CN109316602A - The prescription and application of a kind of long-acting analgesic and the compound sustained-released delivery system for promoting wound healing - Google Patents

The prescription and application of a kind of long-acting analgesic and the compound sustained-released delivery system for promoting wound healing Download PDF

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CN109316602A
CN109316602A CN201811346227.6A CN201811346227A CN109316602A CN 109316602 A CN109316602 A CN 109316602A CN 201811346227 A CN201811346227 A CN 201811346227A CN 109316602 A CN109316602 A CN 109316602A
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oil
group
prescription
steroidal anti
delivery system
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卢伍党
李清清
陈涛
宋卫
顾相应
马延
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XI'AN LIBANG MEDICINE SCIENCE AND TECHNOLOGY Co Ltd
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XI'AN LIBANG MEDICINE SCIENCE AND TECHNOLOGY Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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]

Abstract

The invention belongs to pharmaceutical field, a kind of long-acting analgesic is related generally to and the prescription of the compound sustained-released delivery system that promotes wound healing and application.The main ingredient of system of the present invention is the composition of local anesthetic and non-steroidal anti-inflammatory drugs, further includes solvent and corresponding slow-release material.For main ingredient using local anesthetic and non-steroidal anti-inflammatory drugs compound, local anesthetic can make up analgesic effect weak disadvantage when non-steroidal anti-inflammatory drugs is used alone；And local anaesthetics can enhance the analgesic effect of local anesthetic by reducing the Hyperalgesia of body, inflammatory reaction is inhibited to promote wound healing；In addition, Papillary can reduce the dosage of the two to reduce respective adverse reaction.

Description

A kind of prescription of long-acting analgesic and the compound sustained-released delivery system for promoting wound healing with Using
Technical field
The invention belongs to pharmaceutical field, relates generally to a kind of long-acting analgesic and the compound sustained-released of wound healing is promoted to pass medicine system The prescription of system and application.
Background technique
The nociceptive pain as caused by operation, knife wound, burn etc. is clinically most common and most needs emergent management Acute Pain.If this pain cannot control in time, not only the psychology of patient and each organ dysfunction of physiology are generated great Influence, such as: anxiety, insomnia, dysphoria, nausea and vomiting, the retention of urine, immunosupress, occur pulmonary complication, blood pressure increase And myocardial ischemia danger increase etc..Currently, clinically have up to 70% patient dissatisfied to postoperative analgesia, and The postoperative acute pain of 25%-55% can develop into chronic ache, and the constant pain time reaches half a year or even many decades, even results in residual Barrier.
It therefore, is the pain for mitigating trauma patient, each organ dysfunction of stable patient, improvement patient is rear and shortens patient Hospital stays, the analgesia for nociceptive pain, especially long-acting analgesic are clinical problems anxious to be resolved.
Currently, clinical analgesic drug and it is as follows the long-acting ease pain the characteristics of:
Opium kind analgesics class, such as: morphine, buprenorphine, C16H25NO2, fentanyl, sufentanil, alfentanil, Rui Fen Too Buddhist nun etc..Such medicine work rapidly, analgesic activity it is strong, no organ toxicity holds time short, and action time is a few minutes to several small When not equal (< 6 hours).But such side effects of pharmaceutical drugs is big, and the symptom of long-acting analgesic is needed for postoperative pain etc., it is prolonged and repeated The side effect used is very serious, such as: nausea and vomiting, respiration inhibition, tolerance, physiological dependence, constipation, the retention of urine, amentia Deng；In addition such drug also causes postoperative pain sensation sensitization, obviously increases patient to the demand of antalgesic.
Local anesthetic, the main method by canalis spinalis innerlich anwenden, local infiltration, regional nerve clump or peripheral blockade Administration.It, which represents drug, has: Ropivacaine, lidocaine, Bupivacaine, chirocaine, procaine, totokaine, etc..Its In, the phenomenon that exact analgesic effect of Ropivacaine, long action time, toxicity is low, " feeling-kinesitherapy nerve separation ", is the most obvious It and is ideal medicament for Postoperative Analgesia After.Postoperative pain usually starts to generate after surgery or after anesthetic effect disappearance, general to continue Time is 3-7 days, wherein preceding 3 days pains sensation are the most violent and critical period of Postoperative Analgesia After.But the effect of Ropivacaine Time is to act on for 8 hours, is far from being enough for Postoperative Analgesia After.Therefore, epidural analgesia is clinically generally used, That is, injecting analgesic with constant speed, and dose is added as needed, greatly improve the compliance of patient.But it should Manpower and material resources higher cost spent by method.
Non-steroidal anti-inflammatory drugs can be divided into two classes: oral drugs and injection drug according to administration mode.Oral drugs are main It include: brufen, Meloxicam, celecoxib, Lornoxicam, diclofenac etc.；Injection drug specifically include that SC 69124, Lornoxicam, flurbiprofen ester and ketorolac etc..Such drug is mainly used for medium and small postoperative analgesia.But for major operation Postoperative pain, the analgesic activity of such drug is unobvious, need and other class antalgesics (opiates or local anaesthesia class) close With can be only achieved effect.
Accordingly, with respect to opium kind analgesics, local anesthetic and non-steroidal anti-inflammatory drugs are the ideal medicine of long-acting analgesic Object.We have applied for prescription and preparation method of the patent-without additive analgesia sustained release drug delivery systems, Patent No. CN in 2013 103142458, apply carrying out patent protection to the prescription and preparation method of the sustained release drug delivery systems of local anesthetic.Later, In our companies in 2018 applied again patent-it is a kind of with phosphatide-miscible agent-oil for carrier local anesthetic sustained release preparation with Preparation method improves prescription on the basis of patent before application No. is 201810592597.1, adds in prescription Enter phosphatide and applies for patent protection.On the basis of the two patents, it has been found that local anesthetic is sharing non-steroidal After anti-inflammatory agent, the analgesic activity of delivery system is more superior, can also promote wound healing, be mainly shown as:
1. the analgesic activity that local anaesthetics can be enhanced in non-steroidal anti-inflammatory drugs.After tissue damage, due to spinal cord and periphery forefront The synthesis and secretion of parathyrine cause body to decline the threshold of reaction of stimulation, and algesiroreceptor is to other causes such as histamine, bradykinin The sensibility enhancing of pain substance is to aggravate the pain.Therefore, non-carrier anti-inflammatory agent can be by inhibiting pain caused by prostaglandin Feel analgesic activity that is sensitive and enhancing local anaesthetics.
2. non-steroidal anti-inflammatory drugs can activate endogenic opium nerve endorphin system, enhance analgesic effect, and will not There is the side effect of opium kind analgesics.
3. the antiphlogistic effects of non-steroidal anti-inflammatory drugs can promote wound healing, accelerate Rehabilitation.
4. after operation, the inflammatory reaction of inflammatory reaction, especially periphery and central nervous system, for body by acute pain There is very important effect to postoperative chronic ache.Therefore, early stage inhibits Postoperative inflammatory reaction for effectively inhibiting in time The generation of postoperative chronic ache, the quality of life for improving patient have very important meaning.
5. the dosage of local anesthetic and non-steroidal anti-inflammatory drugs can be dropped after sharing with non-steroidal anti-inflammatory drugs It is low, reduce the toxic side effect of the two.
Clinical investigation shows, clinically relatively simple for the drug of long-acting analgesic at present, is aqueous formulation, when effect Between it is short.Use in conjunction of the present invention local anesthetic and non-steroidal anti-inflammatory drugs are simultaneously prepared into sustained release preparation to reach persistently analgesia simultaneously Promote the purpose of wound healing.It the two is prepared into compound slow release preparation not only can enrich clinical analgesic kind, conveniently Administration can also expand its clinical application range, reduce clinical administration number, reduce clinical adverse, promote wound healing, Good clinical development prospect is highlighted, in addition preparation process thereof of the invention is simple controllably, production cost is low, is easy to implement Industrialization.
Based on the above discovery, we have developed a kind of local anesthetic and the compound sustained-released delivery system of non-steroidal anti-inflammatory drugs, The delivery system can be used for knife wound, postoperative long-acting analgesic and promote wound healing.
Summary of the invention
The purpose of the present invention is to provide a kind of long-acting analgesic and promote the compound sustained-released delivery system of wound healing.
The main ingredient of the system is the composition of local anesthetic and non-steroidal anti-inflammatory drugs, further includes solvent and delays accordingly Release material.Main ingredient can make up exclusive use non-steroidal using local anesthetic and non-steroidal anti-inflammatory drugs compound, local anesthetic Analgesic effect weak disadvantage when anti-inflammatory agent；And local anaesthetics can enhance local anesthetic by reducing the Hyperalgesia of body Analgesic effect inhibits inflammatory reaction to promote wound healing；In addition, Papillary can reduce the dosage of the two to reduce Respective adverse reaction.
The feature of delivery system of the invention are as follows: oil solution type delivery system, preparation stabilization, homogeneity are preferable.
Compound sustained-released delivery system of the present invention, by local anesthetic, non-steroidal anti-inflammatory drugs, solvent and slow-release material Composition, wherein the concentration of local anaesthetics is 10-100mg/ml, and the concentration of non-steroidal anti-inflammatory drugs is 2-30mg/ml, the ratio of solvent For 10%-70% (v/v), remaining is slow-release material, and wherein slow-release material is made of phosphatide and oil, the ratio model of the two volume It encloses for 4:1~1:4.
Preferably, compound sustained-released delivery system of the present invention, consists of the following compositions: the concentration of local anaesthetics is 10- 80mg/ml, the concentration of non-steroidal anti-inflammatory drugs are 4-30mg/ml, and the ratio of solvent is 10%-60% (v/v), remaining for sustained release Material, wherein slow-release material is made of phosphatide and oil, and the proportional region of the two volume is 3:1~1:3.
It is further preferred that compound sustained-released delivery system of the present invention, consists of the following compositions: the concentration of local anaesthetics For 10-50mg/ml, the concentration of non-steroidal anti-inflammatory drugs is 12-20mg/ml, and the ratio of solvent is 10%-50% (v/v), is left It is slow-release material, wherein slow-release material is made of phosphatide and oil, and the proportional region of the two volume is 2:1~1:2.
Most preferably, the concentration of local anaesthetics is 40mg/ml, and the concentration of non-steroidal anti-inflammatory drugs is 20mg/ml.
Wherein, local anesthetic specifically includes that Bupivacaine, chirocaine, Ropivacaine, lidocaine, Bu Luka The free alkali of cause or its corresponding salt, its esters mainly include hydrochloride, mesylate, sulfate, citrate, fumaric acid Salt, lactate, ethyl sulfonate, succinate, glutamate, salicylate, benzene sulfonate, citrate, maleate etc.； Local anesthetic can be one of, two or more composition.Wherein, the preferably free alkali of Ropivacaine And its corresponding salt, the most preferably free alkali of Ropivacaine.
Wherein, non-steroidal anti-inflammatory drugs includes: brufen, sulindac, Etodolac, piroxicam, Meloxicam, chlorine promise former times Health, ketorolac, aminopyrine, SC 69124, celecoxib, aulin, flurbiprofen axetil；Non-steroidal anti-inflammatory drugs can be it A kind of middle, two or more mixture；Its existence form can be free state, be also possible to itself and acid or alkali knot Synthesize corresponding salt.
Wherein, solvent refers to the one kind that can dissolve main ingredient (including local anesthetic and non-steroidal anti-inflammatory drugs), two kinds or two Kind or more mixture；It include: benzyl alcohol, ethyl alcohol, propylene glycol, glycerol, ethyl acetate, ethyl lactate, Ergol, tetrahydro Furans polyvinylether, one of (molecular weight is 200-600Da's) liquid polyethylene glycol, two or more mixing Object.
Slow-release material of the present invention is made of phosphatide and oil.
Wherein phosphatide is natural and/or synthetic phospholipid and hydrogenated phospholipid, it is preferable that the phosphatide is selected from following one kind It is or a variety of: egg yolk lecithin, soybean lecithin, phosphatidyl choline, dioleyl lecithin, Dipalmitoyl Lecithin, two hard esters Acyl lecithin, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, two myristoyl phosphatidylserines, Distearoyl phosphatidyl-ethanolamine, egg PC, Polyene Phosphatidylcholine, glycerolphosphocholine, hydrogenated soybean phosphorus Rouge, hydrogenation yolk phosphide, di-oleoyl phosphatidylserine, phosphatidic acid, dipalmitophosphatidic acid, phosphatidyl-ethanolamine, yolk Phosphatidyl glycerol, phosphatidylinositols；Preferably egg yolk lecithin, soybean lecithin, phosphatidyl choline, in hydrogenated soya phosphatide A kind of, two or more mixture；Most preferably egg yolk lecithin.
Wherein, oil can be selected from the mixture of vegetable oil or artificial synthesized grease or both；
Wherein vegetable oil includes: soybean oil, castor oil, rilanit special, sulfonated castor oil, Emulsifier EL-60, sesame Sesame oil, peanut oil, cottonseed oil, corn oil, olive oil, sunflower oil, tea oil, palm oil, Seabuckthorn Oil, fish oil, garlic oil, safflower A kind of, the two or more mixture of oil；Preferably castor oil, soybean oil, olive oil, sesame oil, corn oil A kind of, two or more mixture；More preferably castor oil, soybean oil or the two mixture.
Wherein artificial synthesized grease includes: midchain oil, ethyl oleate, glyceryl triacetate, middle long-chain oil, single triacetin It is ester, Ergol, isopropyl myristate, tributyl citrate, alkyl (C12-C15) benzene methyl, benzyl phenylacetate, pungent Acetoacetic ester, gallic acid fourth diester, progallin A, propylgallate, methyl myristate, isopentyl palmitate, Ethyl propionate, isoamyl propionate, benzyl propionate, N- N-methyl-2-2-pyrrolidone N, oleic acid and oleate；Preferably ethyl oleate or The mixture of midchain oil or both.
Most preferably, the compound sustained-released delivery system of the present invention consists of the following compositions: the concentration of local anaesthetics is 40mg/ml, The concentration of non-steroidal anti-inflammatory drugs is 20mg/ml, and the ratio of solvent is 30-40% (v/v), and remaining is slow-release material, wherein delaying It releases material to be made of phosphatide and oil, the proportional region of the two volume is 2:1~1:2.
Specifically, the compound sustained-released delivery system of the present invention consists of the following compositions:
Prescription 1:
Prescription 2:
Prescription 3:
Prescription 4:
Prescription 5:
Prescription 6:
Prescription 7:
Prescription 8:
Prescription 9:
Prescription 10:
Prescription 11:
It is another object of the present invention to provide the preparation methods of compound sustained-released delivery system, comprising the following steps:
(1) prepared by medical fluid: precision being weighed a certain amount of local anesthetic and nonsteroidal anti-inflammatory drug is dissolved in certain body It in long-pending solvent, ultrasound, stirring, shearing, shaking or is vortexed to complete drug dissolution, then adds recipe quantity phosphatide, ultrasound, Stirring, shearing, shaking or vortex to phosphatide are completely dissolved, finally addition oil, and ultrasound, stirring shear or are vortexed to mix and prepare Required sustained release drug delivery systems stoste；
(2) aseptic subpackaged: aseptically, the medical fluid prepared to be crossed into miillpore filter and removes impurity, degerming, is then existed Tamponade, gland in a reservoir are dispensed under the protection of sterile nitrogen, can must be used for analgesic compound delivery system, are placed in 2-8 DEG C Lower preservation；
Wherein, in the step (2), the delivery system further includes packaging material；Preferably, the packaging material is selected from following one kind Or it is a variety of: cillin bottle, ampulla, refilling type syringe, clamped bottle,
Wherein, in the step (2), the aperture of the miillpore filter is 0.2 μm.
It is another object of the present invention to provide compound sustained-released delivery systems to treat knife wound, bullet wound, operation, burning in preparation Application after wound in the drug of analgesia and/or the healing of promotion wound.
Compound sustained-released delivery system of the present invention has the function of promoting the healing of wound.
The implementation method of the compound sustained-released delivery system of the present invention that can persistently ease pain and promote wound healing are as follows: wound Neurode injection, muscle or subcutaneous single-point or multi-point injection, nerve root are injected near mouthful, sprinkling infiltration relieves pain, notch applies It smears, be continuously or discontinuously administered by infusion pump.
The present invention is long-acting oily injection agent, is to be dissolved in drug in oleaginous base with the help of solvent, is injected into After in vivo, oily preparation forms local deposit in injection site, and the drug molecule of dissolution is then dispensed into from oily preparation Enter aqueous interstitial liquid, is then rapidly absorbed into blood.Other than finish, the phosphatide of appropriate amount also joined in slow-release material, It can be used as dispersing agent, emulsifier and stabilizer, and there is the intersolubility in increase delivery system between substance, control drug to dash forward Release and extend the effect of pharmaceutical release time.
Specific embodiment
By following experiments example and embodiment, further just prescription of the present invention, preparation method, purposes are illustrated, but do not make For limitation of the invention.
Such as due to patent before: CN103142458, CN108159055 etc. carry medicine body to same type of blank The intersolubility and proportion of each auxiliary material (solvent, phosphatide and oil) have done very in-depth study in system, and this patent will no longer carry out this The research of a part, the directly optimal proportion before are tested as follows.
The dissolubility test of 1 local anaesthetics of test example and the composition of non-steroidal anti-inflammatory drugs in medicine-carried system
The local anaesthetics and non-steroidal anti-inflammatory drugs for weighing formula ratio, sequentially add the solvent of formula ratio, and Gai Sai shakes to complete Dissolution；The phosphatide of formula ratio, Gai Sai are added, suitable oil is added to after being completely dissolved, shakes up for shaking.Place 2-8 DEG C Save, observation 48 hours after main ingredient precipitation situation and record, the results are shown in Table 1.
1 drug preparation stability test result of table
Experimental result is shown: local anesthetic (≤8%) and the composition of non-steroidal anti-inflammatory drugs (≤3%) are to upload medicine It is more stable in system, it is precipitated without drug after 2~8 DEG C of placement 48h, there is preferable dissolubility.
The local anaesthetics and/or non-steroidal anti-inflammatory drugs compound preparation sensory nerve blockade test (heat of the different prescriptions of test example 2 Plate method)
(1) selection of animal
By hot plate method to 230~250g of weight, healthy female sd inbred rats carry out testing preceding screening.Hot plate is warming up to (56 ± 1) DEG C, a wherein metapedes for rat is placed on it, and in addition a metapedes is then in the room temperature condition of laboratory, Observe and record its tested time retracted enough.Then in kind measure an other metapedes for rat.Every metapedes is handed over It for measurement, is spaced 5 minutes, each measurement is averaged three times, is denoted as Basic Pain Threshold value.If paw withdrawal time measurement result is more than 5.0 Second, then the rat Basic Pain Threshold value is undesirable, should give rejecting.
(2) grouping and administration
36 rats are taken to be tested, this experiment is divided into 6 groups, and each group is made a living respectively manages salt water group-group 1, Ropivacaine With SC 69124 composite injection-group 2, Ropivacaine sustained release preparation-group 3 (prescription is selected from patent CN103142458), sieve Piperazine cacaine sustained release preparation-group 4 (prescription is selected from application No. is 201810592597.1 patents), SC 69124 sustained release preparation-group 5, Ropivacaine and SC 69124 compound slow release preparation-group 6 (specific prescription and specification are shown in Table 2), each group are sat in Rat Right respectively Relative medicine is injected around bone nerve cord, it is 10mg/kg that total amount, which is administered, in each group.
The different local anesthetics of table 2 and/or non-steroidal anti-inflammatory drugs compound slow release preparation prescription
(3) method and evaluation
Local anaesthetics and the compound preparation of non-steroidal anti-inflammatory drugs have apparent retardation for rat sciatic nerve, investigate Retardation variation situation is felt after the administration of each group rat, and carries out comprehensive compare and evaluation.To avoid the occurrence of experimental animal body Damage, if rat is more than that 15s paw withdrawal phenomenon does not occur yet in hot-plate, should be denoted as away from hot plate, and by experimental result 15s。
(4) statistical method
For statistical analysis, the χ with SPSS10.0 software2T is examined between inspection and group, and P < 0.05 is statistically significant, P < 0.01 indicates that tool is statistically significant.
(5) evaluation of result of sensory nerve retardance
Experimental result such as table 3, the local anaesthesia experiment of local anaesthetics and non-steroidal anti-inflammatory drugs compound preparation feel mind in investigating Apparent slow release effect is shown through retardance.It is local anaesthetics sustained release preparation group (group 3, group 4), non-compared with blank control group (group 1) Steroidal anti-inflammatory medicine preparation group (group 5), local anaesthetics and non-steroidal anti-inflammatory drugs compound slow release preparation (group 6) have certain duration analgesia Effect；Wherein, the analgesia intensity of non-steroidal anti-inflammatory drugs preparation group (group 5) is weaker than other groups；Local anaesthetics and non-steroidal anti-inflammatory drugs are multiple The analgesia time longest of square sustained release preparation (group 6), even 72 hours or more sustainable 48 hours.Phosphatide in local anaesthetics sustained release preparation Addition (group 4vs group 3) opposite can enhance analgesic activity, extend the release time of drug.Local anaesthetics and non-steroidal anti-inflammatory drugs Compound slow release preparation group can significantly increase the analgesic activity and analgesia time of compound medicine compared with its injection group (group 2).
3 different dosing group of table counts (n=6) to rat intramuscular injection sensory nerve residence time
Influence of the local anaesthetics and/or non-steroidal anti-inflammatory drugs compound preparation of the different prescriptions of test example 3 to rat wound healing
(1) experimental group and dosage: SD rat, 230~250g, male, 36 or so, adaptive feeding 2-3 days Afterwards, it is screened according to weight and is randomly divided into 6 groups, every group is 6, and each group is made a living respectively manages salt water group-group 1, Ropivacaine and pa Auspicious former times cloth composite injection-group 2, Ropivacaine sustained release preparation-group 3 (prescription is selected from patent CN103142458), Ropivacaine Sustained release preparation-group 4 (prescription is selected from application No. is 201810592597.1 patents), SC 69124 sustained release preparation-group 5, sieve piperazine Cacaine and SC 69124 compound slow release preparation-group 6 (specific prescription and specification are shown in Table 2), dosage are 0.5ml/.
(2) basic experiment process: after carrying out screening and being grouped according to weight, each experimental group rat first carries out experimental animal Back depilation, next day operation establish 2cm*1cm rat back full-thickness defects wound model and are calculated as D0, photograph to record.Random point Group, by group administration, administration mode is wound multiple spot intramuscular injection nearby.
(3) observation index: D1, D3, D7, D14, the D21 different time points observation each group rat surface of a wound are cured upon administration respectively The case where conjunction, and score according to wound healing area with recovery situation.
4 different dosing group of table scores (n=6) to SD rat wound healing situation
Grouping D1 D3 D7 D14 D21
Group 1 - 19.76% 50.14% 83.75% 97.68%
Group 2 - 28.45% 58.26% 84.63% 97.54%
Group 3 - 22.65% 54.24% 83.55% 98.55%
Group 4 - 23.52% 53.83% 85.84% 96.01%
Group 5 - 33.75% 65.43% 96.01% 96.52%
Group 6 - 32.35% 69.10% 97.34% 98.65%
(4) evaluation of result: evaluating different groups, different observation point SD comparing property of Rat Wound Healing situation, The result shows that local anaesthetics and non-steroidal anti-inflammatory drugs compound slow release preparation (group 6), which have SD rat wound healing, remarkably promotes work With.With control group (group 1) and local anaesthetics sustained release preparation group (group 3 is organized and 4) is compared, the sustained release preparation group containing non-steroidal anti-inflammatory drugs, That is: the wound of rat in non-steroidal anti-inflammatory drugs preparation group (group 5), local anaesthetics and non-steroidal anti-inflammatory drugs compound slow release preparation group (group 6) Mouth healing rate is dramatically speeded up, and illustrates that the addition of non-steroidal anti-inflammatory drugs can dramatically speed up wound healing.Local anaesthetics and non-steroidal are anti- Scorching drug composition sustained release preparation group (group 6) can dramatically speed up the healing of wound, illustrate medicine compared with its injection group (group 2) The sustained release of object is of great significance to wound healing.
The test of 4 muscle irritation of test example
Whether normal first 1 week of test observes state of mind, appetite, body temperature of rabbit etc..It is infused using rabbit quadriceps muscle of thigh Method takes healthy 6 rabbit to be divided into 3 groups, and every group 3, male and female have concurrently, 2~2.5kg of weight, respectively on the left of the 1st group of rabbit Local anaesthetics and non-steroidal anti-inflammatory drugs compound slow release preparation (group 6) injection (Ropivacaine 30mg/ are injected at hind leg quadriceps muscle of thigh Ml: SC 69124 15mg/ml) 1mL injects sterile saline 1mL at the 2nd group of rabbit left rear limb quadriceps muscle of thigh.It is being administered 2,7 and 15d takes each 1 execution of every group of rabbit respectively afterwards, and solution takes quadriceps muscle of thigh, longitudinally slit, observation injection site muscle Tissue change, such as congested, red and swollen, denaturation, necrosis.Lesion diameter is measured, according to the evaluation criteria of musculature stimulate the reaction It is evaluated.In addition it takes two sides injection site musculature, after conventional treatment, makees histopathologic examination.Result evaluation standard It is shown in Table 5.When rabbit average response score value at 2 grades hereinafter, can determine that the product can be used as intramuscular injection to meet regulation, put down Reaction score value is greater than 2 grades, can determine that be against regulation, which is not available as intramuscular injection.
The reaction classification of 5 musculature of table
Test result
Method is infused using rabbit quadriceps muscle of thigh, upon administration 2,7 and 15d, eye is seen without swelling, touches injection site without scleroma. Dissect deferred shares of stock musculus quadriceps, it is longitudinally slit, the response situation of injection site musculature is observed, determines the order of reaction (being shown in Table 5), It is averagely classified as 1 grade, less than 2 grades, saline control group is 0 grade, injects sterile saline, muscle to rabbit quadriceps muscle of thigh It organizes identical as normal muscle tissues；Injection site does not go out after injecting local anaesthetics and 2,7 and 15d of non-steroidal anti-inflammatory drugs compound preparation The irritative responses such as existing musculature redness, hyperemia, the performance of the rabbit state of mind are good.Microscopically observation muscle fiber is horizontal Line is clear, structural integrity, and no denaturation, necrosis and inflammatory reaction have no apparent pathological change compared with saline control group.
6 injection of table is to rabbit quadriceps muscle of thigh test result
The local anaesthetics and/or non-steroidal anti-inflammatory drugs compound preparation of the different prescriptions of test example 5 are to rat wound inflammatory reaction It influences
(1) foundation of animal model
48 rats are taken to do notch pain model, it is left back to rat with 10% Iodophor after chloral hydrate anesthesia is injected intraperitoneally Limb skin carries out disinfection, and the longitudinal incision for being about 1cm, notch are then done from the 0.5cm of In The Rat Sole proximal end with knife blade Skin and fascia provoke vola muscle and longitudinally cutting with ophthalmic tweezers, keep the start-stop of muscle and attachment complete, are pressed with gauze Skin suture after hemostasis.
(2) grouping and administration
This experiment is divided into 6 groups, and each group is made a living respectively manages salt water group-group 1, (the prescription choosing of Ropivacaine sustained release preparation-group 3 From patent CN103142458), Ropivacaine sustained release preparation-group 4 (prescription be selected from application No. is 201810592597.1 it is special Benefit), SC 69124 sustained release preparation-group 5, (specific prescription and specification are shown in for Ropivacaine and SC 69124 compound slow release preparation-group 6 Table 2) each group injects relative medicine on the right side of the wound immediately after rat modeling respectively at 0.5cm, and each group administration total amount is 10mg/kg。
(3) observation index
4h and each group execution for 24 hours 6 upon administration respectively, draws medicine side lumbar spinal cord Peng's general goal, after tissue homogenate, use is enzyme-linked Immunosorbent adsorption test (ELISA) detects the expression of inflammatory factor TNF-α, IL-1 β, IL-6.
(4) statistical method
It is for statistical analysis with SPSS10.0 software, compare between multiple groups mean using one-way analysis of variance (ANOVA), P < 0.05 be it is statistically significant, P < 0.01 be statistically significant.
(5) evaluation of wound inflammatory reaction nearby
The expression of each inflammatory factor of incision is shown in Table 7, with control group (group 1) and local anaesthetics sustained release preparation group (group 3) it compares, the sustained release preparation group containing non-steroidal anti-inflammatory drugs, it may be assumed that non-steroidal anti-inflammatory drugs preparation group (group 4), local anaesthetics and non-steroidal The expression of each inflammatory factor of rat incision significantly reduces in anti-inflammatory agent compound slow release preparation group (group 5).
The expression of 7 different dosing group incision TNF-α of table, IL-1 β, IL-6
Local anaesthetics and non-steroidal anti-inflammatory drugs dose screening are tested in 6 compound of test example
(1) preparation of the local anesthetic and non-steroidal anti-inflammatory drugs compound slow release preparation of different prescriptions
According to the prescription in table 8, different local anesthetics and non-steroidal anti-inflammatory drugs compound slow release preparation are prepared respectively.
The different local anesthetics of table 8 and non-steroidal anti-inflammatory drugs compound slow release preparation prescription
(2) the different local anesthetics of prescription and the pharmacodynamic study of non-steroidal anti-inflammatory drugs compound slow release preparation
Retardance of the compound slow release preparation of different prescriptions for rat sensory nerve is assessed according to the hot plate method in test example 2 Effect, measures influence of the compound slow release preparation of different prescriptions for rat wound healing according to the method in test example 3, according to Method in test example 5 measures influence of the compound slow release preparation of different prescriptions for mouse wound inflammatory reaction.
Test result:
(i) resistance of the local anesthetic and non-steroidal anti-inflammatory drugs compound slow release preparation of different prescriptions for rat sensory nerve Stagnant effect
Influence of the compound slow release preparation of the different prescriptions of table 9 for rat wound inflammatory reaction
The compound slow release preparation of different prescriptions is as shown in table 9 for the retardation of rat sensory nerve, and (1) group 1 arrives group 6 compound slow release preparation is significantly stronger than rat sensory nerve retardation the effect that group 7 arrives the compound slow release preparation of group 9, Illustrate, it is high in compound preparation, in (local anaesthetics of (80mg/ml, 40mg/ml) dosage acts on the nerve block of compound preparation It is significantly stronger than the nerve block effect of the local anaesthetics (20mg/ml) of low dosage in compound preparation.(2) compound of group 1 to group 3 is slow Release formulation and the compound slow release preparation of group 4 to group 6 do not have apparent difference for rat sensory nerve retardation, illustrate medium The local anaesthetics (40mg/ml) of dosage for rat sensory nerve retardation and high dose local anaesthetics (80mg/ml) for big Mouse sensory nerve retardation is suitable.(3) group 1, group 2, the compound slow release preparation for organizing 3 do not have rat sensory nerve retardation There is apparent difference, likewise, group 4, group 5, the compound slow release preparation of group 6 be not obvious for rat sensory nerve retardation Difference, illustrate, under high, middle dosage local anaesthetics, the nerve block of the non-steroidal anti-inflammatory drugs of various dose for compound preparation Act on no significant impact.
(ii) local anesthetic of different prescriptions and non-steroidal anti-inflammatory drugs compound slow release preparation are for rat wound healing It influences
Influence of the compound slow release preparation of the different prescriptions of table 10 for rat wound healing
Grouping D1 D3 D7 D14 D21
Group 1 - 34.26% 72.61% 95.37% 97.68%
Group 2 - 36.05% 71.96% 94.68% 97.54%
Group 3 - 29.65% 56.94% 85.35% 97.55%
Group 4 - 33.58% 73.13% 95.24% 96.25%
Group 5 - 35.62% 72.42% 96.31% 96.62%
Group 6 - 28.35% 58.13% 87.34% 98.25%
Group 7 - 34.92% 73.25% 96.21% 98.72%
Group 8 - 35.06% 73.61% 95.96% 96.24%
Group 9 - 29.76% 56.34% 86.73% 97.34%
Influence of the compound slow release preparation of different prescriptions for rat wound healing is as shown in table 10, (1) group 1, group 2, group 4, the compound slow release preparation in group 5, group 7 and group 8 is significantly stronger than group 3, group 6 and group 9 for the facilitation of rat wound healing In compound slow release preparation effect, illustrate, it is high in compound preparation, in (30mg/ml, 20mg/ml) dosage non-steroidal anti-inflammatory Medicine is significantly stronger than the promotion wound healing effect of compound preparation the non-steroidal anti-inflammatory drugs (10mg/ of low dosage in compound preparation Ml promotion wound healing effect).(2) group 1 is compared with group 2, and group 4 is compared with group 5, and compound slow release preparation is for rat wound The facilitation of healing does not have apparent difference, illustrates the non-steroidal anti-inflammatory drugs (20mg/ml) of median dose for rat wound The facilitation of healing and the non-steroidal anti-inflammatory drugs (30mg/ml) of high dose are suitable for the facilitation of rat wound healing. (3) group 1, group 4 and the compound slow release preparation in group 7 do not have apparent difference for the facilitation of rat wound healing, equally , group 2, group 5 and the compound slow release preparation of group 8 do not have apparent difference for the facilitation of rat wound healing, illustrate, Under high, middle dosage non-steroidal anti-inflammatory drugs, the local anesthetic of various dose does not have the promotion wound healing effect of compound preparation There is significant impact.
(iii) local anesthetic of different prescriptions and non-steroidal anti-inflammatory drugs compound slow release preparation are anti-for rat wound inflammation The influence answered
Influence of the compound slow release preparation of the different prescriptions of table 11 for rat wound inflammatory reaction
Influence of the compound slow release preparation of different prescriptions for rat wound inflammatory reaction is as shown in table 11, and (1) organizes 1, group 2, group 4, group 5, group 7 and group 8 in compound slow release preparation for inhibit the inflammatory reaction of rat wound effect be significantly stronger than group 3, Group 6 and group 9 in compound slow release preparation effect, illustrate, in compound preparation height, in (30mg/ml, 20mg/ml) dosage it is non- Steroidal anti-inflammatory medicine is significantly stronger than low dosage in compound preparation for the effect of the inhibition rat wound inflammatory reaction of compound preparation The effect of the inhibition rat wound inflammatory reaction of non-steroidal anti-inflammatory drugs (10mg/ml).(2) group 1 is compared with group 2,5 phases of group 4 and group Than compound slow release preparation does not have apparent difference for the inhibiting effect of rat wound inflammatory reaction, illustrates the non-of median dose Steroidal anti-inflammatory medicine (20mg/ml) is for inhibiting the effect of rat wound inflammatory reaction and the non-steroidal anti-inflammatory drugs of high dose (30mg/ml) is suitable for inhibiting the effect of rat wound inflammatory reaction.(3) compound slow release preparation in group 1, group 4 and group 7 For inhibiting the effect of rat wound inflammatory reaction there is no apparent difference, likewise, group 2, group 5, the compound slow release preparation for organizing 8 There is no apparent difference for the effect of inhibition rat wound inflammatory reaction, illustrates, under high, middle dosage non-steroidal anti-inflammatory drugs, Effect no significant impact of the local anesthetic of various dose for the inhibition rat wound inflammatory reaction of compound preparation.
Described in summary, the drug effect of the 5th group of compound preparation is best in test example 6, it may be assumed that the local anesthetic of median dose Local anesthetic and non-steroidal anti-inflammatory drugs composed by the non-steroidal anti-inflammatory drugs (20mg/ml) of (40mg/ml) and median dose The drug effect of compound preparation is best, such as: optimal nerve block effect promotes wound healing effect and inhibits wound inflammatory reaction Effect.
Embodiment 1
Embodiment 2:
Embodiment 3:
Embodiment 4:
Embodiment 5:
Embodiment 6:
Embodiment 7:
Embodiment 8:
Embodiment 9:
Embodiment 10:
Embodiment 11
Embodiment 12
Embodiment 13
。

Claims (10)

1. a kind of long-acting analgesic and the compound sustained-released delivery system for promoting wound healing, by local anesthetic, non-steroidal anti-inflammatory drugs, Solvent and slow-release material composition, wherein the concentration of local anaesthetics is 10-100mg/ml, and the concentration of non-steroidal anti-inflammatory drugs is 2-30mg/ Ml, the ratio of solvent are 10%-70% (v/v), and remaining is slow-release material, wherein local anesthetic is selected from: Bupivacaine, One of chirocaine, Ropivacaine, lidocaine, cloth Shandong cacaine are a variety of；
Wherein, nonsteroidal anti-inflammatory drug is selected from: brufen, sulindac, Etodolac, piroxicam, Meloxicam, chlorine promise former times One of health, ketorolac, aminopyrine, SC 69124, celecoxib, aulin, flurbiprofen axetil are a variety of；
Wherein, solvent is selected from: ethyl alcohol, benzyl alcohol, propylene glycol, glycerol, ethyl acetate, ethyl lactate, tetrahydrofuran polyvinylether With one of polyethylene glycol (molecular weight 200-600Da) or a variety of；
Wherein, slow-release material is made of phosphatide and oil.
2. compound sustained-released delivery system according to claim 1, which is characterized in that consist of the following compositions: local anaesthetics Concentration is 10-80mg/ml, and the concentration of non-steroidal anti-inflammatory drugs is 4-30mg/ml, and the ratio of solvent is 10%-60% (v/v), is remained Under be slow-release material.
3. compound sustained-released delivery system according to claim 1, which is characterized in that consist of the following compositions: local anaesthetics Concentration is 10-50mg/ml, and the concentration of non-steroidal anti-inflammatory drugs is 12-20mg/ml, and the ratio of solvent is 10%-50% (v/v), is remained Under be slow-release material.
4. compound sustained-released delivery system according to claim 1, which is characterized in that the concentration of local anaesthetics is 40mg/ml, non- The concentration of steroidal anti-inflammatory medicine is 20mg/ml.
5. compound sustained-released delivery system according to claim 1, which is characterized in that
Local anesthetic is selected from: one of Bupivacaine, chirocaine, Ropivacaine are a variety of；
Nonsteroidal anti-inflammatory drug is selected from: one of Lornoxicam, ketorolac, SC 69124 and flurbiprofen axetil are a variety of；
Solvent is selected from: one of ethyl alcohol, benzyl alcohol, ethyl lactate and Ergol are a variety of,
Slow-release material is made of phosphatide and oil, and wherein phosphatide is natural and/or synthetic phospholipid and hydrogenated phospholipid, it is preferable that institute It states phosphatide and is selected from one or more of: egg yolk lecithin, soybean lecithin, phosphatidyl choline, dioleyl lecithin, two palm fibres Palmitic acid acyl lecithin, distearoyl lecithin, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, two Pork and beans Cool acyl phosphatidylserine, distearoyl phosphatidyl-ethanolamine, egg PC, Polyene Phosphatidylcholine, glycerophosphatide Phatidylcholine, hydrogenated soya phosphatide, hydrogenation yolk phosphide, di-oleoyl phosphatidylserine, phosphatidic acid, dipalmitophosphatidic acid, Phosphatidyl-ethanolamine, yolk phosphatidylglycerol, phosphatidylinositols；
Wherein, oil can be selected from the mixture of vegetable oil or artificial synthesized grease or both；
Wherein vegetable oil include: soybean oil, castor oil, rilanit special, sulfonated castor oil, Emulsifier EL-60, sesame oil, Peanut oil, cottonseed oil, corn oil, olive oil, sunflower oil, tea oil, palm oil, Seabuckthorn Oil, fish oil, garlic oil, safflower oil A kind of, two or more mixture；
Wherein, artificial synthesized grease include: midchain oil, ethyl oleate, glyceryl triacetate, middle long-chain oil, acetin, Ergol, isopropyl myristate, tributyl citrate, alkyl (C12-C15) benzene methyl, benzyl phenylacetate, sad second Ester, gallic acid fourth diester, progallin A, propylgallate, methyl myristate, isopentyl palmitate, propionic acid Ethyl ester, isoamyl propionate, benzyl propionate, n-methyl-2-pyrrolidone, oleic acid and oleate.
6. compound sustained-released delivery system according to claim 1, which is characterized in that
Phosphatide is selected from: one of egg yolk lecithin, soybean lecithin, phosphatidyl choline, hydrogenated soya phosphatide, two kinds or two Kind or more mixture；
Vegetable oil is selected from: castor oil, soybean oil, olive oil, sesame oil, a kind of, two or more of corn oil mix Close object；
Artificial synthesized grease is selected from one or both of ethyl oleate, midchain oil mixture.
7. compound sustained-released delivery system according to claim 1, which is characterized in that local anesthetic or non-steroidal anti-inflammatory Medicine can be its free alkali and its corresponding salt；Its salt includes mesylate, hydrochloride, citrate, sulfate, lactic acid Salt, succinate, fumarate, glutamate, ethyl sulfonate, benzene sulfonate, citrate, salicylate, maleate Deng；Wherein, preferably mesylate, hydrochloride, citrate and maleate；Most preferably mesylate and hydrochloride.
8. compound sustained-released delivery system according to claim 1, which is characterized in that consist of the following compositions: prescription 1:
Prescription 2:
Prescription 3:
Prescription 4:
Prescription 5:
Prescription 6:
Prescription 7:
Prescription 8:
Prescription 9:
Prescription 10:
Prescription 11:
9. the preparation method of the described in any item compound sustained-released delivery systems of claim 1 to 8, which is characterized in that including following Step:
(1) prepared by medical fluid: precision being weighed a certain amount of local anesthetic and nonsteroidal anti-inflammatory drug is dissolved in certain volume In solvent, then ultrasound, stirring, shearing, shaking or vortex to complete drug dissolution add recipe quantity phosphatide, ultrasound is stirred It mixes, shear, shake or is vortexed to phosphatide and be completely dissolved, finally addition oil, ultrasound, stirring shear or are vortexed to mix and prepare institute Need sustained release drug delivery systems stoste；
(2) aseptic subpackaged: aseptically, the medical fluid prepared to be crossed into miillpore filter and removes impurity, degerming, then sterile Tamponade, gland in a reservoir are dispensed under the protection of nitrogen, can must be used for analgesic compound delivery system, are placed at 2-8 DEG C and are protected It deposits；
Wherein, in the step (2), the delivery system further includes packaging material；Preferably, the packaging material is selected from following a kind of or more Kind: cillin bottle, ampulla, refilling type syringe, clamped bottle,
Wherein, in the step (2), the aperture of the miillpore filter is 0.2 μm.
10. compound sustained-released delivery system described in claim 1 preparation treatment knife wound, bullet wound, operation, burnt degree analgesia and/ Or the application in the drug of the healing of promotion wound.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111840553A (en) * 2019-04-15 2020-10-30 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical preparation and application thereof
WO2020259670A1 (en) * 2019-06-28 2020-12-30 江苏恒瑞医药股份有限公司 Sustained-release lipid composition and preparation method therefor
CN113018248A (en) * 2019-12-23 2021-06-25 南京清普生物科技有限公司 Sustained-release drug delivery system
CN113116813A (en) * 2020-01-14 2021-07-16 中国科学院上海药物研究所 Depot ropivacaine pharmaceutical composition, preparation method and application thereof
CN113117092A (en) * 2020-01-14 2021-07-16 中国科学院上海药物研究所 Non-aqueous sustained-release drug delivery system
CN113616796A (en) * 2021-07-15 2021-11-09 江苏康禾生物制药有限公司 Pain-relieving and anti-inflammatory compound sustained-release preparation
CN113827547A (en) * 2020-06-23 2021-12-24 南京清普生物科技有限公司 Sustained-release preparation composition
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WO2022152232A1 (en) * 2021-01-14 2022-07-21 南京清普生物科技有限公司 Sustained-release preparation composition
WO2022193185A1 (en) * 2021-03-17 2022-09-22 Jiangyin Usun Pharmaceutical Co., Ltd. New conjugates
WO2023115311A1 (en) * 2021-12-21 2023-06-29 南京清普生物科技有限公司 Sustained release preparation composition

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007104732A2 (en) * 2006-03-13 2007-09-20 Advanced In Vitro Cell Technologies, S.L. Stable nanocapsule systems for the administration of active molecules
CN102526753A (en) * 2011-12-15 2012-07-04 成都师创生物医药科技有限公司 In-situ phase change gel slow release system taking phospholipid as substrate and preparation method thereof
CN103142458A (en) * 2013-01-22 2013-06-12 莱普德制药有限公司 Component and preparation method of non-addition analgesia slow release medicine delivering system
CN104427977A (en) * 2012-05-10 2015-03-18 佩因拉佛姆有限公司 Depot formulations of local anesthetic and methods for preparation thereof
CN106535886A (en) * 2014-04-21 2017-03-22 赫伦治疗有限公司 Long-acting polymeric delivery systems
CN108379269A (en) * 2018-04-20 2018-08-10 武汉百纳礼康生物制药有限公司 A kind of sustained release preparation and preparation method thereof for Postoperative Analgesia After
CN108743952A (en) * 2018-06-11 2018-11-06 西安力邦医药科技有限责任公司 Phosphatide-miscible agent-oil sustained release drug delivery systems the prescription and preparation method of local anesthetic

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007104732A2 (en) * 2006-03-13 2007-09-20 Advanced In Vitro Cell Technologies, S.L. Stable nanocapsule systems for the administration of active molecules
CN102526753A (en) * 2011-12-15 2012-07-04 成都师创生物医药科技有限公司 In-situ phase change gel slow release system taking phospholipid as substrate and preparation method thereof
CN104427977A (en) * 2012-05-10 2015-03-18 佩因拉佛姆有限公司 Depot formulations of local anesthetic and methods for preparation thereof
CN103142458A (en) * 2013-01-22 2013-06-12 莱普德制药有限公司 Component and preparation method of non-addition analgesia slow release medicine delivering system
CN106535886A (en) * 2014-04-21 2017-03-22 赫伦治疗有限公司 Long-acting polymeric delivery systems
CN108379269A (en) * 2018-04-20 2018-08-10 武汉百纳礼康生物制药有限公司 A kind of sustained release preparation and preparation method thereof for Postoperative Analgesia After
CN108743952A (en) * 2018-06-11 2018-11-06 西安力邦医药科技有限责任公司 Phosphatide-miscible agent-oil sustained release drug delivery systems the prescription and preparation method of local anesthetic

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113597316B (en) * 2019-04-15 2023-11-24 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical formulation and use thereof
CN111840553A (en) * 2019-04-15 2020-10-30 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical preparation and application thereof
CN113597316A (en) * 2019-04-15 2021-11-02 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical preparation and application thereof
WO2020259670A1 (en) * 2019-06-28 2020-12-30 江苏恒瑞医药股份有限公司 Sustained-release lipid composition and preparation method therefor
CN114007590A (en) * 2019-06-28 2022-02-01 江苏恒瑞医药股份有限公司 Sustained-release lipid composition and preparation method thereof
EP3991722A4 (en) * 2019-06-28 2022-10-05 Jiangsu Hengrui Medicine Co., Ltd. Sustained-release lipid composition and preparation method therefor
CN113018248A (en) * 2019-12-23 2021-06-25 南京清普生物科技有限公司 Sustained-release drug delivery system
CN113018248B (en) * 2019-12-23 2022-07-22 南京清普生物科技有限公司 Sustained-release drug delivery system
WO2021143746A1 (en) * 2020-01-14 2021-07-22 中国科学院上海药物研究所 Non-aqueous sustained release drug delivery system
WO2021143745A1 (en) 2020-01-14 2021-07-22 中国科学院上海药物研究所 Long-acting ropivacaine pharmaceutical composition, preparation method therefor and use thereof
CN113117092A (en) * 2020-01-14 2021-07-16 中国科学院上海药物研究所 Non-aqueous sustained-release drug delivery system
CN113116813A (en) * 2020-01-14 2021-07-16 中国科学院上海药物研究所 Depot ropivacaine pharmaceutical composition, preparation method and application thereof
CN113827547A (en) * 2020-06-23 2021-12-24 南京清普生物科技有限公司 Sustained-release preparation composition
WO2022152232A1 (en) * 2021-01-14 2022-07-21 南京清普生物科技有限公司 Sustained-release preparation composition
WO2022193185A1 (en) * 2021-03-17 2022-09-22 Jiangyin Usun Pharmaceutical Co., Ltd. New conjugates
WO2022194238A1 (en) * 2021-03-17 2022-09-22 Enlitisa (Shanghai) Pharmaceutical Co., Ltd. New peptide conjugates
CN113616796A (en) * 2021-07-15 2021-11-09 江苏康禾生物制药有限公司 Pain-relieving and anti-inflammatory compound sustained-release preparation
CN113941002A (en) * 2021-08-27 2022-01-18 南京清普生物科技有限公司 Slow-release drug delivery system for small-molecule drugs
WO2023115311A1 (en) * 2021-12-21 2023-06-29 南京清普生物科技有限公司 Sustained release preparation composition

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Application publication date: 20190212