminated PLGA. ό shown: Table 6: 60-day release of ketorolac implants

植 入 剂 35% 40% 10-18k 15% 27-43k 50:50 10%PEG4000

Implant 35% 40% 10-18k 15% 27-43k 50:50 10% PEG4000

M

 Implant N 42% 55% 18-28k 0% 3% PEG6000 Implant P 40% 50% 10- 18k 10% 27-43k 50:50 0% Implant M is prepared as follows:

 In terms of weight percent, 35% ketorolac tromethamine and 40% poly D, L-lactic acid (carboxy terminated, molecular weight l OkDa to 18 kDa) and 1 5% poly D, L-lactic acid - CO-glycolic acid (carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 27kDa to 43kDa) and 10% polyethylene glycol (PEG4000) mixed, placed in Turbula three-dimensional mixer (T2F type, WAB machinery) The company) and four stainless steel balls oscillated twice, each time for 15 minutes. The mixture was then placed in a HAAKE micro-double screw extruder (MiniLab type, Thermo Scientific) with an extruder temperature set at 69 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 The preparation method of the implant P is as follows:

 In terms of weight percent, 40% ketorolac tromethamine and 50% poly D, L-lactic acid (carboxy terminated, molecular weight l OkDa to 18 kDa) and 10% poly D, L-lactic acid - CO-glycolic acid (carboxy-terminated, lactic acid to glycolic acid ratio of 50:50, molecular weight range of 27kDa to 43kDa), mixed, placed in Tu "bula three-dimensional mixer (T2F type, WAB Machinery) and four stainless steel balls concussion Twice, 15 minutes each time. The mixture was then placed in a HAAKE mini twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 80 ° C and a speed of 25 rpm. The small rod was 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 The preparation method of implant K, L, N is the same as implant M.

 2) In vitro release test:

 Place the test samples of implants K, L, M, N, P (n=4) in an 8 ml glass tube and add 4 ml of phosphate buffer (pH 7.2, Sigma) at 37 °C. In the water bath, mild vibration (50 rpm). Samples were taken once every day on the 1st and 3rd, and then sampled every 3 days, 4ml each time, for drug concentration analysis, and a new buffer was added for the next release test.

 The detection method is as described in Example 1. The specific results are shown in the table, and the in vitro release curve of the implant P is shown in Fig. 4.

 Table 7: Percent release of different ketorolac implants for 24 h.

结论： 结果表明， 植入剂 K、 L突释现象明显， 植入剂 Ν存在突释现象， 不 呈零级释放曲线。植入剂 Μ、 Ρ为优选处方， 当酮铬酸氨丁三醇重量百分比含量 为 35%-40% , 羧基封端的聚乳酸在药物组合物中的重量百分比为 40%-50% , 羧 基封端的聚乳酸 -乙醇酸在药物组合物中的重量百分比为 10%-15%时， 植入剂没 有突释现象产生， 在 60天内酮咯酸释放完毕， 酮咯酸释放量基本恒定。 植入剂 P为最优选处方， 即酮铬酸氨丁三醇重量百分比含量为 40%,羧基封端的聚乳酸 在药物组合物中的重量百分比为 50%, 羧基封端的聚乳酸-乙醇酸在药物组合物 中的重量百分比为 10%时， 酮铬酸累积释放基本成线性， 释放量呈零级动力学。 实施例 9: 酮咯酸植入剂 （释药 75天）

Conclusion: The results show that the K, L burst release phenomenon is obvious, the implant Ν has a burst release phenomenon, and does not exhibit a zero-order release curve. The implants Μ and Ρ are preferred formulations. When the ketochromate tromethamine is 35%-40% by weight, the carboxyl-terminated polylactic acid is 40%-50% by weight in the pharmaceutical composition. When the weight percentage of the base-terminated polylactic acid-glycolic acid in the pharmaceutical composition is 10% to 15%, no sudden release of the implant occurs, and the release of ketorolac is completed within 60 days, and the amount of ketorolac released is substantially constant. The implant P is the most preferred prescription, that is, the ketochromic acid tromethamine weight percentage is 40%, the carboxyl-terminated polylactic acid is 50% by weight in the pharmaceutical composition, and the carboxyl-terminated polylactic acid-glycolic acid is When the weight percentage in the pharmaceutical composition is 10%, the cumulative release of ketochromic acid is substantially linear, and the release amount is zero-order kinetics. Example 9: Ketorolac acid implant (released for 75 days)

 1) Preparation of ketorolac implant (released for 75 days)

 45% by weight percent, 45% ketorolac tromethamine and 35% poly D, L-lactic acid (carboxy terminated, molecular weight 18kDa to 28kDa) and 20% poly D, L-lactic acid-CO-ethanol The acid (carboxy-terminated, lactic acid to glycolic acid ratio of 50:50, molecular weight range of 24kDa to 38kDa) was mixed and placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, each time. 15 minutes. The mixture was then placed in a HAAKE mini twin-screw extruder (MiniLab type, Thermo Scientific) with the extruder set at 80 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Samples were taken once every 1st and 5th, and then sampled every 5 days, 4ml each time, for drug concentration analysis, and added with new buffer for the next release test.

 The detection method is as described in Example 1. The results showed that the ketorolac implant was released within 75 days of the ketorolac implant. During the period, the cumulative release is basically linear, the release amount is zero-order kinetics, there is no burst release, and the ketorolac release is almost constant. Example 10: Ketorolac acid implant (released for 80 days)

 1) Preparation of ketorolac implant (released for 80 days)

 40% ketorolac tromethamine and 38% poly D, L-lactic acid (carboxy terminated, molecular weight 18kDa to 28kDa) and 22% poly D, L-lactic acid-CO-ethanol The acid (carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 24kDa to 38kDa) was mixed and placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, each time 15 minute. The mixture was then placed in a HAAKE mini twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 80 ° C and a speed of 25 rpm. The extruded small rod has a diameter of 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Samples were taken once every 1st and 5th, and then sampled every 5 days, 4ml each time, for drug concentration analysis, and added with new buffer for the next release test.

The detection method is as described in Example 1. The results showed that the release of ketorolac was completed within 80 days of the ketorolac implant. During the period, the cumulative release is basically linear, the release is zero-order kinetics, no burst release, keto-acid release The dose was essentially constant Example 11: ketorolac implant (release 90 days)

 1) Preparation of ketorolac implants (released for 90 days)

 40% ketorolac tromethamine and 35% poly D, L-lactic acid (carboxy terminated, molecular weight 18kDa to 28kDa) and 20% poly D, L-lactic acid-CO-ethanol by weight percent Acid (carboxy-terminated, lactic acid to glycolic acid ratio 75:25, molecular weight range 27kDa to 43kDa) and 5% polyvinyl alcohol mixed, placed in Turbula three-dimensional mixer (T2F type, WAB Machinery) and four stainless steel balls concussion Twice, 15 minutes each time. The mixture was then placed in a HAAKE micro twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 70 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Samples were taken once every 1st and 5th, and then sampled every 5 days, 4ml each time, for drug concentration analysis, and added with new buffer for the next release test.

 The detection method is as described in Example 1. The results showed that the ketorolac implant was released within 90 days of the ketorolac implant. During the period, the cumulative release is basically linear, the release amount is zero-order kinetics, there is no burst release, and the ketorolac release is almost constant. Example 12: Ketorolac acid implant (released for 100 days)

 1) Preparation of ketorolac implant (released for 100 days)

 40% ketorolac tromethamine and 35% poly D, L-lactic acid (carboxy terminated, molecular weight 18kDa to 28kDa) and 25% poly D, L-lactic acid-CO-ethanol by weight percent The acid (carboxy-terminated, lactic acid to glycolic acid ratio 75:25, molecular weight range 75kDa to 115kDa) was mixed and placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, each time 15 minute. The mixture was then placed in a HAAKE mini twin-screw extruder (MiniLab type, Thermo Scientific) with the extruder set at 80 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Samples were taken once every 1st and 5th, and then sampled every 5 days, 4ml each time, for drug concentration analysis, and added with new buffer for the next release test.

The detection method is as described in Example 1. The results showed that the ketorolac implant was released within 100 days of the ketorolac implant. During the period, the cumulative release was basically linear, the release amount was zero-order kinetics, and there was no burst release, and the amount of ketorolac released was basically constant. Example 13: Ketorolac acid implant (release for 120 days) 1) Preparation of ketorolac implant (released for 120 days)

 Five groups of ketochromic acid implants with 120-day release were prepared by different levels of ketorolac tromethamine and rate modifier, and different molecular weight, different content of carboxyl-terminated PLA and carboxyl-terminated PLGA. 8 shows:

 Table 8: Release of the drug 120-day ketochromic acid implant

 The preparation method of the implant τ is as follows:

 40% ketorolac tromethamine and 45% poly D, L-lactic acid (carboxy terminated, molecular weight 75kDa to 120kDa) and 13% poly D, L-lactic acid-CO-ethanol The acid (carboxy-terminated, lactic acid to glycolic acid ratio of 75:25, molecular weight range of 75kDa to 115kDa) and 2% polyethylene glycol (PEG6000) were mixed and placed in Turbula three-dimensional mixer (T2F type, WAB Machinery) Splash twice with 4 stainless steel balls for 15 minutes each time. The mixture was then placed in a HAAKE micro twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 75 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 The preparation method of the implant 丫 is as follows:

 45% by weight percent, 45% ketorolac tromethamine and 40% poly D, L-lactic acid (carboxy terminated, molecular weight 75kDa to 120kDa) and 15% poly D, L-lactic acid-CO-ethanol The acid (carboxy-terminated, lactic acid to glycolic acid ratio of 75:25, molecular weight range of 75kDa to 115kDa) was mixed and placed in a Tu "bula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice. 15 minutes each time. The mixture was placed in a HAAKE micro twin-screw extruder (MiniLab, Thermo Scientific), the extruder temperature was set at 85 ° C, and the speed was set at 25 rpm. The rod diameter was 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 The preparation method of the implants W, X, Z is as the implant T. 2) In vitro release test:

 Place the test samples (n=4) of the implants T, W, X, 丫, Z in an 8 ml glass tube, and add 4 ml of phosphate buffer (pH 7.2, Sigma) at 37 °C. In the water bath, mild vibration (50 rpm). Samples were taken once every day on the 1st, 3rd, and 7th, and then sampled every 7 days, 4ml each time, for drug concentration analysis, and a new buffer was added for the next release test.

The detection method is as described in Example 1. The specific results are shown in Table 9, and the in vitro release profile of the implant 丫 is shown in FIG. Table 9: 72h percent release of different ketorolac implants.

结论： 结果表明， 植入剂 x、 z突释现象明显， 不呈零级释放曲线。 植入剂 W释药速率过慢， 植入剂 τ、 丫为优选处方， 当酮铬酸氨丁三醇重量百分比含量 为 40%-45%, 羧基封端的聚乳酸在药物组合物中的重量百分比为 40%-45%, 羧 基封端的聚乳酸 -乙醇酸在药物组合物中的重量百分比为 13%-15%时， 植入剂没 有突释现象产生， 在 120 天内酮咯酸释放完毕， 期间累积释放基本成线性， 释 放量呈零级动力学， 酮咯酸释放量基本恒定。植入剂丫为最优选处方， 即酮铬酸 氨丁三醇重量百分比含量为 45%, 羧基封端的聚乳酸在药物组合物中的重量百 分比为 40%,羧基封端的聚乳酸 -乙醇酸在药物组合物中的重量百分比为 15%时, 酮铬酸累积释放基本成线性， 释放量呈零级动力学。 实施例 14: 酮咯酸植入剂 （释药 11 天）

Conclusion: The results show that the x, z burst release of the implant is obvious and does not exhibit a zero-order release curve. The release rate of the implant W is too slow, and the implants τ and 丫 are preferred prescriptions. When the ketochromate tromethamine is 40%-45% by weight, the weight of the carboxyl-terminated polylactic acid in the pharmaceutical composition is The percentage is 40%-45%, and when the weight percentage of the carboxyl-terminated polylactic acid-glycolic acid is 13%-15% in the pharmaceutical composition, the implant has no burst release, and the ketorolac is released within 120 days. The cumulative release during the period was essentially linear, the release was zero-order kinetics, and the ketorolac release was essentially constant. The implant 丫 is the most preferred prescription, that is, the ketochromic acid tromethamine is 45% by weight, the carboxyl-terminated polylactic acid is 40% by weight in the pharmaceutical composition, and the carboxyl-terminated polylactic acid-glycolic acid is When the weight percentage in the pharmaceutical composition is 15%, the cumulative release of ketochromic acid is substantially linear, and the release amount is zero-order kinetics. Example 14: Ketorolac acid implant (released for 11 days)

 1) Preparation of ketorolac implants (release days)

In terms of weight percent, 35% of sodium ketorolac salt and 26% of poly D, L-lactic acid (carboxy terminated, molecular weight 10kDa to 18kDa) and 33°/ _Q poly D, L-lactic acid-CO- Glycolic acid (carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 7kDa to 17kDa) and 6% PEG4000 mixed, placed in Tu "bula three-dimensional mixer (T2F type, WAB Machinery) and four stainless steel balls The mixture was shaken twice for 15 minutes each time. The mixture was then placed in a HAAKE micro twin-screw extruder (MiniLab type, Thermo Scientific) with the extruder temperature set at 80 ° C and the speed set at 25 rpm. The extruded rod was 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Place each test sample (n=4) in an 8 ml glass tube, add 4 ml of phosphate buffer (pH 7.2, Sigma), and place it in a 37 ° C water bath with mild vibration (50 rpm) . Sample 4 ml every 24 hours for drug concentration analysis and add new buffer for the next release test.

 Experimental methods and procedures are as described in Example 1. The results showed that the ketorolac implant was released within 11 days of the ketorolac implant. During the period, the cumulative release is basically linear, there is no sudden release, the release is zero-order kinetics, and the ketorolac release is almost constant. Example 15: Ketorolac acid implant (released for 11 days)

 1) Preparation of ketorolac implants (release days)

In terms of weight percent, 38% ketorolacate and 28% poly D, L-lactic acid (carboxy terminated, molecular weight 10kDa to 18kDa) and 34°/ _Q poly D, L-lactic acid-CO-ethanol Acid (carboxy-terminated, Mixing lactic acid and glycolic acid 50:50, molecular weight range 7kDa to 17kDa) and 6% PEG4000, put into Tu "bula three-dimensional mixer (T2F type, WAB Machinery) and four stainless steel balls to oscillate twice, each time 15 Minutes. Then the mixture was placed in a HAAKE micro twin-screw extruder (MiniLab type, Thermo Scientific), the extruder temperature was set at 80 ° C, and the speed was set at 25 rpm. The extruded rod diameter was 0.5. Mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Experimental methods and procedures are as described in Example 3. The results showed that the ketorolac implant was released within 11 days of the ketorolac implant. During the period, the cumulative release is basically linear, there is no sudden release, the release is zero-order kinetics, and the ketorolac release is almost constant. Example 16: Ketolactin implant (released for 14 days)

 1) Preparation of ketorolac implant (released for 14 days)

 40% ketorolacate 50% poly D, L-lactic acid-CO-glycolic acid (carboxy-terminated, lactate to glycolic acid ratio 75:25, molecular weight range 4kDa to 15kDa) and 10% by weight After mixing sodium lauryl sulfate, put it into the Tu "bula three-dimensional mixer (T2F type, WAB Machinery Co., Ltd.) and four stainless steel balls to shake twice for 15 minutes each time. Then put the mixture into HAAKE micro twin screw extrusion. Machine (MiniLab type, Thermo Scientific), the extruder temperature is set at 67 ° C, the speed is set at 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant is cut into length with a blade. A small sample of 2 mm.

 2) In vitro release test:

 Experimental methods and procedures are as described in Example 4. The results showed that the ketorolac implant was released within 14 days of the ketorolac implant. During the period, the cumulative release is basically linear, there is no sudden release, the release is zero-order kinetics, and the ketorolac release is almost constant. Example 17: Ketorolac acid implant (released for 14 days)

 1) Preparation of ketorolac implant (released for 14 days)

 In terms of weight percent, 33% potassium ketoroate and 10% poly D, L-lactic acid (carboxy terminated, molecular weight 10 kDa to 18 kDa) and 57% poly D-lactic acid-CO-glycolic acid (carboxyl End-capping, lactic acid to glycolic acid ratio 75:25, molecular weight range 4kDa to 15kDa) After mixing, put into a Turbula three-dimensional mixer (T2F type, WAB Machinery) and four stainless steel balls to oscillate twice for 15 minutes each time. The mixture was then placed in a HAAKE micro twin screw extruder (MiniLab, Thermo Scientific) with the extruder temperature set at 67 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Experimental methods and procedures are as described in Example 4. The results showed that the ketorolac implant was released within 14 days of the ketorolac implant. During the period, the cumulative release is basically linear, there is no sudden release, the release is zero-order kinetics, and the ketorolac release is almost constant. Example 18: Ketorolac acid implant (released for 60 days)

1) Preparation of ketorolac implant (released for 60 days) 35% by weight of ketorolac sulphate and 45% poly D, L-lactic acid (carboxy terminated, molecular weight 10kDa to 18kDa) and 12% poly D, L-lactic acid-CO-ethanol Acid (carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 27kDa to 43kDa) and 8% polyethylene glycol

(PEG4000) After mixing, place the Turbula 3D Mixer (T2F, WAB Machinery) and 4 stainless steel balls twice for 15 minutes each time. The mixture was then placed in a HAAKE micro twin screw extruder (MiniLab, Thermo Scientific) with an extruder temperature set at 69 ° C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Experimental methods and procedures are as described in Example 8. The results showed that the ketorolac implant was released within 60 days of the ketorolac sodium salt. During the period, the cumulative release was basically linear, there was no sudden release, and the release amount was zero-order kinetics, and the amount of ketorolac released was basically constant. Example 19: Ketorolac acid implant (released for 60 days)

 1) Preparation of ketorolac implant (released for 60 days)

In terms of weight percent, 38% ketorolacate and 48% poly D, L-lactic acid (carboxy terminated, molecular weight 10kDa to 18kDa) and 14°/ _Q poly D, L-lactic acid-CO-ethanol The acid (carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 27kDa to 43kDa) was mixed and placed in a Turbula three-dimensional mixer (T2F, WAB Machinery) and four stainless steel balls oscillated twice, each time 15 minute. The mixture was then placed in a HAAKE micro twin screw extruder (MiniLab, Thermo Scientific) with the extruder temperature set at 69 ° C and a speed of 25 rpm. The extruded small rod has a diameter of 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Experimental methods and procedures are as described in Example 8. The results showed that the ketorolac implant was released within 60 days of the ketorolac implant. During the period, the cumulative release is basically linear, there is no sudden release, the release is zero-order kinetics, and the ketorolac release is almost constant. Example 20: Ketolactin implant (released for 120 days)

 1) Preparation of ketorolac implant (released for 120 days)

 In terms of weight percent, 41% potassium ketoroate and 43% poly D, L-lactic acid (carboxy terminated, molecular weight 75kDa to 120kDa) and 14% poly D, L-lactic acid-CO-glycolic acid (Carboxyl terminated, 75:25 lactic acid to glycolic acid, molecular weight range 75kDa to 115kDa) and 2% polyethylene glycol (PEG6000) were mixed and placed in a Turbula 3D mixer (T2F, WAB Machinery) and Four stainless steel balls oscillate twice, each time for 15 minutes. The mixture was then placed in a HAAKE mini twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 75 °C and a speed of 25 rpm. The extruded rod is 0.5 mm in diameter. The small rod implant was cut into small pieces of 2 mm in length with a knife.

 2) In vitro release test:

Experimental methods and procedures are as described in Example 13. The results showed that the ketorolac implant was released within 120 days of the ketorolac potassium salt. During the period, the cumulative release is basically linear, there is no sudden release, the release is zero-order kinetics, and the ketorolac release is almost constant. Example 21: ketorolac implant (release for 120 days)

 1) Preparation of ketorolac implant (released for 120 days)

 In terms of weight percent, 43% ketorolacate and 44% poly D, L-lactic acid (carboxy terminated, molecular weight 75kDa to 120kDa) and 13% poly D, L-lactic acid-CO-glycolic acid ( Carboxyl terminated, lactic acid to glycolic acid ratio of 75:25, molecular weight range of 75kDa to 115kDa) After mixing, put into Turbula three-dimensional mixer (T2F type, WAB Machinery) and four stainless steel balls shake twice, each time 15 minutes . The mixture was then placed in a HAAKE micro twin-screw extruder (MiniLab, Thermo Scientific) with the extruder set at 75 ° C and a speed of 25 rpm. The extruded small rod has a diameter of 0.5 mm. The small rod implant was cut into small pieces of 2 mm in length with a blade.

 2) In vitro release test:

 Experimental methods and procedures are as described in Example 13. The results showed that the ketorolac implant was released within 120 days of the ketorolac implant. During the period, the cumulative release is basically linear, there is no sudden release, the release is zero-order kinetics, and the ketorolac release is almost constant.

Claims

Rights request 1. A ketorolac implant with zero-order release effect, characterized in that the pharmaceutical composition includes pharmaceutical active ingredients and a degradable carrier, wherein the pharmaceutical active ingredients are ketorolac, ketorolac ester, ketorolac One of acid tromethamine and ketorolate; the degradable carrier includes carboxyl-terminated polylactic acid and carboxyl-terminated polylactic acid-glycolic acid. 2. The ketorolac implant according to claim 1, wherein the active pharmaceutical ingredient is ketorolac tromethamine. 3. The ketorolac implant according to claim 1, wherein the weight percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 30%-50%. 4. The ketorolac pharmaceutical implant according to claim 1, wherein the weight percentage of the carboxyl-terminated polylactic acid in the pharmaceutical composition is 0-50%, and the carboxyl-terminated polylactic acid-glycolic acid The weight percentage in the pharmaceutical composition is 10%-65%. 5. The ketorolac implant according to claim 1, characterized in that the molecular weight of polylactic acid is 10000-120000; the molecular weight of polylactic acid-glycolic acid is 4000-115000. 6. The ketorolac implant according to claim 1, wherein the weight percentage of lactic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 50 %-75%, the weight percentage of glycolic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 25%-50%. 7. The ketochromic acid implant according to claim 1, wherein the implant releases the drug in a zero-order kinetic manner within 60 days, and the pharmaceutical composition includes active pharmaceutical ingredients and a degradable carrier, The active pharmaceutical ingredient is one of ketorolac, ketorolac ester, ketorolac tromethamine, and ketorolate; the degradable carrier includes carboxyl-terminated polylactic acid and carboxyl-terminated polylactic acid-glycolic acid; The weight percentage of the pharmaceutical active ingredient in the pharmaceutical composition is 35%-40%. 8. The ketorolac implant according to claim 7, wherein the active pharmaceutical ingredient is ketorolac tromethamine. 9. The ketorolac implant according to claim 7, wherein the molecular weight of polylactic acid is 10,000-18,000; the molecular weight of polylactic acid-glycolic acid is 7,000-43,000. 10. The ketorolac implant according to claim 7, wherein the weight percentage of lactic acid in the carboxyl-terminated polylactic acid-glycolic acid polymer is 50%-75%, and the carboxyl-terminated polylactic acid -The weight percentage of glycolic acid in the glycolic acid polymer is 25%-50%.