WO2014114032A1 - 无成瘾性镇痛缓释递药系统及其制备方法 - Google Patents
无成瘾性镇痛缓释递药系统及其制备方法 Download PDFInfo
- Publication number
- WO2014114032A1 WO2014114032A1 PCT/CN2013/074010 CN2013074010W WO2014114032A1 WO 2014114032 A1 WO2014114032 A1 WO 2014114032A1 CN 2013074010 W CN2013074010 W CN 2013074010W WO 2014114032 A1 WO2014114032 A1 WO 2014114032A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drug
- ropivacaine
- oil
- benzyl alcohol
- analgesic
- Prior art date
Links
Classifications
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- 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
-
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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]
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
- B65B3/003—Filling medical containers such as ampoules, vials, syringes or the like
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B31/00—Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers
- B65B31/003—Adding propellants in fluid form to aerosol containers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B7/00—Closing containers or receptacles after filling
- B65B7/16—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons
- B65B7/161—Sealing filled ampoules
Definitions
- the present invention relates to the field of pharmacy, and mainly relates to a type of non-addictive local anesthesia analgesic sustained-release delivery system.
- pain is considered to be the fifth major vital sign of the human body following respiration, pulse, body temperature, and blood pressure. It has acute and chronic points. Postoperative pain is acute pain, which is the body's tissue damage and repair process. A complex physiological and psychological response, which is a must-have for all postoperative patients, and is one of the most urgent problems to be addressed after clinical practice.
- postoperative pain is different from general physiological pain.
- the main mechanism is postoperative Injury stimulates the reverse flow of cytoplasm in the axons of peripheral nerve cells, which causes the release of substance P at the nerve endings, resulting in increased local vascular permeability and tissue edema.
- the inflammatory pain-induced substances released by the damaged tissue are slow.
- postoperative pain can have a major impact on the function of various organs of the patient, which can cause a series of pathophysiological parameters to change, such as pain leading to abnormal autonomic activity, causing elevated catecholamines in the blood, glucagon Increased secretion, decreased insulin secretion by hyperglycemia, increased secretion of adrenocorticotropic hormone, increased secretion of cortisol, aldosterone and vasopressin, and the like.
- the response in physiological functions can be mainly manifested in the following points: 1. Effects on mental and psychological effects - Pain can cause irritability, depression, fear, anxiety, depression, personality changes; 2.
- Cardiovascular system changes M The elevation of catecholamines accelerates heart rate, increases myocardial contractility, increases cardiac output, peripheral vasoconstriction, increased systemic resistance, elevated blood pressure, and even painful shock during severe pain; 3.
- Autonomic nervous system changes can cause autonomic nerves Disorders, such as sleep disorders, loss of appetite, nausea and vomiting, constipation, sweating, blood pressure changes, etc.;
- changes in the immune system pain mainly causes the decline of immunoglobulin, resulting in slow recovery of the body, the function of phagocytic cells produces varying degrees Reduced, humoral immunity and cellular immune function have a certain degree of inhibition, slow synthesis of protein in the body, accelerated decomposition, affecting wound healing; 5, social harm: high incidence of pain, difficult diagnosis and treatment, prolonged disease, medical cost,
- Postoperative analgesia can not only relieve postoperative pain, but also stabilize various physiological indicators of patients, which can reduce the incidence of perioperative complications, improve prognosis and significantly reduce hospitalization days.
- Clinical medicine The drugs for postoperative analgesia and the modes of administration are as follows - Clinical medicine:
- Opioid analgesics morphine, fentanyl, sufentanil, buprenorphine, tramadol, alfentanil, remifentanil, etc .;
- non-steroidal anti-inflammatory painkillers aspirin, indomethacin, aminopyrine, phenylbutazone and so on.
- patient-controlled analgesia intravenous infusion, epidural infusion, ventricle
- transdermal administration such as fentanyl paste
- intracavitary administration constant-velocity intravenous infusion pump input method
- Balanced analgesia preemptive analgesia
- dura mater oral mucosal administration
- nasal mucosal administration etc.
- anesthetic drugs In future research on postoperative analgesia, anesthetic drugs, new opioids, non-retained analgesic drug sustained release preparations, multimodal analgesia, and surgical site near nerve block will be hot topics in this field.
- the purpose is mainly to improve the analgesic intensity and reduce adverse reactions, such as: continuous peripheral nerve block, patient-controlled area analgesia technique, local nerve block technique, etc., such as mid-humeral brachial plexus block, lumbar plexus block, stock Nerve-sciatic nerve block and so on.
- Ropivacaine is a new type of long-acting ffi amine local anesthetic that has been synthesized in recent years. It is the result of optimization of bupivacaine. Its basic structure is 1 propyl 2, 6-piperidinamide hydrochloride. L-isomer ( l-propy l-2, 6-pipeco loxylidide) , ⁇
- the ropivacaine molecule is biphasic from the dura mater: its half-life phase is 14 min and the slow phase is 4 h. Most of the cyclamate binds to plasma proteins (94%) in a concentration-dependent manner with a steady-state volume of 47 L. Its mechanism of action is the same as that of local anesthetics such as procaine, lidocaine, and bupivacaine. It acts by inhibiting nerve cell nanochannels and blocking nerve excitation and conduction [3 ' 4] .
- ropivacaine has obvious physicochemical properties, that is, the separation of sensory-motor nerve block is obvious at low concentration, the anesthesia and pain treatment effect is exact, the cardiotoxicity is small, and the action time is long (a clinical injection can be performed once). Continued analgesia for about 8 hours, etc., suggesting that it will be more widely used in future clinical applications.
- the object of the present invention is to provide a novel non-addictive local anesthesia sustained release analgesic delivery system, the main drug of which refers to an anesthetic analgesic, including a single local anesthetic, including local anesthetics and opioids.
- Analgesic (medium or low doses that do not cause addiction), one of non-steroidal anti-inflammatory analgesics, a mixture of two or more, a vehicle, and a corresponding sustained release agent.
- the delivery system of the present invention can be understood as a pharmaceutical composition, a pharmaceutical composition, a formulation or a pharmaceutical preparation.
- the delivery system is characterized by: an oily or oily solution delivery system, and the formulation is stable and uniform.
- the basic feature of the analgesic in the delivery system is non-addictive, including analgesic drugs with anesthesia and no anesthesia.
- Anesthetic analgesics refer to local anesthetics, including: procaine, lidocaine, bupivacaine, levobupivacaine, ropivacaine, tetracaine, dibucaine,
- the free base of eticacaine, the free base is also preferred, and also includes the salts thereof, and the salts thereof mainly include: mesylate, hydrochloride, citrate, sulfate, lactate, succinate,
- An anesthetic analgesic may be one, two or two of fumarate, glutamate, ethyl sulfonate, besylate, citrate, salicylate, maleate, etc. More than one composition.
- roachine free base and salts thereof may be preferred, and the analgesic may be one, two or more of them.
- ropivacaine free base has the best effect.
- Anesthetic drugs without anesthesia mainly include non-steroidal anti-inflammatory drugs and opioids (medium and low doses that do not cause addiction).
- non-steroidal anti-inflammatory drugs include: aspirin, diclofenac sodium, ibuprofen, naproxen, naproxen, sulindac, mefenamic acid, chlorinated acid, diclofenac, flufenamic acid, B ratio Roxicam, Meloxicam, Aminopyrine, Analgin, Phenacetin, Paracetamol, Parecoxib, Rofecoxib, Valdecoxib, Nimesulide.
- opioid analgesics include: hydromorphone, dextrozine, naloxone, naltrexone, morphine, fentanyl, sufentanil, codeine, patidine, pentazocine, Methadone, etorphine, chlorpheniramine, buprenorphine, tramadol, alfentanil, remifentanil.
- analgesics may also be one of local anesthetic analgesics and non-organic anti-inflammatory analgesics and opioids (medium and low doses that do not cause addiction), two a mixture of two or more kinds; or a mixture of a local anesthetic analgesic and a non-retained analgesic anti-inflammatory analgesic, a mixture of two or more; or a local anesthetic analgesic and An opioid (medium or low dose that does not cause addiction) an analgesic, a mixture of two or more.
- the dose of the opioid analgesic administered in the formulation is emphasized as a medium, low or microdose that does not cause addiction.
- the non-steroidal anti-inflammatory drug and the opioid analgesic in the preparation may be in a free state or combined with an acid or a base to form a corresponding salt, and an analgesic may be selected as one of them. Or a mixture of more than two.
- the analgesic sustained-release delivery system of the present invention comprises an anesthetic analgesic and a liquid adjuvant for a pharmaceutically active ingredient, wherein the concentration of the anesthetic analgesic is 1-160 mg/ml (wA, and the liquid adjuvant is sustained by the drug solvent and the drug.
- the composition of the drug, the drug solvent ratio is 1% - 75% (v / v), the drug sustained release agent ratio is 25% - 99% "' / ⁇ ).
- the preferred drug delivery system has the following composition: an analgesic concentration of 1-90 mg/m! (w/v), and an excipient composition ratio of preferably: a drug solvent ratio of 1% - 50% (v/v), the ratio of drug release agent is 50% - 99% (v / v).
- the most preferred delivery system of the present invention comprises: an analgesic concentration of 12-50 mg/ml (w/v), an excipient composition ratio of: drug vehicle 10% - 40% C v/v), a drug sustained release agent 60% - 90% (v/v) c,
- the choice of drug solvent and sustained release agent mainly refers to the current products on the market.
- the selected examples are mainly oily long-acting intramuscular injections, mainly as shown in the following table - Table 1: Some commonly used oily long-acting intramuscular injections currently in circulation in the market Statistics
- castor oil contraceptive drug solvent refers to the dissolution of local anesthetic analgesics (may include a local anesthetic analgesic, a mixture of two or more; or dissolve local anesthetic analgesics A natural or synthetic organic solvent, or a mixture of solvents, that does not cause addictive low or medium doses of opioid analgesics, non-organic anti-inflammatory analgesics.
- the drug solvent preferably includes benzyl alcohol, ethanol, monoethyl oleate, ethyl lactate (green solvent, drug) 3 ⁇ 4 excipient, low toxicity, and tetrahydrofuran polyglycol ether (Medical Excipient Handbook, Fourth Edition, UK) RC Luo, Zheng Junmin translation, 3 i3- 314 pages), one of benzyl benzoate, a mixture of two or more, of which, preferably, ethanol, benzyl alcohol, benzyl benzoate, lactate B a mixture of esters, tetrahydrofuran polyglycol ethers, two or more.
- the drug sustained release agent may be soybean oil, or may be selected from sesame oil, sunflower oil, peanut oil, castor oil, corn oil, rapeseed oil, olive oil, cottonseed oil or other natural vegetable oil or artificially modified semi-natural oil of natural vegetable oil (such as: hydrogenated castor oil, etc.), oil purification and corresponding derivatives.
- the drug sustained release agent may also be selected from synthetic oils and fats, mainly including medium chain (carbon chain length (VC 12 ) oleate (for example: octanoic acid phthalate, one of phthalic acid triglycerides or a mixture of the two) , long chain (carbon chain length C 14 - C 24 ) trioleate, triacetin or other corresponding derivatives, ethyl oleate, white oil, dimethicone, low melting animal fats and oils.
- medium chain (carbon chain length (VC 12 ) oleate for example: octanoic acid phthalate, one of phthalic acid triglycerides or a mixture of the two
- long chain carbon chain length C 14 - C 24
- trioleate triacetin or other corresponding derivatives
- ethyl oleate white oil, dimethicone, low melting animal fats and oils.
- the drug sustained-release preparation may also be one of a natural vegetable oil, a semi-natural vegetable fat artificially modified, a purified fat, a synthetic fat, and a low-melting animal fat, a mixture of two or more kinds.
- the drug sustained release agent is more preferably soybean oil, and may preferably be one of oleic acid ethyl alcohol, castor oil, sesame oil, peanut oil, a mixture of two or more, and most preferably soybean oil, ethyl oleate, hydrazine.
- sesame oil two or more
- the corresponding solvent and slow release sputum should be non-irritating (or low irritant), and need to be refined, sterilized and pyrogen.
- anesthetic analgesic a part of the preferred delivery system of the present invention, comprising an anesthetic analgesic and a pharmaceutically acceptable adjuvant.
- the anesthetic analgesic concentration is 30-50 mg / ml (wA ? excipient composition ratio: the drug solvent ratio is 10% - 40% (v / v), the drug sustained release agent ratio is 60% - 90% ( v/v).
- the drug solvent is selected from the group consisting of: phenylhydrin, benzyl benzoate, and anhydrous ethanol.
- the drug sustained release agent is selected from the group consisting of: soybean oil, ethyl oleate, and eucalyptus oil.
- Another object of the present invention is to provide a method for preparing an addictive anesthesia analgesic sustained release delivery system.
- the preparation method of the non-addictive anesthesia analgesic sustained-release delivery system of the present invention comprises the following steps - A preparation of a stock solution; one of two or more kinds of anesthetic analgesics which are precisely weighed in a certain amount The mixture is dissolved in a certain volume of the drug solvent, ultrasonically or vortexed until the drug is completely dissolved, and then a prescribed amount of one, two or more sustained release agents are added, and ultrasonic or vortex mixing is used to prepare the desired sustained release. Drug system stock solution.
- B Aseptic dispensing Under sterile conditions, remove the prepared drug solution through the membrane to remove impurities, remove bacteria, and then dispense in a vial or ampoule, a refillable syringe, a spray bottle, an aerosol bottle (if it is an aerosol) Bottles, you need to add the drug solution, then fill the propellant, and finally cover), etc., the pressure plug, the gland, can be used for the sustained release drug delivery system for analgesia.
- compositions of the present invention can be prepared into a variety of different pharmaceutical dosage forms.
- composition of the present invention can be prepared into the following dosage forms: an injection, a spray, an aerosol, an ointment, a cream, a coating agent, a plaster, etc., preferably an injection, a coating agent, an aerosol, a spray, and most preferably an injection. .
- the drug carrying device may be a vial, an ampoule, a fillable syringe, a spray bottle or an aerosol bottle.
- the non-addictive local anesthesia analgesic sustained-release delivery system is implemented by injecting analgesia to nerve nodes and nerve roots near the wound; single or multi-point injection of muscle, subcutaneous single or multiple injection or incision Applying, spraying, invigorating and relieving pain; continuous or intermittent slow administration of analgesia with an automatic, semi-automatic, manual infusion pump.
- Still another object of the present invention is to demonstrate the clinical application of the delivery system of the present invention in the preparation of a medicament having local analgesic action.
- a further object of the present invention is to demonstrate the clinical use of the delivery system, which is mainly for providing anesthesia and analgesic pain after surgery, and can also be used for mechanical injury wounds such as cuts, abrasions, stab wounds, burn wounds, burn wounds.
- Anesthetic analgesia can also be anesthetic analgesia caused by cancer.
- the invention has no addictive anesthesia analgesic sustained release delivery system (preferably ropivaca because of ⁇ description):
- the present invention prepares a sustained-release delivery system for anesthesia and analgesia by using ropivacaine as a main drug.
- the most characteristic feature is non-addictiveness. It can be used for local anesthesia and analgesia in the wound or other painful parts of the body, especially local anesthesia and analgesia of the wound after surgery.
- the administration method is single or multi-point injection of wound muscle, single or multiple injection under the skin. At present, there is no sustained release drug delivery system prepared from such drugs in China and abroad, and it is used in post-operative anesthesia and analgesia.
- the refined natural vegetable oil or synthetic oil is used as an oily sustained release agent (natural vegetable oil such as soybean oil, peanut oil, sesame oil, castor oil, etc. is a common auxiliary material for vaccines, contraceptives, and body vitamin supplement injections. It is used in the field of wound analgesia such as postoperative wounds, inflammatory wounds, mechanically damaged wounds, burnt wounds, and war wounds.
- the present invention proposes that a mixture of any one of benzyl alcohol, benzyl benzoate and ethyl oleate and ethanol has good miscibility with soybean oil, sesame oil, corn oil, etc., and is used as the present invention.
- the prescription system of the prescription is used as the present invention.
- the present invention finds a mixed solvent of benzyl benzoate, benzyl alcohol, ethanol, or both, which can significantly improve the drug loading of the drug delivery system compared with a single solvent, and has a good mutual interaction. Solubilization (in the experiment, the drug was selected as: roachine free base, ropivacaine mesylate, ropivacaine hydrochloride).
- the sustained-release preparation was prepared with ropivacaine as the main drug, and the animal (rat foot plate hot plate stimulation method, postoperative pain model Von Frey needle mechanical pain test method)
- the duration of the neurocatheter block of mepivacin injection is about 2 hours (the literature shows that the analgesic time of the human is about 6-8 hours), while the sustained release of the present invention
- the drug delivery system selected drug ropivacaine free base or mesylate) works quickly and the duration of action is significantly prolonged.
- the preferred active drug, ropivacaine, in the delivery system of the present invention has a local vasoconstriction for 3 ⁇ 4, and after local administration, the amount of wound bleeding can be reduced, and the wound can be swollen and healed.
- the active drug ropivacaine used in the delivery system of the present invention has local vasoconstriction, and after local administration, the dose of the drug into the blood circulation system through the blood vessel can be reduced, and the cardiotoxicity and nerve of the drug are partially reduced. Toxicity, compared with central analgesics, clinical deception is significantly less.
- the analgesic pump used by the patient after surgery is used for constant analgesia or epidural infusion of drugs for analgesia.
- the clinical main wounds are close to intramuscular injection and wounds.
- the infiltration, ganglion injection, and the like are applied locally, so the product of the present invention is convenient to use and safer.
- the preferred ropivacaine sustained-release delivery system of the present invention in addition to being used for local anesthesia and analgesia after surgery, can also be prepared into different administration forms, and can be used for a blistering disease, a lesion or a drug.
- neuropathic pain facial neuralgia, trigeminal neuralgia, joint pain, muscle pain, inflammatory pain of the external hemorrhoids, pain caused by cancer, cuts, abrasions, Stab wounds and other mechanical damage wounds, pain, burn wounds, pain relief, burn wounds and pain relief, as well as gunshots, explosions, gunpowder, chemical-induced pain caused by war wounds, etc.
- the form of administration is diverse, can be injected, smeared, sprayed Wait.
- the most preferred main drug ropivacaine free base of the present invention, the local anesthetic sustained-release preparation prepared by the same, the ropivacaine has certain characteristics of motor nerve and sensory nerve phase separation, local anesthesia and analgesia
- the motor block is lighter and the patient's exercise recovers faster.
- Figure 1 Time-lapse curve of sensory nerve block in rats with ropivacaine sustained-release preparation (group 1)
- FIG. 1 Ropivacaine sustained-release preparation (Group 2) Time curve of sensory nerve block in rats
- Figure 4 Ropivacaine sustained-release preparation (Group 4) Time curve of sensory nerve block in rats
- Figure 5 Time-lapse curve of intramuscular sensory nerve block in ropivacaine sustained-release preparation (Group 5)
- Figure 6 Ropivacaine sustained-release preparation (Group 6) Time curve of sensory nerve block in rats
- Figure 7 Ropivacaine sustained-release preparation (Group 7) Time curve of sensory nerve block in rats
- Figure 8 Ropivacaine sustained-release preparation (group 8) Time curve of sensory nerve block in rats
- Figure 9 Intramuscular injection of different groups of ropivacaine sustained release preparations (postoperative pain model) Time chart of sensory nerve block time
- the prescriptions 1-8 are from the formulation of Table 4.
- compositions, preparation method and use of the present invention are further illustrated by the following Experimental Examples and Examples, but are not to be construed as limiting.
- the experimental results show that the solubility of ropivacaine free base in anhydrous ethanol and benzyl alcohol is more than 150 mg/rn! at room temperature, and the solubility is better.
- benzyl benzoate, ethyl lactate, tetrahydrofuran The solubility of the glycol ether is second; the ropivacaine mesylate in the absolute ethanol, benzyl alcohol, ethyl lactate exceeds 190 mg / mi, the solubility is good, the solubility in the monoacetin is the second; hydrochloric acid
- the solubility of ropivacaine in benzyl alcohol is more than i00 mg/mi, and the solubility is better.
- the drug solvent can be selected from the group consisting of anhydrous ethanol, benzoquinone, benzyl benzoate and ethyl lactate.
- monoglyceride and tetrahydrofuran polyglycol ether can be selected, wherein anhydrous ethanol and benzyl alcohol are compared. it is good.
- Anhydrous ethanol, benzyl alcohol, ethyl lactate, benzyl benzoate, monoterpene monoacetate, tetrahydrofuran polyglycol ether are used as drug solvents, respectively, with ethyl oleate, phthalic acid first oil ester, castor oil Soybean oil, corn oil, sesame oil, medium chain Gan' oil: triester is miscible, and white oil and hydrogenated castor oil can be added to some mixed solvents to observe mutual miscibility.
- Preferred partial delivery systems such as:
- Benzene alcohol / benzyl benzoate chain first oil triester benzyl alcohol / ethyl oleate / soybean oil
- Benzyl alcohol /ethyl oleate / soybean oil / white oil
- Procaine and tetracaine have slight precipitation in the ethyl oleate//soybean oil delivery system, and the other local anesthetic drugs are in oil.
- the solubility in the acid ethyl ester/soybean oil delivery system is good.
- Experimental Example 7 Effects of different groups of intramuscular injection on wound healing in rats Experimental grouping and dosage: SD rats, 230-250 g, male, 65 or so, adapted for feeding for 2-3 days, screened according to body weight and divided into 10 groups, each group was 6.
- each group was model control group, ropivacaine injection group, ropivacaine preparation - group 1, ropivacaine preparation group-2, ropivacaine preparation - Group 3, ropivacaine preparation-4, ropivacaine preparation-5, ropivacaine preparation 6, ropivacaine preparation-7, ropivacaine preparation-8 (specific prescription) See Table 4 for the specifications, the model control group was injected with normal saline, ropivacaine injection group, and ropivacaine preparation-] ⁇ 8 groups were administered at 0.5 ml/head.
- Basic experimental protocol procedure After screening and grouping according to body weight, the rats in each experimental group were subjected to back hair removal.
- each group dose is 0.5 ml /
- the needle tail is facing the front side. Raise the needle 45 degrees, until the needle tip reaches the bone and retract 1mm, injecting the drug.
- Test method The heat radiation/lifting method allows the rat to stand freely on the glass plate, and then the test is given after the animal is quiet.
- the radiant heat source is focused by a lens and emits a light beam with a diameter of about 4 mm.
- the irradiation intensity is adjusted (about 52' )), and the radiation source is placed under the glass plate, and the glass plate is irradiated to the bottom of the rat's hind paw.
- the light source is connected to the timer, and when the illumination starts, the stopwatch is started at the same time.
- the measured time interval is the evasion Should be (lifting) the incubation period.
- the upper limit of the exposure time is 15 sec, and the excess is 15 sec.
- the time from the placement of the hot plate to the retraction of the test paws was recorded, and each hind paw was measured twice (to prevent the plantar burn in rats, if the first measurement was 13 sec, the second test was not needed).
- the interval between consecutive measurements of the same hind paw should be greater than 10 mi.
- the average value of the second determination is the pain threshold for each hind paw.
- Level 1 The paws move normally, can be dorsiflexed, stretched, and everted;
- the paw can be dorsiflexed, curled (bent and adducted) and then stretched out but weakly stretched;
- the paw can be dorsiflexed, but can not be stretched after curling (bending and adduction);
- Grade 4 The paw loses dorsiflexion, the ability to curl and stretch, and the rat has gait defects.
- i level indicates no motion block
- level 2 indicates partial motion block
- level 3 and level 4 indicate complete motor block, lh, 2h, 4h, 8h, 24h, 32h, 48h, 56h after administration.
- 72h the motor block of the hind paw of the rats in each group was observed.
- the evaluation grades were recorded and the duration of motor block was examined.
- SPSS software was used for statistical processing. The data were compared by one-way variance. The results were expressed as mean ⁇ standard deviation; the motor block rating score was converted (level 1 is equal to 2, level 2 is equal to 2, and level 3 is equal to 3 , Level 4 is equal to 4), and then compared using the rank sum test, corpse ⁇ (X G5 indicates statistical difference, ⁇ 0.01 indicates significant statistical significance.
- Postoperative pain model establishment method Rats were anesthetized by intraperitoneal injection of 10% chloral hydrate, about 0.5 cm from the right heel, ffi hand The knife cuts the right hind paw of the rat vertically into a 1 cm long wound, and then finds the hamstrings and muscles under the skin.] 3 ⁇ 4 small elbow scorpion picks up, and vertically cuts 3 4 knives on it (maintaining ribs) With muscles constantly, causing damage, blotting with absorbent cotton, sutured the skin of the foot, and finally injecting 50 mg of ampicillin sodium into the left hind limb to prevent infection.
- Administration mode It is located on the line between the right femur of the rat and the ischial tuberosity, close to the right femur greater than 1/3 of the line.
- the needle is raised 45° upwards in the anterior medial direction until the needle tip hits the bone and then retracts 1mm, and finally the drug is injected.
- Detection method mechanical tingling-lifting method: Let the rat stand freely on the iron net, wait for it to be quiet, use the electronic 3 ⁇ 4iiFrey to measure the right hind foot, take the max value as the pain threshold, and each rat has Liu 2 Times, the interval is more than 5 minutes, and the average is taken.
- Determination time Before administration, Ihu 2h, 4hu 8h, 24h, 32h, 48h, 56h, 72h after administration.
- Measurement data were compared by one-way analysis of variance, expressed as mean ⁇ standard deviation ( ⁇ ⁇ ), p ⁇ (), 05 means statistically significant, P ⁇ 0.01 means significant statistical significance.
- Ropivacaine mesylate is formulated according to commercially available specifications .
- Methanesulfonic acid Luo Pecaine Injection Group 1 8.02 ⁇ 2.45 61.25 ⁇ 5.28** 50,47 ⁇ 3,90** 10.2 ⁇ 1.99** 1:1.4 ⁇ 3.32:12,25 ⁇ 4,58 14,23 ⁇ 3, 74 15,48 ⁇ 3,04 16,03 ⁇ 3,14 18.22 ⁇ 4.
- Ropivacaine sustained-release preparation 2 groups 8,35 ⁇ 2,36 59.3 ⁇ 6.75** 44.51 ⁇ 6.05 ⁇ 53.32 ⁇ 6.42« 45.05 ⁇ 3.93 « 39.72 ⁇ 3.41 « 20.58 ⁇ 3.5Q « 17.65 ⁇ 7.34* 16,57 ⁇ 4,05 18,92 ⁇ 7.
- Solvent 2 group 8.83 ⁇ 2,34 16.2 ⁇ 10.50** 9,8 ⁇ 1,92 10.63 ⁇ 3.25 * 11.77 ⁇ 2.54 12,57 ⁇ 5, 17 14.8 ⁇ 3.86 14,13 ⁇ 4, 15 15,03 ⁇ 2.51 16.57 ⁇ 5.
- Ropivacaine sustained-release preparation 3 groups 8.55 ⁇ 2.37 53.17 ⁇ 13.13« :47,58 ⁇ 7,44** 47.17 ⁇ 5.16** 41.67 ⁇ 10.18** 38.82 ⁇ 6.54** 23,88 ⁇ 8,01** 22.421:8.56* 16.53 ⁇ 4.92 18,5 ⁇ 4, solvent 3 groups 8,87 ⁇ 3,63 20, 65 ⁇ 12,83*.
- Ethyl oleate (or vegetable oil such as soybean oil)
- Preparation process Take a prescribed amount of benzyl alcohol, put 10 mg of ropivacaine free base, vortex, fully dissolve it to obtain a drug solution; then slowly add vegetable oil such as ethyl oleate or soybean oil to the drug solution To 10 ml, vortex to mix, membrane filtration to remove impurities, sterilization, sub-package to vial, sealed, light-tested, packaged.
- vegetable oil such as ethyl oleate or soybean oil
- Ethyl oleate (or vegetable oil such as soybean oil) added to 2.5 mi
- Preparation process Take the prescribed amount of benzyl alcohol, slowly add 1600 mg of ropivacaine free base in batches, vortex, and fully dissolve to obtain a drug solution; then slowly add ethyl oleate (or vegetable oil such as soybean oil) Into the drug solution to 10 mi, vortex to mix, membrane filtration to remove impurities, sterilization, dispense into the vial, sealed, after the light inspection, packaging.
- ethyl oleate or vegetable oil such as soybean oil
- Ethyl oleate (or castor oil) is added to 10 ml
- Preparation process Take the prescribed amount of ethanol, slowly put 10 mg of ropivacaine free base to vortex, fully dissolve it to obtain the drug solution; then slowly add ethyl oleate (or castor oil) to the drug solution to 10 Ml, vortex mixing, membrane filtration, sterilization, disintegration into the vial, sealed, after the light inspection, packaging.
- ethyl oleate or castor oil
- Ethyl oleate (or castor oil) is added to 10 ml
- Preparation process Take the prescribed amount of ethanol, slowly inject 750 mg of ropivacaine free base in batches, vortex, and fully dissolve to obtain a drug solution; then slowly add ethyl oleate (or castor oil) to the drug solution.
- ethyl oleate or castor oil
- Formulation formulation Roscaine free base 10 mg
- Ethyl oleate (or vegetable oil such as soybean oil) is added to 10 ml
- Preparation process Take the prescribed amount of benzyl benzoate, put: i O mg ropivacaine free base, vortex, make it fully dissolved, get the drug solution; then slow the ethyl oleate (or vegetable oil such as soybean oil) Add to the drug solution to 10 mi, vortex to mix, filter and remove impurities, except if, dispense into a vial, seal, and pass the lamp after inspection.
- benzyl benzoate put: i O mg ropivacaine free base, vortex, make it fully dissolved, get the drug solution; then slow the ethyl oleate (or vegetable oil such as soybean oil) Add to the drug solution to 10 mi, vortex to mix, filter and remove impurities, except if, dispense into a vial, seal, and pass the lamp after inspection.
- Ethyl oleate (or vegetable oil such as soybean oil) added to O mi
- Preparation process Take the prescribed amount of benzyl benzoate, slowly add 500 mg of ropivacaine free base, vortex, and fully dissolve it to obtain a drug solution: then slowly add ethyl oleate (or vegetable oil such as soybean oil) Into the drug solution to 10 mi, vortex to mix, membrane filtration to remove impurities, sterilization, dispense into the vial, sealed, after the light inspection, packaging.
- ethyl oleate or vegetable oil such as soybean oil
- Formulation formulation Roscaine free base 50 mg
- Ethyl oleate (or vegetable oil such as soybean oil) is added to 10 ml
- Preparation process take a prescribed amount of benzyl alcohol and a small amount of ethyl oleate (or vegetable oil such as soybean oil), put 50 mg of ropivacaine free base, vortex, fully dissolve to obtain a drug solution; then oleic acid B Ester (or vegetable oil such as soybean oil) is slowly added to the drug solution to 10 nil, vortexed and mixed, membrane filtered to remove impurities, sterilized, dispensed into a vial, sealed, and qualified after lamp inspection.
- ethyl oleate or vegetable oil such as soybean oil
- Ethyl oleate (or vegetable oil such as soybean oil) is added to 10 ml
- Preparation process Take the prescribed amount of benzyl alcohol, slowly put 1000 mg of ropivacaine free base, vortex, fully dissolve it to obtain the drug solution; then slowly add ethyl oleate (or vegetable oil such as soybean oil) to the drug Mix 10 ml into the solution, vortex and mix, remove the membrane by filtration, remove the bacteria, dispense into the vial, seal, and pass the lamp after inspection.
- ethyl oleate or vegetable oil such as soybean oil
- Ethyl oleate (or castor oil) is added to 10 ml
- Ethyl oleate (or castor oil) is added to 10 ml
- Preparation process Take the prescribed amount of ethanol, slowly inject 600 mg of ropivacaine free base, vortex, and fully dissolve to obtain a drug solution; then slowly add ethyl oleate (or castor oil) to the drug solution to 10 mi, vortex mixing, membrane filtration, removal, sterilization, dispensing into vials, sealing, after passing the lamp inspection, packaging.
- ethyl oleate or castor oil
- Preparation process Take the prescribed amount of benzyl alcohol, slowly inject 300 mg of romadin free base, gently heat and vortex to fully dissolve to obtain a drug solution; then slowly add ethyl oleate to the drug solution to 0 Ml, vortex mixing, membrane filtration, sterilization, sterilizing, dispensing into vials, sealing, after passing the lamp inspection, packaging.
- Preparation process Take the prescribed amount of ethanol, slowly put 250 mg of ropivacaine free base, gently heat and vortex, fully dissolve it to obtain the drug solution; then slowly add ethyl oleate to the drug solution to i0 mi , vortex mixing, membrane filtration, sterilization, sterilizing, dispensing into the vial, sealing, after the light inspection, packaging.
- Preparation process Take the prescribed amount of benzyl alcohol, ethanol, slowly input 450 nig ropivacaine free base, gently heat and vortex, fully dissolve, to obtain a drug solution; then slowly add ethyl oleate to the drug solution Mix to 10 ml, vortex,
- Preparation process Take the prescribed amount of benzyl alcohol, slowly add 350 mg of ropivacaine free base and gently heat and vortex to fully dissolve to obtain the drug solution; then slowly add castor oil to the drug solution to 10 ml vortex Mix, filter, remove impurities, remove bacteria, dispense into a vial, seal, and pass the lamp after inspection.
- soybean oil is slowly added to the drug solution to 10 ml, and the mixture is mixed, and the membrane is removed by filtration, sterilized, dispensed into a vial, sealed, and the lamp is qualified, and then packaged.
- Preparation process Take the prescribed amount of ethanol, slowly input 250 mg of ropivacaine free base, gently heat and vortex, fully dissolve it to obtain the drug solution; then slowly add castor oil to the drug solution to 10 mi, vortex Rotate and mix thoroughly, remove the membrane by filtration, remove the bacteria, dispense into the vial, seal, and pass the lamp after inspection.
- Preparation process take the prescribed amount of benzyl alcohol, ethyl oleate, slowly input 300 mg ropivacaine free base, gently heat and vortex, fully dissolve, to obtain a drug solution; then slowly add soybean oil to the drug solution Medium to 10 ml, vortex mixing, membrane filtration, sterilization, sterilizing, dispensing into vials, sealing, after passing the lamp inspection, packaging.
- Preparation process Take a prescribed amount of benzyl alcohol, benzoic acid benzylic acid, 300 mg of ropivacaine free base, vortex, fully dissolve, to obtain a drug solution; then slowly add large ⁇
- Preparation process Take the prescribed amount of ethanol, ethyl oleate, put 250 mg of ropivacaine free base, vortex, fully dissolve it to obtain a drug solution; then slowly add soybean oil to the drug solution to 10 mi, Vortex to mix, membrane filtration to remove impurities, sterilization, sub-package into the vial, sealed, after the light inspection, packaging.
- Preparation process Take the prescribed amount of ethanol, benzyl benzoate, slowly inject 300 mg of ropivacaine free base, gently heat and vortex to fully dissolve to obtain a drug solution; then slowly add soybean oil to the drug solution Medium to 0 mi, vortex mixing, membrane filtration, removal, sterilization, dispensing into vials, sealing, after passing the lamp inspection, packaging.
- Formulation formulation Roscaine free base 450 mg
- Castor oil is added to 10 mi
- Preparation process Take the prescribed amount of benzyl alcohol, benzyl benzoate, slowly put 450 mg ropivacaine free base, gently heat and vortex, fully dissolve it, get the drug solution: slowly add castor oil to the drug Mix 10 ml into the solution, vortex and mix, filter and remove impurities, filter the bacteria, dispense into the vial, seal, and pass the lamp after inspection.
- Preparation process Take the prescribed amount of ethanol, ethyl oleate, slowly inject 300 mg of ropivacaine free base, gently heat and vortex to fully dissolve to obtain a drug solution; then slowly add castor oil to the drug solution Medium to 10 ml, vortex mixing, membrane filtration, sterilization, sterilizing, dispensing into vials, sealing, after passing the lamp inspection, packaging.
- Preparation process Take the prescribed amount of ethanol, benzyl benzoate, put 400 mg of ropivacaine free base, gently heat and vortex, fully dissolve to obtain the drug solution; then slowly add castor oil to the drug solution To i0 mi, vortex to mix, membrane filtration to remove impurities, sterilization, dispense into the vial, seal, after the light inspection, packaging.
- Castor oil is added to ⁇ 0 mi
- Preparation process Take the prescribed amount of ethanol, benzyl benzoate, put 500 mg of ropivacaine free base, gently heat and vortex, fully dissolve to obtain the drug solution; then slowly add castor oil to the drug solution to 10 ml, vortex mixing, membrane filtration, sterilization, sterilizing, dispensing into vials, sealing, after passing the lamp inspection, packaging.
- Formulation formulation Ropivacaine mesylate 120 mg
- Preparation process Take the prescribed amount of ethanol, put 20 mg of ropivacaine mesylate, vortex, and fully dissolve to obtain the drug solution; then slowly add ethyl oleate to the drug solution to 10 ml, vortex Mixing hooks, membrane filtration and impurity removal, except if, sub-packaging into vials, sealing, after passing the lamp inspection, packaging.
- Formulation formulation Ropivacaine mesylate 120 mg
- Ethyl oleate (or vegetable oil such as soybean oil) is added to ⁇ 0 mi
- Preparation process Take a prescribed amount of benzyl alcohol, put 120 mg of ropivacaine mesylate, vortex, and fully dissolve it to obtain a drug solution; then slowly add ethyl oleate (or vegetable oil such as soybean oil) to the drug. Mix 10 ml into the solution, vortex and mix, remove the membrane by filtration, remove the bacteria, dispense into the vial, seal, and pass the lamp after inspection.
- ethyl oleate or vegetable oil such as soybean oil
- Formulation formulation Ropivacaine mesylate 120 mg
- Ethyl oleate (or vegetable oil such as soybean oil) added to 10 mi
- Preparation process Take the prescribed amount of benzyl alcohol, ethanol, slowly put 120 mg of ropivacaine mesylate, vortex, fully dissolve it to obtain the drug solution; then slow the ethyl oleate (or vegetable oil such as soybean oil) Add to the drug solution to 10 mi, vortex to mix, filter to remove impurities, remove bacteria, dispense into the vial, seal, after the lamp is qualified, package.
- Preparation process Take a prescribed amount of ethyl lactate, put 450 mg of ropivacaine free base, heat and vortex to fully dissolve to obtain a drug solution; then slowly add ethyl oleate to the drug solution to 10 m!, vortex mixing, membrane filtration, sterilization, sterilizing, dispensing into vials, sealing, after passing the lamp inspection, packaging.
- Preparation process Take a prescribed amount of ethyl lactate, put 400 mg of ropivacaine free base, vortex, fully dissolve it to obtain a drug solution; then slowly add triacetin to the drug solution to 10 mi, vortex Rotate and mix thoroughly, remove the membrane by filtration, remove the bacteria, dispense into the vial, seal, and pass the lamp after inspection.
- Formulation formulation Roscaine free base 350 mg
- Preparation process Take the prescribed amount of ethanol and benzyl alcohol, slowly add 350 mg of ropivacaine free base, gently heat and vortex to fully dissolve to obtain the drug solution; slowly add 4ml of ethyl oleate to the drug solution Stir well and mix, then add soybean oil slowly to 0 mi, vortex and mix, filter and remove impurities, remove bacteria, dispense into vials, seal, and pass the lamp after inspection.
- Castor oil (containing hydrogenated castor oil 15% (W7Y) added to 10 ml
- Preparation process Take the prescribed amount of ethanol, slowly inject 250 mg of ropivacaine free base, gently heat and vortex to fully dissolve to obtain the drug solution; eucalyptus oil (containing hydrogenated castor oil 15% (W/V) Slowly add to 10 ml, vortex to mix, filter to remove impurities, remove bacteria, dispense into the vial, seal, after the light is qualified, package.
- eucalyptus oil containing hydrogenated castor oil 15% (W/V) Slowly add to 10 ml, vortex to mix, filter to remove impurities, remove bacteria, dispense into the vial, seal, after the light is qualified, package.
- Castor oil (containing hydrogenated castor oil 15% (W7V) to 10 ml
- Preparation process Take the prescribed amount of benzyl alcohol, slowly inject 300 mg of ropivacaine free base, gently heat and vortex to fully dissolve to obtain the drug solution; castor oil (containing hydrogenated castor oil 15% (W/V) Slowly add to 10 mi, vortex mixed hook, membrane filtration and impurity removal, except if, dispense into the vial, seal, and pass the lamp after inspection.
- castor oil containing hydrogenated castor oil 15% (W/V) Slowly add to 10 mi, vortex mixed hook, membrane filtration and impurity removal, except if, dispense into the vial, seal, and pass the lamp after inspection.
- Soybean oil (white oil 15% (W/V) added to 10 ml
- Preparation process Take the prescribed amount of benzyl alcohol, slowly inject 300 mg of romadin free base, gently heat and vortex to fully dissolve to obtain the drug solution; soy oil (containing 15% white oil (W/V) Slowly add to 10 ml, vortex to mix, membrane filtration to remove impurities, sterilization, dispense into the vial, seal, after the light inspection, packaging.
- Formulation formulation Roscaine free base 350 mg
- Preparation process Take the prescribed amount of benzyl alcohol, benzyl benzoate, slowly input 350 mg ropivacaine free base, 350 mg dextrozine, lightly heat and vortex, fully dissolve, to obtain a drug solution; Slowly add to 10 ml, vortex to mix, membrane filtration to remove impurities, sterilization, dispense into the vial, seal, after the light inspection, packaging.
- Preparation process take the prescribed amount of absolute ethanol, benzyl benzyl acetate, slowly input 300 mg ropivacaine free base, 350 mg dextrozine, lightly heat and vortex, fully dissolve, to obtain a drug solution; Soybean oil is slowly added to 10 mi, vortex mixed hook, membrane filtration and impurity removal, except if, dispensed into a vial, sealed, and qualified after lamp inspection.
- Preparation process Take the prescribed amount of benzyl alcohol, benzyl benzoate, slowly input 450 mg ropivacaine free base, 400 mg dextrozine, heat and vortex, fully dissolve, to obtain a drug solution; castor oil Slowly add to 10 ml, vortex to mix, membrane filtration to remove impurities, sterilization, dispense into the vial, seal, after the light inspection, packaging.
- Preparation process take the prescribed amount of benzyl alcohol, benzyl benzoate, slowly input 350 mg ropivacaine free base, 350nig parecoxib, lightly vortex and vortex, fully dissolve, to obtain a drug solution; Soybean oil is slowly added to 10 ml, vortexed and mixed, membrane filtered to remove impurities, sterilized, dispensed into vials, sealed, and qualified after lamp inspection.
- Soybean oil is added to 10 m!
- Preparation process Take the prescribed amount of benzyl alcohol, slowly input 300 mg ropivacaine free base, 250nig parecoxib, slightly heat and vortex, fully dissolve it to obtain the drug solution; slowly add soybean oil to 10 Mi, vortex mixing, membrane filtration, sterilization, sterilizing, dispensing into vials, sealing, after passing the lamp inspection, packaging.
- Preparation process Take the prescribed amount of benzyl alcohol, absolute ethanol, slowly inject 450 mg ropivacaine free base, 450mg parecoxib, gently heat and vortex to fully dissolve, to obtain a drug solution; The ester was slowly added to 10 mi, vortexed and mixed, membrane filtered to remove impurities, sterilized, dispensed into a vial, sealed, and qualified after lamp inspection.
- Preparation process Take the prescribed amount of benzyl alcohol, slowly put 400 mg ropivacaine free base, 350mg parecoxib, gently heat and vortex, fully dissolve it to get the drug solution; slowly add castor oil to 10 Ml, vortex mixing, membrane filtration, sterilization, disintegration into the vial, sealed, after the light inspection, packaging.
- Formulation formulation procaine free base 150 mg
- Castor oil is added to 10 m
- Preparation process Take the prescribed amount of benzyl alcohol, benzyl benzoate, slowly input] 5 () mg procaine free base, vortex, make it fully dissolved, get the drug solution; slowly add oyster sauce to 10 Ml, vortex mixing, membrane filtration, removal of the window, dispensing into the vial, sealing, after the light inspection, packaging.
- Preparation process Take the prescribed amount of benzyl alcohol, benzyl benzoate, slowly inject 150 mg of dibucaine free base, gently heat and vortex to fully dissolve to obtain a drug solution; slowly add castor oil to 10 Ml, vortex mixing, membrane filtration, sterilization, disintegration into the vial, sealed, after the light inspection, packaging.
- Formulation formulation Atticacaine free base 180 mg
- Preparation process Take the prescribed amount of ethanol, benzyl benzoate, slowly put 180 mg of atecaine free base, gently heat and vortex to fully dissolve, get the drug solution: slowly add soybean oil to 0 mi, Vortex to mix, membrane filtration to remove impurities, sterilization, sub-package into the vial, sealed, after the light inspection, packaging.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Mechanical Engineering (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Dispersion Chemistry (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020157022974A KR101716793B1 (ko) | 2013-01-22 | 2013-04-10 | 무중독성 진통 서방형 약물전달시스템 및 이의 제조방법 |
US14/762,573 US11364299B2 (en) | 2013-01-22 | 2013-04-10 | Non-addictive analgesic sustained-release drug delivery system and preparation method thereof |
EP13872302.8A EP2949316B1 (en) | 2013-01-22 | 2013-04-10 | Non-addictive analgesic sustained-release drug delivery system and preparation method thereof |
JP2015554013A JP6205676B2 (ja) | 2013-01-22 | 2013-04-10 | 非依存性の鎮痛徐放性ドラッグデリバリーシステム及びその製造方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310022657.3 | 2013-01-22 | ||
CN201310022657.3A CN103142458B (zh) | 2013-01-22 | 2013-01-22 | 无成瘾性镇痛缓释递药系统的组方与制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014114032A1 true WO2014114032A1 (zh) | 2014-07-31 |
Family
ID=48540977
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2013/074010 WO2014114032A1 (zh) | 2013-01-22 | 2013-04-10 | 无成瘾性镇痛缓释递药系统及其制备方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US11364299B2 (zh) |
EP (1) | EP2949316B1 (zh) |
JP (1) | JP6205676B2 (zh) |
KR (1) | KR101716793B1 (zh) |
CN (1) | CN103142458B (zh) |
WO (1) | WO2014114032A1 (zh) |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8852638B2 (en) | 2005-09-30 | 2014-10-07 | Durect Corporation | Sustained release small molecule drug formulation |
BRPI0811319A2 (pt) | 2007-05-25 | 2015-02-10 | Tolmar Therapeutics Inc | Composição fluida, método de formação de uma composição fluida, implante biodegrádavel formado in situ, método de formação de um implante biodegradável in situ, kit, implante e método de trataento |
GB2513060B (en) | 2010-06-08 | 2015-01-07 | Rb Pharmaceuticals Ltd | Microparticle buprenorphine suspension |
US9272044B2 (en) | 2010-06-08 | 2016-03-01 | Indivior Uk Limited | Injectable flowable composition buprenorphine |
CN113388606A (zh) | 2011-09-26 | 2021-09-14 | 凯杰有限公司 | 用于分离细胞外核酸的快速方法 |
EP2877155B1 (en) | 2012-07-26 | 2020-10-28 | Camurus AB | Opioid formulations |
GB201404139D0 (en) | 2014-03-10 | 2014-04-23 | Rb Pharmaceuticals Ltd | Sustained release buprenorphine solution formulations |
CN103933040A (zh) * | 2014-03-25 | 2014-07-23 | 王寿世 | 一种加强型神经阻滞药物组合物 |
CN103933041B (zh) * | 2014-04-21 | 2016-03-16 | 青岛市中心医院 | 一种包含布比卡因的局部麻醉组合物及其应用 |
GB201419091D0 (en) * | 2014-10-27 | 2014-12-10 | Camurus Ab | Formulations |
CA2987378C (en) * | 2015-05-28 | 2023-08-01 | Lumosa Therapeutics Co., Ltd. | Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester |
WO2016198571A1 (en) | 2015-06-10 | 2016-12-15 | Qiagen Gmbh | Method for isolating extracellular nucleic acids using anion exchange particles |
CN105030775A (zh) * | 2015-07-13 | 2015-11-11 | 广州金中健医疗器材有限公司 | 一种无成瘾性局部麻醉镇痛缓释递药系统及其制备方法 |
WO2017036408A1 (zh) * | 2015-09-01 | 2017-03-09 | 四川海思科制药有限公司 | S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶晶体及其缓释制剂 |
CN108659100A (zh) * | 2017-03-28 | 2018-10-16 | 上海新生源医药集团有限公司 | 具有镇痛作用的多肽及其应用 |
JP6850371B2 (ja) * | 2017-07-04 | 2021-03-31 | シャンドン ダンホン ファーマスーティカル カンパニー リミテッドShandong Danhong Pharmaceutical Co., Ltd. | デゾシン類似体エステルを含む徐放懸濁液およびその製造方法 |
CA3073734A1 (en) * | 2017-08-28 | 2019-03-07 | Tlc Biopharmaceuticals, Inc. | Sustained-release anesthetic compositions and methods of preparation thereof |
AU2018358372A1 (en) * | 2017-10-30 | 2020-05-28 | Kaken Pharmaceutical Co., Ltd. | External preparation for treating trichophytosis unguium |
EP3720420A1 (en) * | 2017-12-06 | 2020-10-14 | Huzhou Hui Zhong Ji Shi Biotechnology Co., Ltd. | Injectable long-acting local anesthetic semi-solid gel formulations |
CN109896992A (zh) * | 2017-12-08 | 2019-06-18 | 武汉软件工程职业学院 | 制备离子液体的方法及其应用 |
KR20200136990A (ko) * | 2018-03-30 | 2020-12-08 | 티엘씨 바이오파머슈티컬즈 인코포레이티드 | 서방형 마취제 조성물 및 이의 제조 방법 |
CN108379269B (zh) * | 2018-04-20 | 2020-08-21 | 武汉百纳礼康生物制药有限公司 | 一种用于术后镇痛的缓释制剂及其制备方法 |
CN108743952B (zh) * | 2018-06-11 | 2021-08-31 | 西安力邦医药科技有限责任公司 | 局部麻醉药的磷脂-混溶剂-油缓释递药系统组方与制备方法 |
CN110935024B (zh) * | 2018-09-21 | 2023-08-08 | 合肥合源药业有限公司 | 长效组合物 |
CN109316602A (zh) * | 2018-11-13 | 2019-02-12 | 西安力邦医药科技有限责任公司 | 一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用 |
CN111388418B (zh) * | 2018-12-31 | 2022-09-06 | 北京泰德制药股份有限公司 | 一种含有罗哌卡因或其药用盐的药物组合物 |
CN111840553A (zh) * | 2019-04-15 | 2020-10-30 | 湖州依诺唯新药物制剂有限公司 | 脂性药物制剂及其应用 |
CN110327336B (zh) * | 2019-07-09 | 2022-07-26 | 成都大学 | 昔萘酸甲哌卡因及其长效缓释制剂 |
WO2021141959A1 (en) * | 2020-01-10 | 2021-07-15 | Pacira Pharmaceuticals, Inc. | Treatment of pain by administration of sustained-release liposomal anesthetic compositions |
CN113117092A (zh) * | 2020-01-14 | 2021-07-16 | 中国科学院上海药物研究所 | 一种非水缓释递药系统 |
EP4091612A4 (en) | 2020-01-14 | 2024-01-24 | Shanghai Inst Materia Medica Cas | PHARMACEUTICAL COMPOSITION OF LONG-ACTING ROPIVACAINE, PREPARATION METHOD AND USE THEREOF |
CN115068414B (zh) * | 2021-03-16 | 2023-07-21 | 湖南慧泽生物医药科技有限公司 | 供注射用罗哌卡因长效溶液制剂及其制备方法 |
CN115463084B (zh) * | 2021-06-10 | 2024-05-28 | 北京泰德制药股份有限公司 | 一种长效镇痛用复方油溶液制剂及其制备方法 |
WO2023115311A1 (zh) * | 2021-12-21 | 2023-06-29 | 南京清普生物科技有限公司 | 一种缓释制剂组合物 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1533764A (zh) * | 2003-04-02 | 2004-10-06 | 王玉万 | 含非甾体抗炎药物的缓释注射剂 |
CN101926757A (zh) * | 2010-09-01 | 2010-12-29 | 北京大学 | 一种难溶性药物的液体组合物及其制备方法 |
CN102370619A (zh) * | 2010-08-18 | 2012-03-14 | 罗和国 | 脂肪乳乳化局麻药 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003077885A2 (en) * | 2002-03-12 | 2003-09-25 | Neurogesx, Inc. | Free-base formulations of local anesthetics |
US20040001889A1 (en) * | 2002-06-25 | 2004-01-01 | Guohua Chen | Short duration depot formulations |
BR0318319A (pt) | 2003-05-25 | 2006-07-18 | Yuwan Wang | métodos de preparação e formulações/composições sustentadas pelo uso de dimeticona como veìculo |
AU2006326018B2 (en) * | 2005-12-14 | 2013-04-18 | Nuvo Research Inc. | Compositions and methods for dermally treating pain |
US20100041704A1 (en) * | 2007-01-12 | 2010-02-18 | Aberg A K Gunnar | Dermal compositions of substituted amides and the use thereof as medication for pain and pruritus |
BRPI0807880A2 (pt) * | 2007-03-02 | 2014-06-17 | Combe Internat Ltd | Composição anestésica em spray. |
US20140066481A1 (en) | 2010-04-01 | 2014-03-06 | Pharmanest Ab | Water-Free Pharmaceutical Compositions Suitable for Local Anaesthetics |
-
2013
- 2013-01-22 CN CN201310022657.3A patent/CN103142458B/zh active Active
- 2013-04-10 US US14/762,573 patent/US11364299B2/en active Active
- 2013-04-10 KR KR1020157022974A patent/KR101716793B1/ko active IP Right Grant
- 2013-04-10 WO PCT/CN2013/074010 patent/WO2014114032A1/zh active Application Filing
- 2013-04-10 EP EP13872302.8A patent/EP2949316B1/en active Active
- 2013-04-10 JP JP2015554013A patent/JP6205676B2/ja active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1533764A (zh) * | 2003-04-02 | 2004-10-06 | 王玉万 | 含非甾体抗炎药物的缓释注射剂 |
CN102370619A (zh) * | 2010-08-18 | 2012-03-14 | 罗和国 | 脂肪乳乳化局麻药 |
CN101926757A (zh) * | 2010-09-01 | 2010-12-29 | 北京大学 | 一种难溶性药物的液体组合物及其制备方法 |
Non-Patent Citations (14)
Title |
---|
BO XIONQ; QIQING SHI; XUAN WANQ: "Effect of local ropivacaine infiltration on post-op pain in pediatric appendectomy", CHINESE JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, vol. 13, no. 5, 2008, pages 5731 |
JINHUI XIAO: "Clinical observation on application of ropivacaine at different concentrations in labor analgesia", MODEM CHINESE DOCTOR, vol. 45, no. 6, 2007, pages 111 |
JUNMIN ZHENG: "Handbook of Pharmaceutical Adjuvants", pages: 313 - 314 |
NIIYAMA Y; KAWAMATA T; SHIMIZU H ET AL.: "The addition of epidural morphine to ropivacaine improves epidural analgesia after lower abdominal surgery", CAN J ANAESTH, vol. 52, no. 2, 2005, pages 181 |
QIHONG ZHAO; PENG WEI; WENTAO DAI: "Comparative researches on transaxillary brachial plexus block using ropivacaine at different concentrations", APPLIED JOURNAL OF GENERAL PRACTICE, vol. 5, no. 4, 2007, pages 2931 |
SAKELLARIS G; PETRAKIS I; MAKATOUNAKI K ET AL.: "Effects of ropivacaine infiltration on cortisol and prolactin responses to post operative pain after inguinal hemioraphy in children", PEDIATR SURG, vol. 39, no. 9, 2004, pages 1400 |
See also references of EP2949316A4 |
SHANGLONG YAO; HUAQING SHU: "Develeopment in pain therapeutics", JOURNAL OF CLINICAL INTERNAL MEDICINE, vol. 22, no. 12, 2005, pages 793 - 796 |
SHENGJIAO WU; WENLI CHENG; FENG GUO ET AL.: "Clinical observation of low concentration of ropivacaine hydrochloride in combination with fentanyl in epidural self-controlled labor analgesia", JIANGXI MEDICAL JOURNAL, vol. 43, no. 1, 2008, pages 361 |
SHITONG LI; XINLIANG ZHUANG, LOCAL ANESTHETICS, 2009, pages 76 - 83 |
SHUNFU CHEN: "Comparison of gynecologic post-operative analgesic effect of ropivacaine and bupivacaine", JIUJIANG MEDICINE, vol. 17, no. 3, 2002, pages 1331 |
STRICHARTZ GR; BERDE CB: "Miller's Anesthesia", article "Local Anesthetics" |
WANGJUN TANG; GUANGFEN YIN ET AL.: "Progress in post-operative pain and analgesia", JOURNAL OF DALI MEDICAL UNIVERSITY, vol. 2, no. 9, 2000, pages 68 - 70 |
ZONGLIN YANG; RONGZHI ZHENG; YUQIN ZHANG: "Merits of continuous epidural infusion with 0.1 % ropivacaine and 0.1% bupivacaine in post-op analgesia in elderly patients having received lower limb surgeries", SHAANXI MEDICAL JOURNAL, vol. 37, no. 2, 2008, pages 2461 |
Also Published As
Publication number | Publication date |
---|---|
CN103142458B (zh) | 2015-09-09 |
KR20150109474A (ko) | 2015-10-01 |
EP2949316A4 (en) | 2016-04-20 |
US20150359891A1 (en) | 2015-12-17 |
CN103142458A (zh) | 2013-06-12 |
US11364299B2 (en) | 2022-06-21 |
KR101716793B1 (ko) | 2017-03-15 |
EP2949316B1 (en) | 2020-07-01 |
JP6205676B2 (ja) | 2017-10-04 |
EP2949316A1 (en) | 2015-12-02 |
JP2016505631A (ja) | 2016-02-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2014114032A1 (zh) | 无成瘾性镇痛缓释递药系统及其制备方法 | |
KR101351771B1 (ko) | 바람직하게 saib와 같은 당 에스테르를 포함하는지속적인 국소 마취제 조성물 | |
AU2013294915C1 (en) | Opioid formulations | |
ES2357769T3 (es) | Uso de palonosetrón para tratar la náuseas y los vómitos postoperatorios. | |
CA3037089C (en) | Sublingual pharmaceutical composition of edaravone and (+)-2-borneol | |
NO20110342L (no) | Fentanylpreparat for nasal administrering | |
KR20190060007A (ko) | 덱스메데토미딘 경피 전달 장치를 이용한 통증을 관리하는 방법 | |
CN109562281A (zh) | 酚类trpv1激动剂的前药与局部麻醉药和血管收缩剂联合用于改善局部麻醉 | |
US20240075024A1 (en) | Opioid formulations | |
US20220193014A1 (en) | Lipid pharmaceutical preparation and application thereof | |
IL266448B1 (en) | Topical datumidine formulations | |
MX2007003948A (es) | Composicion farmaceutica en forma de tableta sublingual que comprende un antiinflamatorio no esteroideo y un analgesico opiaceo para el manejo del dolor. | |
TW201406403A (zh) | 用於治療外科手術疼痛之麻醉乳液調配物 | |
WO2022193975A1 (zh) | 供注射用罗哌卡因长效溶液制剂及其制备方法 | |
JP2020519593A (ja) | 溶解度を増強させた薬物含有製剤 | |
WO2007022609A1 (en) | Pharmaceutical composition of morphine in ready-to-use injectable solution form and single dosage form of morphine for epidural or intrathecal administration | |
US20100190860A1 (en) | Methods for selectively enhancing antinociceptive potency of local anesthetics | |
JP5376481B1 (ja) | 経皮吸収用医薬組成物 | |
US20220387421A1 (en) | Drug products for intranasal administration and uses thereof | |
CN105030775A (zh) | 一种无成瘾性局部麻醉镇痛缓释递药系统及其制备方法 | |
KR20080105857A (ko) | 치질환 및 기타 항문 직장 질환 치료 활성을 가지는조성물과 이의 제조 방법 및 이를 이용한 치질환 치료제 | |
RU2622980C1 (ru) | Средство для эффективного купирования острого и/или хронического болевого синдрома и способ его применения | |
RU2323721C2 (ru) | Местноанестезирующее и антисептическое средство | |
Swaminathan | Comparative Evaluation of Transdermal Diclofenac and Oral Diclofenac in Management of Post Operative Pain in Bilateral Extractions: An In Vivo study | |
WO2005097115A1 (de) | Verwendung von repinotan zur hemmung der opiat/opioid-induzierten atemdepression |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13872302 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2015554013 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14762573 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: IDP00201505151 Country of ref document: ID Ref document number: 2013872302 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20157022974 Country of ref document: KR Kind code of ref document: A |