WO2014190832A1 - Implant de kétorolac et procédé pour le préparer - Google Patents

Implant de kétorolac et procédé pour le préparer Download PDF

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Publication number
WO2014190832A1
WO2014190832A1 PCT/CN2014/076309 CN2014076309W WO2014190832A1 WO 2014190832 A1 WO2014190832 A1 WO 2014190832A1 CN 2014076309 W CN2014076309 W CN 2014076309W WO 2014190832 A1 WO2014190832 A1 WO 2014190832A1
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Prior art keywords
ketorolac
implant
release
acid
terminated
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PCT/CN2014/076309
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English (en)
Chinese (zh)
Inventor
林军
石海涛
林穗珍
胡海燕
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Guangzhou Cellprotek Pharmaceutical Co Ltd
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Guangzhou Cellprotek Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Ketorolac acid implant and preparation method thereof Ketorolac acid implant and preparation method thereof
  • 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
  • ketorolac is (soil) 5-benzoyl-2,3-dihydro-1H-pyrazine-carboxylic acid with a molecular weight of 225 g/mol.
  • NSAIDs non-steroidal anti-inflammatory drug
  • 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.
  • ketorolac 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).
  • 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.
  • the implant 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.
  • the ketorolac implant composition 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.
  • 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.
  • 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.
  • the pharmaceutically active ingredient is ketorolac tromethamine.
  • the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 30% to 50%.
  • 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.
  • 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%.
  • 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.
  • 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.
  • the pharmaceutically active ingredient is ketorolac tromethamine.
  • the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 30% to 40%.
  • 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.
  • 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%.
  • 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.
  • the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt
  • the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt
  • sodium salt sodium salt
  • hyaluronic acid collagen
  • collagen chondroitin
  • gelatin aquerhyaluronic acid
  • 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.
  • the pharmaceutically active ingredient is ketorolac tromethamine.
  • the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 35% to 45%.
  • 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.
  • 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%.
  • 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.
  • the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt
  • the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt
  • sodium salt sodium salt
  • hyaluronic acid collagen
  • collagen chondroitin
  • gelatin aquerhyaluronic acid
  • 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.
  • the pharmaceutically active ingredient is ketorolac tromethamine.
  • the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 35% to 40%.
  • 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.
  • 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%.
  • 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.
  • the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt
  • the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt
  • sodium salt sodium salt
  • hyaluronic acid collagen
  • collagen chondroitin
  • gelatin aquerhyaluronic acid
  • 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.
  • the pharmaceutically active ingredient is ketorolac tromethamine.
  • the weight percentage of the pharmaceutically active ingredient in the pharmaceutical composition is from 40% to 45%.
  • the weight percentage of the carboxyl-terminated polylactic acid in the pharmaceutical composition is 40% to 45%, carboxy
  • carboxy is 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.
  • 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%.
  • 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.
  • the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt
  • the release rate modifier is polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium fatty acid, sodium polyacrylate, mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt
  • sodium salt sodium salt
  • hyaluronic acid collagen
  • collagen chondroitin
  • gelatin aquerhyaluronic acid
  • the release rate modifier is preferably PEG6000 and is 2% by weight of the pharmaceutical composition.
  • ketorolac implants of the present invention are useful for the treatment of acute pain, chronic pain, local non-infectious inflammation, and local tissue damage.
  • 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.
  • the invention also relates to a method of preparing a ketorolac implant, the specific steps are as follows:
  • step 2) 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 ⁇ ), 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.
  • the formulations provided by the present invention are stable under different pH and temperature environments.
  • FIG. 1 In vitro release profile of ketorolac implant B shown in Example 3
  • FIG. 4 In vitro release profile of the ketorolac implant P shown in Example 8.
  • ketorolac tromethamine 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
  • phosphate buffer pH 7.2, Sigma
  • ketorolac content in buffer using reversed-phase high performance liquid chromatography HPLC
  • sample use ⁇ DS column Waters Xterra, C18, 5 ⁇ , 4.6X150mm
  • methanol/water/acetic acid 58/41/1, V/V/V
  • UV detector at 247nm.
  • phosphate buffer pH 7.2, Sigma
  • Example 3 Ketorolac acid implant (released for 11 days)
  • 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:
  • the preparation method of the implant B is as follows:
  • the preparation method of the implant C is as follows:
  • 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.
  • T2F type Turbula three-dimensional mixer
  • 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.
  • 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.
  • 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.
  • 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)
  • ketorolac tromethamine and rate modifiers were used to prepare 5 groups of ketorolac implants for 14 days, as shown in Table 4 below:
  • the preparation method of the implant H is as follows:
  • the preparation method of the implant I is as follows:
  • 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.
  • 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.
  • 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 ⁇ 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)
  • phosphate buffer pH 7.2, Sigma
  • phosphate buffer pH 7.2, Sigma
  • Example 7 Ketorolac acid implant (released for 45 days)
  • phosphate buffer pH 7.2, Sigma
  • Example 8 Ketolacric acid implant (released for 60 days)
  • ketorolac implant released for 60 days
  • ketorolac implants 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. ⁇ shown: Table 6: 60-day release of ketorolac implants
  • 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:
  • ketorolac tromethamine 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.
  • L-lactic acid carboxy terminated, molecular weight l OkDa to 18 kDa
  • L-lactic acid - CO-glycolic acid Carboxy-terminated, lactic acid to glycolic acid ratio 50:50, molecular weight range 27kDa to 43kDa
  • PEG4000 polyethylene glycol
  • 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:
  • ketorolac tromethamine 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.
  • implant K, L, N is the same as implant M.
  • 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.
  • the results show that the K, L burst release phenomenon is obvious, the implant ⁇ has a burst release phenomenon, and does not exhibit a zero-order release curve.
  • the implants ⁇ and ⁇ are preferred formulations.
  • the ketochromate tromethamine is 35%-40% by weight
  • the carboxyl-terminated polylactic acid is 40%-50% by weight in the pharmaceutical composition.
  • 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)
  • phosphate buffer pH 7.2, Sigma
  • Example 10 Ketorolac acid implant (released for 80 days)
  • ketorolac implant released for 80 days
  • phosphate buffer pH 7.2, Sigma
  • ketorolac implant release 90 days
  • phosphate buffer pH 7.2, Sigma
  • Example 12 Ketorolac acid implant (released for 100 days)
  • ketorolac implant released for 100 days
  • phosphate buffer pH 7.2, Sigma
  • 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)
  • 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:
  • the preparation method of the implant ⁇ is as follows:
  • 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 ⁇ is as follows:
  • 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.
  • phosphate buffer pH 7.2, Sigma
  • 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 ⁇ is shown in FIG. Table 9: 72h percent release of different ketorolac implants.
  • the implant ⁇ 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)
  • 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.
  • phosphate buffer pH 7.2, Sigma
  • Example 15 Ketorolac acid implant (released for 11 days)
  • ketorolacate and 28% poly D 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.
  • Thermo Scientific HAAKE micro twin-screw extruder
  • the extruder temperature was set at 80 ° C
  • 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.
  • Example 16 Ketolactin implant (released for 14 days)
  • 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.
  • Example 17 Ketorolac acid implant (released for 14 days)
  • Example 18 Ketorolac acid implant (released for 60 days)
  • ketorolac implant released for 60 days
  • 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
  • Example 19 Ketorolac acid implant (released for 60 days)
  • ketorolac implant released for 60 days
  • Example 8 Ketolactin implant (released for 120 days)
  • ketorolac implant released for 120 days
  • 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.
  • ketorolac implant released for 120 days
  • Example 13 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.

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Abstract

La présente invention concerne un implant de kétorolac et un procédé pour le préparer. L'implant comprend du kétorolac et un support dégradable, il est préparé au moyen d'un procédé d'extrusion en fusion à chaud, il peut libérer des médicaments selon une cinétique d'ordre zéro dans une période de temps de libération pré-établie et peut être utilisé pour prévenir ou traiter une douleur aiguë et chronique et une inflammation. L'implant de kétorolac préparé dans la présente invention présente une libération stable, ne présente pas d'effet de libération brutale et présente des avantages significatifs en utilisation clinique.
PCT/CN2014/076309 2013-05-29 2014-04-26 Implant de kétorolac et procédé pour le préparer Ceased WO2014190832A1 (fr)

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US20150290170A1 (en) * 2012-10-26 2015-10-15 Allergan, Inc. Ketorolac-containing sustained release drug delivery systems
WO2014066653A1 (fr) * 2012-10-26 2014-05-01 Allergan, Inc. Systèmes d'administration intraoculaire de médicament à libération prolongée contenant du kétorolac
US20150272877A1 (en) * 2012-10-26 2015-10-01 Allergan, Inc. Ketorolac-containing sustained release drug delivery systems
CN103263413B (zh) * 2013-05-29 2015-02-25 广州市赛普特医药科技有限公司 一种酮咯酸植入剂及其制备方法
CN105310974B (zh) * 2014-08-01 2019-08-23 山东绿叶制药有限公司 罗替戈汀及其衍生物或其药用盐的植入剂
CN106580868B (zh) * 2017-01-24 2020-06-16 广州帝奇医药技术有限公司 一种植入剂及其制备方法

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US20090263451A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Anti-Inflammatory and/or Analgesic Agents for Treatment of Myofascial Pain
US20100015049A1 (en) * 2008-07-16 2010-01-21 Warsaw Orthopedic, Inc. Methods and compositions for treating postoperative pain comprising nonsteroidal anti-inflammatory agents
CN103263413A (zh) * 2013-05-29 2013-08-28 广州市赛普特医药科技有限公司 一种酮咯酸植入剂及其制备方法

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US8956636B2 (en) * 2008-04-18 2015-02-17 Warsaw Orthopedic, Inc. Methods and compositions for treating postoperative pain comprosing ketorolac

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US20090263451A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Anti-Inflammatory and/or Analgesic Agents for Treatment of Myofascial Pain
US20100015049A1 (en) * 2008-07-16 2010-01-21 Warsaw Orthopedic, Inc. Methods and compositions for treating postoperative pain comprising nonsteroidal anti-inflammatory agents
CN103263413A (zh) * 2013-05-29 2013-08-28 广州市赛普特医药科技有限公司 一种酮咯酸植入剂及其制备方法

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