WO2016070826A1 - 一种罗哌卡因缓释凝胶制剂及其制备与应用 - Google Patents

一种罗哌卡因缓释凝胶制剂及其制备与应用 Download PDF

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WO2016070826A1
WO2016070826A1 PCT/CN2015/093883 CN2015093883W WO2016070826A1 WO 2016070826 A1 WO2016070826 A1 WO 2016070826A1 CN 2015093883 W CN2015093883 W CN 2015093883W WO 2016070826 A1 WO2016070826 A1 WO 2016070826A1
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ropivacaine
sustained
gel
preparation
group
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PCT/CN2015/093883
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English (en)
French (fr)
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叶强
严庞科
张轩邈
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四川海思科制药有限公司
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Priority to CN201580038632.XA priority Critical patent/CN106659676A/zh
Publication of WO2016070826A1 publication Critical patent/WO2016070826A1/zh

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    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the invention relates to a ropivacaine temperature-sensitive phase change sustained-release gel preparation for local injection using poloxamer 407 as a substrate and a preparation method thereof.
  • the present invention provides a sustained release preparation of a sustained local analgesia with poloxamer 407 as a matrix.
  • the present invention provides a ropivacaine sustained-release gel formulation comprising a block copolymer of oxirane and propylene oxide, and a preparation and use thereof 407 and the anesthetic ropivacaine, wherein the gel formulation is used to provide post-operative analgesia and is expected to provide a local analgesic effect of about 20-72 hours or longer at the site of administration.
  • Ropivacaine is a simple levorotatory isomer. It is a novel long-acting amide local anesthetic. Its mechanism of action is the same as that of other local anesthetics. It inhibits nerve excitation and conduction by inhibiting the sodium channel of nerve cells. Compared with bupivacaine, etc., it has the advantages of short onset time, strong degree of separation and blockage, and low toxicity.
  • ropivacaine hydrochloride injection is often used in clinical practice, mainly for surgical anesthesia and postoperative pain treatment, wherein the skin analgesia time is 4.4 hours on average, and the ordinary injection has a shorter action time after administration. Frequent administration is required, and the cost of medical care is relatively high and causes great inconvenience to postoperative patients.
  • the temperature-sensitive phase change gel for injection means that when the temperature is lower than the body temperature, it is injected into the administration site as a solution or a suspension by a common syringe, and a semi-solid gel is formed after the temperature of the drug reaches the body temperature in a short time. .
  • the gel formed at the site of administration, as a drug depot, can achieve a slow release of the drug, thereby reducing the frequency of dosing and reducing the peak of the drug, thereby reducing potential toxicity and minimizing patient suffering.
  • the object of the present invention is to provide a sustained-release preparation of ropivacaine gel suitable for use in a temperature-sensitive phase change gel for post-surgical analgesia, which can release local anesthetic for a long time, and is expected to be applied at the site of application. Provides a local analgesic effect of about 20-72 hours or longer.
  • ropivacaine preparation is mainly an injection. Since the drug is rapidly eliminated at the local injection site and cannot maintain an effective concentration in the local tissue for a long period of time, it is necessary to develop a sustained release preparation for injection of ropivacaine to meet the requirements. More clinical needs.
  • the inventors have found that the above object can be achieved by adding poloxamer 407 as a substrate, which is a solution or suspension at a low temperature, and gels the solution or suspension as the temperature rises to the temperature of the human body.
  • the ropivacaine was slowly released from the gel matrix, and further studies were carried out based on these findings to complete the present invention.
  • the present invention provides the following gel formulations and methods for their preparation.
  • the present invention first provides a ropivacaine sustained-release gel preparation comprising the following weight percentage components:
  • ropivacaine is selected from ropivacaine free base or its pharmacy Acceptable salt.
  • a gel formulation according to the invention wherein ropivacaine is present in the formulation in solution or suspension prior to administration, preferably wherein ropivacaine is in solution (usually at room temperature) or suspended Drug particles (including micron sized drug particles and nano sized drug particles) are present in the formulation.
  • the gel preparation according to the present invention wherein the ropivacaine is selected from ropivacaine hydrochloride, and ropivacaine is present in the preparation in a solution or suspension before administration. .
  • the gel preparation according to the present invention wherein the ropivacaine weight percentage is preferably from 3 to 8%, further preferably from 2 to 6%, further preferably from 4 to 6%, still more preferably 4%; poloxamer
  • the content of 407% by weight is preferably 16 to 19%, more preferably 16 to 17%, still more preferably 16.5%.
  • the gel preparation according to the present invention wherein the pharmaceutically acceptable salt of ropivacaine is ropivacaine hydrochloride and ropivacaine mesylate, preferably ropivacaine hydrochloride.
  • the gel preparation according to the present invention wherein ropivacaine or a pharmaceutically acceptable salt thereof can be pulverized by air flow pulverization and mechanical milling to have an average particle diameter as small as micrometers or nanometers.
  • a gel formulation according to the present invention wherein the salt solution has a pH of from 2 to 8.5.
  • a gel formulation according to the present invention wherein the salt solution is a buffered saline solution.
  • the buffer salt solution is a phosphate buffer (for example, 50 mM), an acetate buffer, a tromethamine buffer, or a citrate buffer.
  • the gel preparation according to the present invention wherein the phosphate buffer has a pH of 6.5 to 7.5.
  • the phosphate buffer has a pH of 7.2.
  • the pH of the salt solution used should be not less than 7.
  • the ropivacaine-containing sustained release gel formulation comprises the following weight percent components:
  • the salt solution has a pH ⁇ 7.
  • the ropivacaine-containing sustained release gel formulation comprises the following components by weight: 1% to 20% ropivacaine 14% to 22% of poloxamer 407, and the balance is a salt solution.
  • the invention also provides a preparation method of the ropivacaine sustained-release gel preparation, the preparation method comprising the following steps:
  • the temperature control is less than 15 ° C, adding a prescription amount of poloxamer 407 to the salt solution under stirring, stirring and uniformly dissolved, to obtain a blank gel, the pH of the salt solution is 7.0-8.5;
  • the temperature control is less than 15 ° C, and the blank gel obtained in (a) is filtered and sterilized with a filter of less than or equal to 0.22 ⁇ m to obtain a sterile blank gel;
  • the invention also provides a preparation method of another ropivacaine sustained-release gel preparation, which comprises the following steps:
  • the temperature control is less than 15 ° C, adding a prescription amount of poloxamer 407 into the water or salt solution with stirring, stirring and uniformly dissolved, a blank gel is obtained, the pH of the salt solution is 7.0-8.5;
  • the temperature control is less than 15 ° C, and the blank gel obtained in (a) is filtered and sterilized with a filter of less than or equal to 0.22 ⁇ m to obtain a sterile blank gel;
  • the invention also provides a preparation method of another ropivacaine sustained-release gel preparation, which comprises the following steps:
  • the temperature control is less than 15 ° C, adding a prescription amount of poloxamer 407 to the salt solution under stirring, and uniformly dissolving, to obtain a blank gel, the pH of the salt solution is: 2.0 ⁇ pH ⁇ 7;
  • the pH of the salt solution of step (a) is from 2 to 6.5 when a ropivacaine sustained release gel formulation is prepared in solution.
  • the ropivacaine sustained release gel preparation using poloxamer 407 as a base will be specifically described below.
  • Ropivacaine is a local anesthetic which is dissolved in water in the form of a water-soluble salt. After injection, the local tissue concentration is maintained in the effective concentration range for a short period of time, and the duration of the anesthetic effect is short.
  • the ropivacaine sustained-release gel preparation of the present invention has a more gradual release rate and a longer duration of drug action, thereby reducing toxic side effects, reducing the number of administrations, and improving patient compliance.
  • the content of cain is in the range of 1% to 20% (w/w), preferably 3 to 8% (w/w), more preferably 2 to 6%, still more preferably 4 to 6 based on the total amount of the gelling agent. % (w/w), more preferably 4% (w/w).
  • Poloxamer 407 is an odorless, odorless white granule composed of a block copolymer of ethylene oxide and propylene oxide, non-toxic, water-soluble and stable. As the temperature rises from 4 ° C to 37 ° C, a solution containing more than a certain percentage of poloxamer 407 will change from a low viscosity solution to a semi-solid gel, thereby forming a gel drug reservoir at the site of injection administration. In addition, it also has good biocompatibility, so poloxamer 407 has good superiority in drug controlled release and sustained release.
  • the content of the poloxamer 407 is in the range of 14% to 22% (w/w), preferably 16 to 19% (w/w) based on the total amount of the gelling agent, and further preferably. 16 to 17% (w/w), more preferably 16.5% (w/w).
  • the ropivacaine sustained-release gel preparation of the present invention can be combined as needed by using the above ropivacaine pharmaceutically acceptable salt, ropivacaine free base, poloxamer 407, water or a salt solution or the like.
  • the ropivacaine sustained release gel preparation of the present invention is prepared.
  • a blank gel of poloxamer 407 was prepared and then sterilized by filtration using a 0.22 ⁇ m filter.
  • the drug is heat-sterilized and then mixed to prepare a ropivacaine sustained-release gel preparation of the present invention.
  • sterile ropivacaine sustained-release gel formulations for injection can also be produced by other processes, such as low-bacteria processes plus high-temperature terminal sterilization.
  • the process for preparing the above ropivacaine sustained-release gel preparation involves the following methods:
  • the water for injection was weighed, and at a low temperature (for example, below 15 ° C), a predetermined amount of poloxamer 407 was slowly added while stirring, and after stirring uniformly, it was allowed to stand at 2-8 ° C for 24 hours to remove air bubbles.
  • a low temperature for example, below 15 ° C
  • a 0.22 ⁇ m filter was used for filter sterilization.
  • the heat-sterilized ropivacaine was weighed and dissolved or suspended in a filter-sterilized blank gel at low temperature (less than 15 ° C).
  • the present invention also provides the use of a ropivacaine sustained release gel formulation for the preparation of a topical analgesic drug, wherein the analgesic is administered before and after the medical treatment.
  • the invention provides a ropivacaine sustained-release gel preparation for preparing a local analgesic medicine, wherein the dose of ropivacaine is 0.5 mg/Kg to 50 mg/Kg, preferably the dose of ropivacaine It is further preferred that the dose of ropivacaine is from 2.5 mg/kg to 10 mg/kg, more preferably 5 mg/kg, from 1 mg/kg to 25 mg/kg.
  • the present invention provides a use of a ropivacaine sustained release gel preparation for the preparation of a topical analgesic drug, wherein the administration is carried out once every 0.5 to 7 days, preferably once every 1 to 3 days.
  • the present invention provides a use of a ropivacaine sustained release gel formulation for the preparation of a topical analgesic drug, wherein sustained local analgesia is maintained for at least 8 hours to 72 hours after administration to a subject, preferably after administration to a subject Continuous local analgesia for at least 12 hours to 48 hours.
  • the present invention provides a use of a ropivacaine sustained-release gel preparation for the preparation of a local analgesic drug, wherein the administration is carried out by a route selected from the group consisting of subcutaneous injection, intradermal injection, intramuscular injection, intravenous injection, intraarterial administration. Injection, intramuscular injection, transdermal absorption, intranasal, inhalation, by topical delivery or subcutaneous administration, preferably by subcutaneous injection, intradermal injection or intramuscular injection, more preferably subcutaneous injection.
  • the present invention provides a ropivacaine sustained-release gel preparation for use in the preparation of a local anesthetic, which further comprises administering to the subject one or more active ingredients other than the ropivacaine gel preparation,
  • the other active ingredients described are selected from the group consisting of drugs having sedative or hypnotic or anesthesia assisted effects.
  • the present invention provides a use of a ropivacaine sustained-release gel preparation for the preparation of a local anesthetic, which is preferably selected from the group consisting of a ⁇ -aminobutyric acid receptor agonist and a ⁇ -aminobutyric acid receptor enhancer.
  • a local anesthetic which is preferably selected from the group consisting of a ⁇ -aminobutyric acid receptor agonist and a ⁇ -aminobutyric acid receptor enhancer.
  • Agent M receptor antagonist, N2 receptor antagonist, serotonin receptor antagonist, sodium channel antagonist or opioid receptor agonist.
  • the present invention provides a use of a ropivacaine sustained release gel formulation for the preparation of a local anesthetic, preferably a solution selected from the group consisting of an intravenous anesthetic, an inhaled anesthetic or an anesthetic adjuvant.
  • the invention provides the use of a ropivacaine sustained-release gel preparation for preparing a local anesthetic, wherein the intravenous anesthetic is selected from the group consisting of propofol, sodium fospropofol, midazolam, ketamine , thiopental sodium, sodium oxybate or etomidate, and pharmaceutically acceptable salts thereof; said inhalation anesthetic selected from the group consisting of sevoflurane, isoflurane, enflurane, desflurane, A Oxyfluorin or nitrous oxide; the anesthetic adjuvant is selected from the group consisting of a sedative hypnotic, an anticholinergic, a muscle relaxant, an antiemetic, a local anesthetic or an analgesic.
  • the intravenous anesthetic is selected from the group consisting of propofol, sodium fospropofol, midazolam, ketamine , thiopental sodium, sodium oxy
  • the sedative-hypnotic agent is selected from the group consisting of diazepam, flurazepam, chlordiazepoxide, estazolam, clonazepam, glutamine, methylpropionate, buspirone, Midazolam, dexmedetomidine, droperidol, promethazine, chlorpromazine, barbital, phenobarbital, pentobarbital, barbital, barcobarbital or sulphur Sodium pentoxide, and pharmaceutically acceptable salts thereof;
  • the anticholinergic agent is selected from the group consisting of atropine or scopolamine, and pharmaceutically acceptable salts thereof;
  • the muscle relaxant is selected from the group consisting of vecuronium bromide and rocuron bromide Ammonium, pancuronium bromide, pipecuronium bromide, micuriochlor, atracurium or succinylcholine, and pharmaceutically acceptable salts thereof; said antiemetic
  • the present invention provides an embodiment of a ropivacaine sustained release gel formulation in unit dosage form, wherein the unit dosage form comprises from 20 mg to 1200 mg of ropivacaine, preferably in a unit dosage form comprising from 100 mg to 600 mg of ropivacaine. Further, it is further preferred that the unit dosage form comprises 200 mg of ropivacaine.
  • the ropivacaine sustained release gel formulation in unit dosage form of the present invention refers to a unit dosage form of the smallest package unit prepared for administration or injection, such as a capsule or a tablet. , a bottle of injection.
  • the present invention provides an embodiment for formulating a ropivacaine sustained-release gel preparation, wherein the preparation comprises a solution of 5 mg/mL to 80 mg/mL of ropivacaine before forming a gel, preferably the preparation is formed into a condensate
  • the solution before the gel contains 10 mg/mL to 60 mg/mL of ropivacaine, and it is further preferred that the solution before the gel formation contains 20 mg/mL to 50 mg/mL of ropivacaine.
  • the present invention provides an article of manufacture comprising: a single or multiple doses of a formulation and a packaging material.
  • packaging material comprises a container for containing the single or multiple doses of the formulation.
  • the container comprises a label that exhibits one or more of the following: the disease state to which the formulation is administered, storage information, administration information, and/or information on how to administer the Instructions for the preparation of the preparation.
  • the invention is a pharmaceutical preparation with poloxamer 407 as a matrix, and is clinically intended for postoperative analgesia.
  • the release rate of the invention is more gradual and the duration of the drug is longer, thereby reducing toxic side effects, reducing the number of administrations, and improving patient compliance.
  • the local anesthetic time of ropivacaine can be significantly increased compared to the commercially available ropivacaine injection.
  • w/w for expressing the content of each component forming the gel preparation of the present invention means “weight (g) of each component / weight (g) of the gel formulation”.
  • Rovacaine is a ropivacaine free base or a pharmaceutically acceptable salt of ropivacaine.
  • “Micronized ropivacaine” is an average particle size of ropivacaine of less than 1 mm.
  • Nemo-treated ropivacaine is an average particle size of ropivacaine of less than 1 ⁇ m.
  • “Pharmaceutically acceptable salt” means a salt which is safe, non-toxic and which is pharmaceutically acceptable for veterinary use or human pharmaceutical use and which has the desired pharmacological activity, such salts including, but not limited to, inorganic a salt formed by an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or with an organic acid such as acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, pyruvic acid, lactic acid, Malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, B Sulfonic acid, trifluoromethanesulfonic acid, 1,2-ethanedisul
  • Figure 1 is a schematic diagram of the pharmacodynamic experiment in guinea pigs.
  • the water for injection was weighed, and poloxamer 407 (BASF Corp.) was slowly added while stirring in an ice water bath. After the poloxamer 407 was completely dissolved, a prescribed amount of ropivacaine hydrochloride was added and stirred. The drug is completely dissolved, and the filter is sterilized by filtration using a 0.22 ⁇ m filter membrane at a temperature controlled temperature of less than 15 ° C, and is obtained by dispensing.
  • poloxamer 407 BASF Corp.
  • the water for injection was weighed, and poloxamer 407 (BASF Corp.) was slowly added while stirring in an ice water bath. After the poloxamer 407 was completely dissolved, a prescribed amount of ropivacaine hydrochloride was added and stirred. The drug is completely dissolved, and the filter is sterilized by filtration using a 0.22 ⁇ m filter membrane at a temperature controlled temperature of less than 15 ° C, and is obtained by dispensing.
  • poloxamer 407 BASF Corp.
  • the water for injection was weighed, and poloxamer 407 (BASF Corp.) was slowly added while stirring in an ice water bath. After the poloxamer 407 was completely dissolved, a prescribed amount of ropivacaine mesylate was added. Stirring to completely dissolve the drug, and filtering and sterilizing using a 0.22 ⁇ m filter membrane at a temperature control of less than 15 ° C, and dispensing is obtained.
  • poloxamer 407 BASF Corp.
  • Example 27 Dry heat sterilization of ropivacaine hydrochloride and ropivacaine base
  • 25mg of micronized ropivacaine hydrochloride and ropivacaine base powder were separately placed in a 5mL vial and placed in a dry heat sterilization cabinet (100-level purification to open the door sterilization oven, Nanjing Feilong Pharmaceutical Equipment Co., Ltd.) It was sterilized by dry heat at 140 ° C for 3 hours.
  • the local anesthetic effect and duration of efficacy of the ropivacaine sustained-release gel were evaluated using the guinea pig intradermal papule method.
  • White adult male guinea pigs weighing 300g-400g were selected for each group, including 6 positive control groups (0.5% ropivacaine injection), vehicle control group (normal saline), and similar control group (1.3% Bubi
  • the cain liposome injection suspension) and the sustained release gel group (4) were divided into 7 groups as shown in the following table.
  • the hair of the 5 ⁇ 8 cm area of the back of the guinea pig was shaved to avoid irritation on the next day.
  • the size of the papule was marked in red on the back of the guinea pig.
  • a single intradermal injection of 0.25 mL of drug solution per marked area was needled at different time points to stimulate the muscle contraction as a pain index.
  • Six acupunctures were performed in each papule, and the acupuncture was separated by 3-5 seconds to count the needles that the guinea pig could not respond to.
  • the test drug has a local anesthetic effect at the injection site.
  • the anesthetic effect of 0.5% ropivacaine hydrochloride injection lasted only about 2 hours, and the anesthesia time of the 1.3% bupivacaine liposome injection suspension was only about 10 hours.
  • the local anesthetic duration of the ropivacaine sustained release gel formulation was significantly longer than 0.5% ropivacaine hydrochloride injection and 1.3% bupivacaine liposome injection suspension, of which 4% ropivacaine hydrochloride
  • the local anesthetic time of the solution gel reached 24 hours. It is worth mentioning that the time of pharmacodynamic action of the same anesthetic drug in animals and human body is mostly different. For example, the anesthetic effect of 1.3% bupivacaine liposome in guinea pig is about 10 hours, but At the corresponding human body action time is at least 24 hours (Skolnik A, Gan TJ.
  • the salt form of ropivacaine such as hydrochloride
  • the presence of ropivacaine free base in the gel (dissolved or suspended) against ropivaca Since the duration of anesthesia of the sustained release gel has a significant effect, the release rate of the drug can be adjusted by adjusting the form of the drug in the gel and the salt form of the drug, thereby achieving the purpose of adjusting the duration of the local anesthesia.
  • Test purpose To evaluate the local analgesic effect (analgesic duration) of different ropivacaine sustained release gel formulations.
  • Test animals Guangxi Bama miniature pig, male, 6 to 7 weeks old, weighing 3 to 5 kg. The postoperative pain model was established after 5 to 7 days of adaptive feeding.
  • Postoperative pain model establishment method anesthesia with isoflurane inhalation anesthesia.
  • the incision was positioned 3 cm from the midline of the left back, parallel to the midline of the back, and the incision was 3 cm.
  • the small pig enters the anesthesia state, the prone/side is placed, and the left back area is prepared for skin preparation.
  • the operation area is disinfected (75% alcohol, iodophor, 75% alcohol), and the predetermined incision is cut, and the skin and fascia are cut, without damaging the muscle.
  • Test group 6 rats in each group, divided into positive control group (0.5%, 1.5% and 3% ropivacaine hydrochloride injection), vehicle control group (normal saline), similar control group (1.3% bupivacaine lipid)
  • vehicle control group normal saline
  • similar control group 1.3% bupivacaine lipid
  • the plastid injection suspension) and the ropivacaine sustained-release gel preparation group (3) were divided into 6 groups as shown in the following table.
  • Mode of administration and dose subcutaneous injection at the incision, each group of animals were infiltrated and injected corresponding test preparations, the dosage volume was: 1ml/cm, a total of 3ml, and the injection was evenly injected at 3 points on both sides of the incision, a total of 6 points Injection, 0.5 mL / point, the injection points on both sides are about 1 cm apart, suture the incision.
  • Analgesic effect test The tactile measurement kit (Von Frey) was used to detect the postoperative analgesia effect.
  • the Von Frey needle was used to stimulate the skin 0.5 cm away from the incision, and the pain was measured (evasion response: 90-180 degrees torsion, leaving the tester to avoid the stimulus), and the measurement time points were 1 d before surgery (as the base value).
  • each time point was measured 6 times, each interval 5-10S.
  • the pain threshold after acupuncture changes, the time interval of the detection time point is shortened in the subsequent measurement period to more accurately determine the specific failure time. Finally, the time point at which the pain threshold of 6 measurements was restored to the pre-operative baseline value was used as the failure time.
  • Postoperative incision recovery observation and pathological examination 1 day before surgery (basal value) and postoperative, daily observation The mouth is healed and scored.
  • test group and the control group are close to the tactile measurement results, that is, on the day when all the animals are restored, all the animals are euthanized, and the local tissues are administered by necropsy, and the main site is observed, and the administration site and the surrounding skin and subcutaneous fascia and muscle are taken.
  • Tissue take the fixed section (middle of the incision), in addition, when the obvious observation of the obvious lesions, also take the site of the disease) fixed, embedded, sectioned, hematoxylin-eosin staining, observed under the microscope.
  • the time of pharmacodynamic action of the same anesthetic drug in animals and human body is mostly different.
  • the anesthetic effect of 1.3% bupivacaine liposome on small pigs is about 8 hours.
  • the corresponding human body action time is at least 24 hours (Skolnik A, Gan TJ. New formulations of bupivacaine for the treatment of postoperative pain: liposomal bupivacaine and SABER-Bupivacaine. Expert Opin Pharmacother. 2014 Aug; 15 (11): 1535-42 .), that is, 2 to 3 times, from which it is estimated that the anesthetic effect of 4% ropivacaine hydrochloride sustained release gel in the human body can reach 48 to 72 hours.
  • the concentration of ropivacaine has a significant effect on the duration of anesthesia of the ropivacaine sustained-release gel, so it can be achieved by adjusting the drug concentration in the ropivacaine sustained-release gel. Adjust the purpose of local anesthesia duration.

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Abstract

罗哌卡因缓释凝胶制剂、其制备方法及用途，所述凝胶制剂包括1-20wt%的罗哌卡因、14-22wt%的泊洛沙姆407和余量的水或盐溶液。

Description

一种罗哌卡因缓释凝胶制剂及其制备与应用 技术领域
本发明涉及了一种以泊洛沙姆407作为基质的，用于局部注射的罗哌卡因温敏性相变缓释凝胶制剂及其制备方法。
本发明提供了一种以泊洛沙姆407作为基质的持续局部镇痛的药物缓释制剂。具体地说，本发明提供了一种罗哌卡因缓释凝胶制剂及其制备与应用，所述凝胶制剂包含一种环氧乙烷和环氧丙烷的嵌段共聚物泊洛沙姆407和麻醉剂罗哌卡因，其中所述凝胶制剂用于提供手术后镇痛并且预计在施用部位提供大约20-72小时或更长的局部镇痛作用。
背景技术
罗哌卡因是单纯的左旋异构体，是一种新型的长效酰胺类局麻药，其作用机制与其它局麻药相同，通过抑制神经细胞钠离子通道，阻断神经兴奋与传导。同布比卡因等相比，具有起效时间短、分离阻滞的程度强、毒性小等优点。目前临床常使用盐酸罗哌卡因注射液，主要用于外科手术麻醉以及术后疼痛的治疗，其中皮肤镇痛时间平均为4.4小时，这种普通注射液在给药后，作用时间较短，需要频繁给药，医护费用相对较高并给术后患者带来很大不便。
注射用温敏相变凝胶是指在温度低于体温时，通过普通注射器以溶液或混悬液形式注射到给药部位，在用药部位短时间内温度达到人体温度后，形成半固体凝胶。在给药部位形成的凝胶，作为一个药物贮库，可以达到缓慢释放药物的作用，从而减小给药频率并降低药物峰值，以减少潜在毒性并最大限度减少患者的痛苦。
本发明目的在于提供一种适合用于医疗手术后镇痛的温敏相变凝胶的罗哌卡因凝胶缓释制剂，该凝胶缓释制剂可以长时间释放局麻药，预计在施用部位提供大约20-72小时或更长的局部镇痛作用。
发明内容
本发明的目的在于提供一种用于医疗手术后镇痛的凝胶缓释制剂，以减少给药次数，提高药物安全性及患者顺应性。
目前市售的罗哌卡因制剂主要为注射液，由于药物在局部注射部位消除迅速，不能在局部组织长期保持有效浓度，所以有必要开发罗哌卡因的注射用缓释制剂，以满足更多的临床需求。
发明人研究发现，可通过加入泊洛沙姆407作为基质实现上述目的，所述制剂在低温下为溶液或混悬液，随着温度升高至人体温度附近，溶液或混悬液发生胶凝，罗哌卡因从凝胶基质中缓慢释放出来，基于这些发现进行进一步研究而完成了本发明。
更具体地，本发明提供了以下的凝胶制剂及其制备方法。
为实现上述发明目的，本发明首先提供一种罗哌卡因缓释凝胶制剂，所述罗哌卡因缓释凝胶制剂包括如下重量百分比成分：
1％～20％的罗哌卡因、14％～22％的泊洛沙姆407、以及余量为水或盐溶液；所述的罗哌卡因选自罗哌卡因游离碱或者其药学上可接受盐。
根据本发明所述的凝胶制剂，其中，在施用前，罗哌卡因以溶液或者混悬的形式存在于制剂中，优选地，其中罗哌卡因以溶液(通常室温下)或混悬药物颗粒(包括微米尺寸的药物颗粒和纳米尺寸的药物颗粒)形式存在于制剂中。
优选地，根据本发明所述的凝胶制剂，其中，所述的罗哌卡因选自盐酸罗哌卡因，在给药前，罗哌卡因以溶液或者混悬的形式存在于制剂中。
根据本发明所述的凝胶制剂，其中罗哌卡因重量百分比含量优选为3～8％，进一步优选为2～6％，进一步优选4～6％，更进一步优选4％；泊洛沙姆407重量百分比含量优选为16～19％，进一步优选16～17％，更进一步优选16.5％。
根据本发明所述的凝胶制剂，其中所述罗哌卡因药学上可接受的盐为罗哌卡因盐酸盐和罗哌卡因甲磺酸盐，优选罗哌卡因盐酸盐。
根据本发明所述的凝胶制剂，其中罗哌卡因或者其药学上可接受的盐可通过气流粉碎和机械研磨等粉碎方式使其平均粒径小至微米或纳米级。
根据本发明所述的凝胶制剂，其中所述盐溶液pH为2～8.5。
根据本发明所述的凝胶制剂，其中所述盐溶液为缓冲盐溶液。
根据本发明所述的凝胶制剂，其中所述缓冲盐溶液为磷酸盐缓冲液(例如50mM)、醋酸盐缓冲液、氨基丁三醇缓冲液或者枸橼酸盐缓冲液。
根据本发明所述的凝胶制剂，其中所述磷酸盐缓冲液pH为6.5～7.5。
其中更优选所述磷酸盐缓冲液pH为7.2。
其中可以理解的是，当罗哌卡因为其碱的形式时，使用的盐溶液pH应当不小于7。
也就是说，当罗哌卡因为其碱的形式时，所述含罗哌卡因缓释凝胶制剂包括如下重量百分比成分：
1％～20％的罗哌卡因、14％～22％的泊洛沙姆407、以及余量为水或盐溶液；所述盐溶液pH≥7。
根据本发明一些具体实施方案，当罗哌卡因为其药学上可接受的盐时，所述含罗哌卡因缓释凝胶制剂包括如下重量百分比成分：1％～20％的罗哌卡因、14％～22％的泊洛沙姆407、以及余量为盐溶液。
本发明还提供了所述的罗哌卡因缓释凝胶制剂的制备方法，所述制备方法包括如下步骤：
(a)控温小于15℃，在搅拌下往盐溶液中加入处方量的泊洛沙姆407，搅拌均匀溶解后，得到空白凝胶，所述盐溶液pH为7.0-8.5；
(b)控温小于15℃，将(a)得到的空白凝胶用小于或等于0.22μm的滤膜进行过滤除菌，得无菌空白凝胶；
(c)称取经热灭菌的罗哌卡因药学上可接受的盐，控温小于15℃，将其溶解或混悬于(b)制备得到的无菌空白凝胶中得混悬形式的罗哌卡因缓释凝胶制剂。
本发明还提供了另一种所述的罗哌卡因缓释凝胶制剂的制备方法，所述制备方法包括如下步骤：：
(a)控温小于15℃，在搅拌下往水或者盐溶液中加入处方量的泊洛沙姆407，搅拌均匀溶解后，得到空白凝胶，所述盐溶液pH为7.0-8.5；
(b)控温小于15℃，将(a)得到的空白凝胶用小于或等于0.22μm的滤膜进行过滤除菌，得无菌空白凝胶；
(c)称取经热灭菌的罗哌卡因碱，控温小于15℃，将其混悬于(b)制备得到的无菌空白凝胶中得混悬形式的罗哌卡因缓释凝胶制剂。
本发明还提供了另一种所述的罗哌卡因缓释凝胶制剂的制备方法，所述制备方法包括如下步骤：
(a)控温小于15℃，在搅拌下往盐溶液中加入处方量的泊洛沙姆407，搅拌均匀溶解后，得到空白凝胶，所述盐溶液pH为：2.0≤pH＜7；
(b)控温小于15℃，在(a)得到的空白凝胶中加入处方量的罗哌卡因药学上可接受的盐，搅拌溶解，用小于或等于0.22μm的滤膜进行过滤除菌，得溶液形式的罗哌卡因缓释凝胶制剂。
根据本发明一些具体实施方案，当制备的是溶液形式的罗哌卡因缓释凝胶制剂时，步骤(a)的盐溶液的pH为2-6.5。
下文将具体说明以泊洛沙姆407作为基质的罗哌卡因缓释凝胶制剂。
罗哌卡因：
罗哌卡因是一种局部麻醉药，其以水溶性盐的形式溶解在水中，其普通注射液在注射后，局部组织浓度维持在有效浓度范围内的时间短，麻醉效果的持续时间短。在本发明中的罗哌卡因缓释凝胶制剂释药速率更加平缓、药效持续时间更长，从而能够降低毒副作用、减少给药次数，提高患者顺应性，所述制剂中，罗哌卡因的含量范围为基于所述凝胶剂的总量为1％～20％(w/w)，优选3-8％(w/w)，进一步优选2-6％，进一步优选4-6％(w/w)，更优选4％(w/w)。
泊洛沙姆407：
泊洛沙姆407为无臭、无味的白色颗粒，由环氧乙烷和环氧丙烷的嵌段共聚物组成，无毒，且水溶性、稳定性好。随着温度从4℃上升到37℃，含泊洛沙姆407超过一定百分比浓度的溶液会从低粘度的溶液变成半固体的凝胶，从而在注射给药部位形成凝胶药物储库。除此之外，其还具有良好的生物相容性，因此泊洛沙姆407在药物控释缓释方面，具有良好的优越性。在本发明中，泊洛沙姆407的含量范围为基于所述凝胶剂的总量为14％～22％(w/w)，优选为16～19％(w/w)，更进一步优选16～17％(w/w)，更优选16.5％(w/w)。
本发明的罗哌卡因缓释凝胶制剂可通过将上述罗哌卡因药学上可接受的盐、罗哌卡因游离碱、泊洛沙姆407、水或者盐溶液等，根据需要进行组合，从而制备得到本发明的罗哌卡因缓释凝胶制剂。
先制备得到泊洛沙姆407的空白凝胶，再使用0.22μm的滤膜进行过滤除菌。药物进行热灭菌，再进行混合，从而制备得到本发明的罗哌卡因缓释凝胶制剂。除此之外，用于注射的无菌罗哌卡因缓释凝胶制剂也可通过其他工艺方法生产，如低菌工艺流程加高温终端灭菌。
制备上述罗哌卡因缓释凝胶制剂的工艺，涉及到以下方法：
1、空白凝胶的制备：
称取注射用水，在低温下(如低于15℃)，边搅拌，边缓慢加入处方量的泊洛沙姆407，搅拌均匀后，在2-8℃静置24小时，除去气泡。
2、空白凝胶的无菌过滤：
在低温下(如低于15℃)，使用0.22μm的滤膜进行过滤除菌。
3、缓释凝胶的制备：
称取经热灭菌的罗哌卡因，在低温下(小于15℃)，溶解或混悬于过滤除菌的空白凝胶。
本发明还提供罗哌卡因缓释凝胶制剂在制备局部镇痛药物中的应用，其中所述镇痛药为医疗手术前及手术后给药。
本发明提供罗哌卡因缓释凝胶制剂在制备局部镇痛药物中的应用，其中罗哌卡因的给药剂量是0.5mg/Kg至50mg/Kg，优选罗哌卡因的给药剂量为1mg/Kg至25mg/Kg，进一步优选罗哌卡因的给药剂量为2.5mg/Kg至10mg/Kg，更进一步优选5mg/Kg。
本发明提供罗哌卡因缓释凝胶制剂在制备局部镇痛药物中的应用，其中每隔0.5日至7日进行给药1次，优选每隔1日至3日进行给药1次。
本发明提供罗哌卡因缓释凝胶制剂在制备局部镇痛药物中的应用，其中施用于受试对象后维持至少8小时至72小时的持续局部镇痛，优选施用于受试对象后维持至少12小时至48小时的持续局部镇痛。
本发明提供罗哌卡因缓释凝胶制剂在制备局部镇痛药物中的应用，其中通过选自如下的途径进行给药：皮下注射、皮内注射、肌肉内注射、静脉内注射、动脉内注射、肌肉内注射、透皮吸收、鼻内、吸入、通过局部递送或者皮下，优选通过皮下注射、皮内注射或者肌肉内注射给药，更优选皮下注射给药。
本发明提供罗哌卡因缓释凝胶制剂在制备局部麻醉药物中的应用，其中还包括对受试对象联合给予一种或多种除罗哌卡因凝胶制剂以外的其它活性成分，所述的其它活性成分选自具有镇静催眠或麻醉辅助作用的药物。
本发明提供罗哌卡因缓释凝胶制剂在制备局部麻醉药物中的应用，优选方案，所述的其它活性成分选自γ-氨基丁酸受体激动剂、γ-氨基丁酸受体增强剂、M受体拮抗剂、N2受体拮抗剂、5-羟色胺受体拮抗剂、钠离子通道拮抗剂或阿片受体激动剂。
本发明提供罗哌卡因缓释凝胶制剂在制备局部麻醉药物中的应用，优选方案，本发明优选方案，所述的其它活性成分选自静脉麻醉药、吸入麻醉药或麻醉辅助剂。
本发明提供罗哌卡因缓释凝胶制剂在制备局部麻醉药物中的应用，本发明优选方案，所述的静脉麻醉药选自丙泊酚、磷丙泊酚钠、咪达唑仑、氯胺酮、硫喷妥钠、羟丁酸钠或依托咪酯，以及它们的药学上可接受的盐；所述的吸入麻醉药选自七氟烷、异氟烷、恩氟烷、地氟烷、甲氧氟烷或氧化亚氮；所述的麻醉辅助剂选自镇静催眠药、抗胆碱药、肌松药、止吐药、局部麻醉药或镇痛药。
本发明优选方案，所述的镇静催眠药选自地西泮、氟西泮、氯氮卓、艾司唑仑、氯硝西泮、格鲁米特、甲丙氨酯、丁螺环酮、咪达唑仑、右美托咪定、氟哌利多、异丙嗪、氯丙嗪、巴比妥、苯巴比妥、戊巴比妥、异戊巴比妥、司可巴比妥或硫喷妥钠，以及它们的药学上可接受的盐；所述的抗胆碱药选自阿托品或东莨菪碱，以及它们的药学上可接受的盐；所述的肌松药选自维库溴铵、罗库溴铵、泮库溴铵、哌库溴铵、米库氯铵、阿曲库铵或琥珀酰胆碱，以及它们的药学上可接受的盐；所述的止吐药选自托烷司琼、帕洛诺司、格拉司琼、多拉司琼、东莨菪碱、赛克力嗪或甲氧氯普胺，以及它们的药学上可接受的盐；所述的局部麻醉药选自利多卡因、罗哌卡因、丙胺卡因、布比卡因、阿替卡因或达克罗宁，以及它们的药学上可接受的盐；所述的镇痛药选自芬太尼、瑞芬太尼、舒芬太尼、阿芬太尼、吗啡、哌替啶、地佐辛、布托啡诺、羟考酮或奈福泮，以及它们的药学上可接受的盐。
本发明提供一种实施方案，单位剂量形式的罗哌卡因缓释凝胶制剂，其中所述单位剂量形式包含20mg至1200mg的罗哌卡因，优选单位剂量形式包含100mg至600mg的罗哌卡因，进一步优选单位剂量形式包含200mg的罗哌卡因。
可以理解的是，本发明所述的单位剂量形式的罗哌卡因缓释凝胶制剂指的是制备的独立服用或注射的最小包装单位的单位剂量药物形式，譬如一粒胶囊、一粒药片、一瓶注射液。
本发明提供一种实施方案，配制成罗哌卡因缓释凝胶制剂，其中该制剂在形成凝胶前的溶液包含5mg/mL至80mg/mL的罗哌卡因，优选该制剂在形成凝胶前的溶液包含10mg/mL至60mg/mL的罗哌卡因，进一步优选该制剂在形成凝胶前的溶液包含20mg/mL至50mg/mL的罗哌卡因。
本发明提供一种制造品，它包含：单个或多个剂量的制剂以及包装材料。
本发明优选方案，其中所述的包装材料包含用于容纳所述的单个或多个剂量的制剂的容器。
本发明优选方案，其中所述的容器包含标签，该标签显示选自如下的一项或多项内容：给予所述制剂所针对的疾病状态、贮藏信息、给药信息和/或关于如何给予所述制剂的用法说明。
本发明为以泊洛沙姆407作为基质的药物制剂，临床拟用于术后镇痛。相对盐酸罗哌卡因注射液，本发明释药速率更加平缓、药效持续时间更长，从而能够降低毒副作用、减少给药次数，提高患者顺应性。与市售的罗哌卡因注射液相比，可以显著提高罗哌卡因的局部麻醉时间。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
在本说明书中，用于表达形成本发明凝胶制剂的各组分含量的“w/w”是指“各组分的重量(g)/凝胶制剂的重量(g)”。
“罗哌卡因”是罗哌卡因游离碱或者罗哌卡因药学可接受的盐。
“罗哌卡因碱”是罗哌卡因游离碱。
“微粉化罗哌卡因”是罗哌卡因平均粒径小于1mm。
“纳米化罗哌卡因”是罗哌卡因平均粒径小于1μm。
“药学上可接受的盐”是指安全、无毒并且其对于兽医使用或者人类药物使用上药学可接受的，并且具有所期望的药理学活性的盐，这样的盐包括，但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等酸形成的盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、o-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、三氟甲磺酸、1,2-乙二磺酸、苯磺酸、对氯苯磺酸、2-萘磺酸、对甲苯磺酸、樟脑磺酸、4-甲基二环[2.2.2]辛-2-烯-1-羧酸、葡萄糖醛酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、2-羟基丙酸、草酸和黏糠酸等酸形成的盐。
附图说明
图1为豚鼠体内的药效实验示意图。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
实施例1：制备1.5％盐酸罗哌卡因溶液型凝胶
处方：
Figure PCTCN2015093883-appb-000001
称取注射用水，在冰水浴下边搅拌边缓慢加入泊洛沙姆407(巴斯夫公司(BASF Corp.))，待泊洛沙姆407溶解完全后，再加入处方量的盐酸罗哌卡因，搅拌使药物完全溶解，在控温小于15℃下使用0.22μm的滤膜进行过滤除菌，分装即得。
实施例2：制备3％盐酸罗哌卡因溶液型凝胶
Figure PCTCN2015093883-appb-000002
称取注射用水，在冰水浴下边搅拌边缓慢加入泊洛沙姆407(巴斯夫公司(BASF Corp.))，待泊洛沙姆407溶解完全后，再加入处方量的盐酸罗哌卡因，搅拌使药物完全溶解，在控温小于15℃下使用0.22μm的滤膜进行过滤除菌，分装即得。
实施例3：制备4％盐酸罗哌卡因溶液型凝胶
Figure PCTCN2015093883-appb-000003
称取注射用水，在冰水浴下边搅拌边缓慢加入泊洛沙姆407(巴斯夫公司(BASF  Corp.))，待泊洛沙姆407溶解完全后，再加入处方量的盐酸罗哌卡因，搅拌使药物完全溶解，在控温小于15℃下使用0.22μm的滤膜进行过滤除菌，分装即得。
实施例4：制备4％甲磺酸罗哌卡因溶液型凝胶
处方：
Figure PCTCN2015093883-appb-000004
称取注射用水，在冰水浴下边搅拌边缓慢加入泊洛沙姆407(巴斯夫公司(BASF Corp.))，待泊洛沙姆407溶解完全后，再加入处方量的甲磺酸罗哌卡因，搅拌使药物完全溶解，在控温小于15℃使用0.22μm的滤膜进行过滤除菌，分装即得。
实施例5：制备4％盐酸罗哌卡因混悬型凝胶
处方：
Figure PCTCN2015093883-appb-000005
配制50mM的磷酸盐缓冲液(pH7.2)：称取12.24g的Na2HPO4·12H2O与2.46g的NaH2PO4·2H2O，蒸馏水溶解并稀释至1000ml,NaOH或HCl调节pH至7.2，即得。
称取50mM磷酸盐缓冲液，在冰水浴下边搅拌边缓慢加入泊洛沙姆407，待溶解完全后，静置除气泡。在控温小于15℃利用0.22μm的滤膜进行过滤除菌，再加入经140摄氏度干热灭菌3小时(百级净化对开门灭菌烘箱，南京飞龙制药设备有限公司)的微粉化盐酸罗哌卡因，搅拌分散均匀，分装即得。
实施例6：制备4％罗哌卡因碱混悬型凝胶
处方：
Figure PCTCN2015093883-appb-000006
Figure PCTCN2015093883-appb-000007
称取50mM磷酸盐缓冲液(配方和配制方法同实施例5)，在冰水浴下边搅拌边缓慢加入泊洛沙姆407，待溶解完全后，静置除气泡。在控温小于15℃利用0.22μm的滤膜进行过滤除菌，再加入经140℃干热灭菌3小时(百级净化对开门灭菌烘箱，南京飞龙制药设备有限公司)的微粉化罗哌卡因碱，搅拌分散均匀，分装即得。
实施例7：制备6％盐酸罗哌卡因混悬型凝胶
处方：
Figure PCTCN2015093883-appb-000008
称取50mM磷酸盐缓冲液(配方和配制方法同实施例5)，在冰水浴下边搅拌边缓慢加入泊洛沙姆407，待溶解完全后，静置除气泡。在控温小于15℃利用0.22μm的滤膜进行过滤除菌，再加入经140℃干热灭菌3小时(百级净化对开门灭菌烘箱，南京飞龙制药设备有限公司)的微粉化盐酸罗哌卡因，搅拌分散均匀，分装即得。
实施例8：制备4％盐酸罗哌卡因混悬型凝胶
处方：
Figure PCTCN2015093883-appb-000009
称取50mM磷酸盐缓冲液(配方和配制方法同实施例5)，在冰水浴下边搅拌边缓慢加入泊洛沙姆407，待溶解完全后，再加入微粉化盐酸罗哌卡因，搅拌分散均匀，将样品以2mL/瓶的量分装至5mL西林瓶中并密封。将西林瓶置于高压蒸汽灭菌器(不锈钢立式压力蒸汽灭菌器，上海申安医疗器械厂)中以121℃灭菌15分钟。高压蒸汽灭菌处理后，冷却样品置室温，然后置于4℃冷藏。
在高压蒸汽灭菌处理之后，未观察到凝胶样品有明显的颜色变化。使用Waters公司的Xbridge C18色谱柱(5μm,250×4.6mm),使用乙腈-磷酸盐缓冲液(取1mol/L 磷酸二氢钠溶液1.3mL,0.5mol/L磷酸氢二钠溶液32.5mL,加水至1000mL,调节pH至8.0)(50:50)为流动相，检测波长为240nm,进行HPLC分析。将灭菌后的凝胶样品溶解于流动相中并进行分析。HPLC分析表明凝胶样品中盐酸罗哌卡因降解产物少于1％，有关物质在中国药典要求的限度范围内。以上结果说明该凝胶样品可以耐受高压蒸汽灭菌处理。
实施例9-26：罗哌卡因凝胶的制备
处方：
Figure PCTCN2015093883-appb-000010
Figure PCTCN2015093883-appb-000011
“--”表示无此成分。
称取处方量的水或缓冲液，在冰水浴下边搅拌边缓慢加入处方量的泊洛沙姆407，待溶解完全后，静置除气泡。在控温小于15℃利用0.22μm的滤膜进行过滤除菌，再加入处方量的经140摄氏度干热灭菌3小时(百级净化对开门灭菌烘箱，南京飞龙制药设备有限公司)的微粉化罗哌卡因，搅拌分散均匀，分装即得。
实施例27：对盐酸罗哌卡因和罗哌卡因碱进行干热灭菌
将25mg微粉化的盐酸罗哌卡因和罗哌卡因碱粉末分别装入5mL西林瓶中，放置于干热灭菌柜(百级净化对开门灭菌烘箱，南京飞龙制药设备有限公司)中以140℃干热灭菌3小时。
使用Waters公司的Xbridge C18色谱柱(5μm,250×4.6mm),使用乙腈-磷酸盐缓冲液(取1mol/L磷酸二氢钠溶液1.3ml,0.5mol/L磷酸氢二钠溶液32.5mL,加水至1000mL,调节pH至8.0)(50:50)为流动相，检测波长为240nm,进行HPLC分析。将干热灭菌的药物粉末溶解于流动相中并进行分析。HPLC分析表明干热灭菌后的盐酸罗哌卡因和罗哌卡因碱的纯度为99％以上，有关物质在中国药典要求的限度范围内。
实施例28：豚鼠体内的药效实验
使用豚鼠皮内丘疹法评估罗哌卡因缓释凝胶的局部麻醉效果和药效持续时间。试验选用体重在300g-400g的白色成年雄性豚鼠,每组6只，分阳性对照组(0.5％罗哌卡因注射液)、溶媒对照组(生理盐水)、同类对照药组(1.3％布比卡因脂质体注射用混悬液)、缓释凝胶组(4个)，共7组，如下表所示。
序号 受试样品
1 生理盐水
2 0.5％罗哌卡因注射液
3 1.3％布比卡因脂质体注射用混悬液(Exparel,美国Pacira公司)
4 4％盐酸罗哌卡因溶液型凝胶(实施例3)
5 4％盐酸罗哌卡因混悬型凝胶(实施例5)
6 4％罗哌卡因碱混悬型凝胶(实施例6)
7 6％盐酸罗哌卡因混悬型凝胶(实施例7)
试验前一天，将豚鼠背部5×8cm区域的毛剃光，避免在第二天产生刺激。试验时，在豚鼠背部用红色标记丘疹大小。每个标记区域单次皮内注射0.25mL药液。注射药液后于不同时间点用针刺其标记区域，以刺激处肌肉收缩为疼痛指标。在每个丘疹内进行6次针刺，针刺间隔3-5秒，对豚鼠不能做出反应的针刺进行计数。
实验结果如图1所示：
在豚鼠皮内丘疹法中，当豚鼠的针刺无反应次数达到3次以上时，表明受试药物在注射部位有局部麻醉作用。从图中可以看出，0.5％盐酸罗哌卡因注射液的麻醉效果只持续了约2小时，1.3％布比卡因脂质体注射用混悬液的麻醉时间也只有约10小时，4种罗哌卡因缓释凝胶制剂的局部麻醉持续时间显著长于0.5％盐酸罗哌卡因注射液和1.3％布比卡因脂质体注射用混悬液，其中4％盐酸罗哌卡因溶液型凝胶的局部麻醉时间达到了24小时。值得一提的是，同一麻醉药物在动物体和人体里的药效作用时间大多情况下是有差别的，例如1.3％布比卡因脂质体在豚鼠的麻醉作用时间为10小时左右，但在相对应的人体作用时间则为至少24小时(Skolnik A,Gan TJ.New formulations of bupivacaine for the treatment of postoperative pain:liposomal bupivacaine and SABER-Bupivacaine.Expert Opin Pharmacother.2014Aug；15(11):1535-42.)，即2-3倍，由此推算，4％盐酸罗哌卡因缓释凝胶制剂在人体内的麻醉作用时间可达48-72小时。此外，从图中可还以看出，罗哌卡因的盐型(如盐酸盐)或者罗哌卡因游离碱在凝胶中的存在方式(溶解状态或混悬状态)对罗哌卡因缓释凝胶的麻醉持续时间有显著的影响，因此可以通过调整药物在凝胶中的存在形式和药物的盐型来调整药物的释放速率，进而达到调整局部麻醉持续时间的目的。
实施例29不同罗哌卡因缓释凝胶制剂在小型猪体内的药效学实验
试验目的：评价不同罗哌卡因缓释凝胶制剂的局部镇痛效果(镇痛持续时间)。
试验动物：广西巴马小型猪，雄性，6～7周龄，体重3～5Kg。适应性饲养5～7天后进行术后痛模型的建立。
术后痛模型建立方法：麻醉选用异氟烷吸入麻醉。切口定位于左后背距背中线3cm，平行于背中线，切口3cm。待小型猪进入麻醉状态后俯卧/侧卧，择左后背区域备皮。备皮完成后进行术区消毒(75％酒精，碘伏，75％酒精)，并切开预定切口，切开皮肤及筋膜，不损伤肌肉。
试验分组：每组6只，分阳性对照组(0.5％，1.5％和3％盐酸罗哌卡因注射液)、溶媒对照组(生理盐水)、同类对照药组(1.3％布比卡因脂质体注射用混悬液)、罗哌卡因缓释凝胶制剂组(3个)共6组，如下表所示。
序号 受试样品
1 生理盐水
2 0.5％盐酸罗哌卡因注射液
3 1.5％盐酸罗哌卡因注射液
4 3％盐酸罗哌卡因注射液
5 1.3％布比卡因脂质体注射用混悬液(Exparel，美国Pacira公司)
6 1.5％盐酸罗哌卡因溶液型凝胶(实施例1)
7 3％盐酸罗哌卡因溶液型凝胶(实施例2)
8 4％盐酸罗哌卡因溶液型凝胶(实施例3)
给药方式和给药剂量：切口处皮下注射，各组动物分别浸润注射对应的受试制剂，给药体积为：1ml/cm，共3ml，切口两侧各分3点均匀注射，共6点注射，0.5mL/点，两侧注射点相距约1cm，缝合切口。术后3天，每天肌肉注射青霉素预防感染。
镇痛效果检测：选用触觉测量套件(Von Frey)检测术后切口镇痛效果。先采用Von Frey针刺激距切口0.5cm处皮肤，测量其痛觉(逃避反应：扭转90～180度，离开测试者以避开刺激)，测量时间点分别为术前1d(作为基础值)，术后15min、30min、1h、3h、6h、9h、12h、24h、36h、48h、72h每个时间点测量6次，每次间隔5-10S。当针刺后的痛阈值发生变化时，在后续的测定周期中缩短检测时间点的时间间隔，以便较为准确地测定具体的失效时间。最后以6次测定的痛阈值中有3次恢复到手术前基础值水平的时间点作为失效时间。
术后切口恢复情况观察和病理学检查：术前1d(基础值)及术后，每天观察切 口愈合情况并评分。当供试品组与对照组触觉测量结果接近时，即所有动物药效恢复当天，安乐死所有动物，剖检给药局部组织，大体观察，并取给药部位及周围皮肤及皮下筋膜、肌肉组织(取固定切面(切口中部)，另外，当大体观察发现明显病变时，也取该部位病检)进行固定，包埋，切片，苏木精-伊红染色，显微镜下观察。
表1：不同罗哌卡因缓释凝胶制剂在小型猪术后镇痛模型中的药效持续时间(mean±SD，n＝6)
试验样品 药效持续时间(h)
0.5％盐酸罗哌卡因注射液 5.42±1.24
1.5％盐酸罗哌卡因注射液 6.15±1.82
3％盐酸罗哌卡因注射液 7.23±2.05
1.3％布比卡因脂质体注射用混悬液 7.61±1.36
1.5％盐酸罗哌卡因溶液型凝胶(实施例1) 9.74±1.82
3％盐酸罗哌卡因溶液型凝胶(实施例2) 18.65±3.43
4％盐酸罗哌卡因溶液型凝胶(实施例3) 24.61±3.57
在试验过程中，1.5％和3％盐酸罗哌卡因注射液组中的动物都出现了药物相关的中枢神经系统毒性反应，其中3％盐酸罗哌卡因注射液组中的所有受试动物都出现了严重的中枢神经系统毒性反应，所有受试动物在注射给予3％盐酸罗哌卡因注射液后20min(全麻恢复后5min)均出现无法站立，侧卧，四肢摆动，约2.5h恢复。而3个罗哌卡因缓释凝胶制剂组都未发现与给药相关的中枢毒性，表明本发明罗哌卡因缓释凝胶制剂可以有效控制药物的释放，并且具有很宽的安全窗。
实验结果：如表1所示，0.5％和1.5％盐酸罗哌卡因注射液的麻醉效果只持续了约6小时，而3％盐酸罗哌卡因注射液的麻醉效果也只持续了约7小时，表明只增加盐酸罗哌卡因注射液中的药物浓度并不能有效延长其镇痛时间，反而会带来中枢系统神经毒性等安全隐患。1.3％布比卡因脂质体注射用混悬液的麻醉时间只有约8小时，而3种罗哌卡因缓释凝胶制剂的局部麻醉持续时间显著长于三种浓度的盐酸罗哌卡因注射液和1.3％布比卡因脂质体注射用混悬液，其中4％盐酸罗哌卡因溶液型凝胶的局部麻醉时间最长，达到了24小时以上。
值得一提的是，同一麻醉药物在动物体和人体里的药效作用时间大多情况下是有差别的，例如1.3％布比卡因脂质体在小型猪上的麻醉作用时间为8小时左右，但在 相对应的人体作用时间则为至少24小时(Skolnik A，Gan TJ.New formulations of bupivacaine for the treatment of postoperative pain：liposomal bupivacaine and SABER-Bupivacaine.Expert Opin Pharmacother.2014Aug；15(11)：1535-42.)，即2～3倍，由此推算，4％盐酸罗哌卡因缓释凝胶在人体内的麻醉作用时间可达48～72小时。从表中可还以看出，罗哌卡因的浓度对罗哌卡因缓释凝胶的麻醉持续时间有显著影响，因此可以通过调整罗哌卡因缓释凝胶中的药物浓度来达到调整局部麻醉持续时间的目的。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明和范围的前提下本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内，本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (34)

  1. 一种罗哌卡因缓释凝胶制剂，所述罗哌卡因缓释凝胶制剂包括如下重量百分比成分：
    1％～20％的罗哌卡因、14％～22％的泊洛沙姆407、以及余量为水或盐溶液；所述的罗哌卡因选自罗哌卡因游离碱或者其药学上可接受盐。
  2. 根据权利要求1所述的罗哌卡因缓释凝胶制剂，其中所述的凝胶制剂在施用前，罗哌卡因以溶液或者混悬的形式存在于制剂中。
  3. 根据权利要求1所述的罗哌卡因缓释凝胶制剂，其中罗哌卡因重量百分比含量为2-6％；泊洛沙姆407重量百分比含量为16～19％。
  4. 根据权利要求1～3任意一项所述的罗哌卡因缓释凝胶制剂，所述罗哌卡因药学上可接受的盐为罗哌卡因盐酸盐或罗哌卡因甲磺酸盐。
  5. 根据权利要求1所述的罗哌卡因缓释凝胶制剂，其中所述盐溶液pH为2～8.5。
  6. 根据权利要求5所述的罗哌卡因缓释凝胶制剂，其中所述盐溶液为缓冲盐溶液。
  7. 根据权利要求6所述的罗哌卡因缓释凝胶制剂，其中所述缓冲盐溶液为磷酸盐缓冲液、醋酸盐缓冲液、枸橼酸盐缓冲液或氨基丁三醇缓冲液。
  8. 根据权利要求7所述的罗哌卡因缓释凝胶制剂，其中所述磷酸盐缓冲液pH为6.5～7.5。
  9. 一种权利要求1～8任意一项所述的罗哌卡因缓释凝胶制剂的制备方法，所述制备方法包括如下步骤：
    (a)控温小于15℃，在搅拌下往盐溶液中加入处方量的泊洛沙姆407，搅拌均匀溶解后，得到空白凝胶，所述盐溶液pH为7.0-8.5；
    (b)控温小于15℃，将(a)得到的空白凝胶用小于或等于0.22μm的滤膜进行过滤除菌，得无菌空白凝胶；
    (c)称取经热灭菌的罗哌卡因药学上可接受的盐，控温小于15℃，将其混悬于(b)制备得到的无菌空白凝胶中得混悬形式的罗哌卡因缓释凝胶制剂；
    或者
    (a)控温小于15℃，在搅拌下往水或者盐溶液中加入处方量的泊洛沙姆407，搅拌均匀溶解后，得到空白凝胶，所述盐溶液pH为7.0-8.5；
    (b)控温小于15℃，将(a)得到的空白凝胶用小于或等于0.22μm的滤膜进行过滤除菌，得无菌空白凝胶；
    (c)称取经热灭菌的罗哌卡因碱，控温小于15℃，将其混悬于(b)制备得到的无菌空白凝胶中得混悬形式的罗哌卡因缓释凝胶制剂；
    或者
    (a)控温小于15℃，在搅拌下往盐溶液中加入处方量的泊洛沙姆407，搅拌均匀溶解后，得到空白凝胶，所述盐溶液pH为：2.0≤pH＜7；其中优选为2-6.5；
    (b)控温小于15℃，在(a)得到的空白凝胶中加入处方量的罗哌卡因药学上可接受的盐，搅拌溶解，用小于或等于0.22μm的滤膜进行过滤除菌，得溶液形式的罗哌卡因缓释凝胶制剂。
  10. 权利要求1～8任意一项所述的罗哌卡因缓释凝胶制剂在制备局部镇痛药物中的应用，其中所述局部镇痛药物为医疗手术后给药。
  11. 根据权利要求10所述的应用，其中罗哌卡因的给药剂量是0.5mg/Kg至50mg/Kg。
  12. 根据权利要求11所述的应用，其中罗哌卡因的给药剂量是1mg/Kg至25mg/Kg。
  13. 根据权利要求12所述的应用，其中罗哌卡因的给药剂量为2.5mg/Kg至10mg/Kg。
  14. 根据权利要求13所述的应用，其中罗哌卡因的给药剂量为5mg/Kg。
  15. 根据权利要求11～14中任一项所述的应用，其中每隔0.5日至7日给药1次。
  16. 根据权利要求15所述的应用，其中每隔1日至3日给药1次。
  17. 根据权利要求11～16中任一项所述的应用，其中施用于受试对象后维持至少8小时～72小时的持续局部镇痛。
  18. 根据权利要求17所述的应用，其中施用于受试对象后维持至少12小时～48 小时的持续局部镇痛。
  19. 根据权利要求11～18中任一项所述的应用，其中通过选自如下的途径进行给药：皮下注射、皮内注射或者肌肉内注射。
  20. 根据权利要求19所述的应用，其中通过皮下注射给药。
  21. 权利要求1～8任意一项所述的罗哌卡因缓释凝胶制剂在制备局部镇痛药物中的应用，其中包括对受试对象联合给予一种或多种除罗哌卡因缓释凝胶制剂以外的其它活性成分，所述的其它活性成分选自具有镇静催眠或麻醉辅助作用的药物。
  22. 根据权利要求21所述的应用，所述的其它活性成分选自γ-氨基丁酸受体激动剂、γ-氨基丁酸受体增强剂、M受体拮抗剂、N2受体拮抗剂、5-羟色胺受体拮抗剂、钠离子通道拮抗剂或阿片受体激动剂。
  23. 根据权利要求21所述的应用，所述的其它活性成分选自静脉麻醉药、吸入麻醉药或麻醉辅助剂。
  24. 根据权利要求23所述的应用，所述的静脉麻醉药选自丙泊酚、磷丙泊酚钠、咪达唑仑、氯胺酮、硫喷妥钠、羟丁酸钠或依托咪酯，以及它们的药学上可接受的盐；所述的吸入麻醉药选自七氟烷、异氟烷、恩氟烷、地氟烷、甲氧氟烷或氧化亚氮；所述的麻醉辅助剂选自镇静催眠药、抗胆碱药、肌松药、止吐药、局部麻醉药或镇痛药。
  25. 根据权利要求24所述的应用，所述的镇静催眠药选自地西泮、氟西泮、氯氮卓、艾司唑仑、氯硝西泮、格鲁米特、甲丙氨酯、丁螺环酮、咪达唑仑、右美托咪定、氟哌利多、异丙嗪、氯丙嗪、巴比妥、苯巴比妥、戊巴比妥、异戊巴比妥、司可巴比妥或硫喷妥钠，以及它们的药学上可接受的盐；所述的抗胆碱药选自阿托品或东莨菪碱，以及它们的药学上可接受的盐；所述的肌松药选自维库溴铵、罗库溴铵、泮库溴铵、哌库溴铵、米库氯铵、阿曲库铵或琥珀酰胆碱，以及它们的药学上可接受的盐；所述的止吐药选自托烷司琼、帕洛诺司、格拉司琼、多拉司琼、东莨菪碱、赛克力嗪或甲氧氯普胺，包括它们的药学上可接受的盐；所述的局部麻醉药选自利多卡因、罗哌卡因、丙胺卡因、布比卡因、阿替卡因或达克罗宁，以及它们的药学上可接受的盐；所述的镇痛药选自芬太尼、瑞芬太尼、舒芬太尼、阿芬太尼、吗啡、哌替啶、地佐辛、布托啡诺、羟考酮或奈福泮，以及它们的药学上可接受的盐。
  26. 单位剂量形式的权利要求1～8任意一项所述的罗哌卡因缓释凝胶制剂，其中所述单位剂量形式包含20mg～1200mg的罗哌卡因。
  27. 根据权利要求26所述的缓释凝胶制剂，其中所述单位剂量形式包含100mg～600mg的罗哌卡因。
  28. 根据权利要求27所述的缓释凝胶制剂，其中所述单位剂量形式包含200mg的罗哌卡因。
  29. 配制成权利要求1～8任意一项所述的罗哌卡因缓释凝胶制剂，其中该制剂在形成凝胶前的溶液包含5mg/mL～80mg/mL的罗哌卡因。
  30. 根据权利要求29所述的罗哌卡因缓释凝胶制剂，其中该制剂在形成凝胶前的溶液包含10mg/mL～60mg/mL的罗哌卡因。
  31. 根据权利要求30所述的罗哌卡因缓释凝胶制剂，其中该制剂在形成凝胶前的溶液包含20mg/mL～50mg/mL的罗哌卡因。
  32. 一种制造品，它包含：单个或多个剂量的根据权利要求26～31中任一项的制剂以及包装材料。
  33. 根据权利要求32所述的制造品，其中所述的包装材料包含用于容纳所述的单个或多个剂量的制剂的容器。
  34. 根据权利要求33所述的制造品，其中所述的容器包含标签，该标签显示选自如下的一项或多项内容：给予所述制剂所针对的疾病状态、贮藏信息、给药信息和/或关于如何给予所述制剂的用法说明。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116172943A (zh) * 2023-02-15 2023-05-30 上海市肿瘤研究所 一种可注射的缓释凝胶制剂及其制备与应用
RU2812902C2 (ru) * 2019-02-26 2024-02-05 ТиЭлСи БАЙОФАРМАСЬЮТИКАЛС, ИНК. Фармацевтические композиции для применения при лечении боли

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000195A2 (en) * 2000-06-26 2002-01-03 Epicept Corporation Methods and compositions for treating pain of the mucous membrane
CN103816111A (zh) * 2014-02-26 2014-05-28 中国人民解放军第二军医大学 一种罗哌卡因纳米脂质载体温敏原位凝胶及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000195A2 (en) * 2000-06-26 2002-01-03 Epicept Corporation Methods and compositions for treating pain of the mucous membrane
CN103816111A (zh) * 2014-02-26 2014-05-28 中国人民解放军第二军医大学 一种罗哌卡因纳米脂质载体温敏原位凝胶及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HU , JIE ET AL.: "Rheological Properties of Poloxamer 407 Aqueous Solutions", ACTA PHARMACEUTICA SINICA, vol. 46, no. 2, 28 February 2011 (2011-02-28), pages 227 - 231, ISSN: 0531-4870 *
ZHU, QUANGANG ET AL.: "Preparation and Determination of Ropivacaine Hydrochloride Thermosensitive Gel Injection", JOURNAL OF PHARMACEUTICAL PRACTICE, vol. 31, no. 5, 25 September 2013 (2013-09-25), pages 366, 367 and 383, ISSN: 1006-0111 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2812902C2 (ru) * 2019-02-26 2024-02-05 ТиЭлСи БАЙОФАРМАСЬЮТИКАЛС, ИНК. Фармацевтические композиции для применения при лечении боли
CN116172943A (zh) * 2023-02-15 2023-05-30 上海市肿瘤研究所 一种可注射的缓释凝胶制剂及其制备与应用
CN116172943B (zh) * 2023-02-15 2024-01-26 上海市肿瘤研究所 一种可注射的缓释凝胶制剂及其制备与应用

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