CN115414324A - Emulsion carrying local anesthetic and preparation method thereof - Google Patents

Emulsion carrying local anesthetic and preparation method thereof Download PDF

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Publication number
CN115414324A
CN115414324A CN202110603153.5A CN202110603153A CN115414324A CN 115414324 A CN115414324 A CN 115414324A CN 202110603153 A CN202110603153 A CN 202110603153A CN 115414324 A CN115414324 A CN 115414324A
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parts
emulsion
local anesthetic
oil
combination
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马光辉
韦祎
袁淼淼
刘静璇
周炜清
那向明
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Institute of Process Engineering of CAS
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Institute of Process Engineering of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/395—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
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics

Abstract

The invention relates to a local anesthetic-carrying emulsion and a preparation method thereof, wherein the local anesthetic-carrying emulsion is an O/W type emulsion prepared by using a local anesthetic and an auxiliary material as preparation raw materials and combining an O/W type emulsion method with a rapid membrane emulsion method. The emulsion carrying the local anesthetic is prepared by creatively adopting an O/W type emulsification method and a rapid membrane emulsification method as preparation raw materials, is different from the traditional emulsion preparation method (mechanical stirring, ultrasound, homogenization and the like), and can be used for preparing the emulsion with uniform and controllable particle size, strong stability, high drug encapsulation efficiency and accurate and stable drug release by combining the O/W emulsification method and the rapid membrane emulsification method.

Description

Emulsion carrying local anesthetic and preparation method thereof
Technical Field
The invention belongs to the technical field of biological medicines, relates to a local anesthetic-carrying emulsion and a preparation method thereof, and particularly relates to a local anesthetic-carrying emulsion which is uniform in particle size, high in drug encapsulation rate, good in sustained and controlled release effect and strong in stability and a preparation method thereof.
Background
With the improvement of living standard, the demand of people for painless operation is more and more urgent. The local anesthetic can be used for controlling postoperative acute or chronic pain, and mainly comprises laparotomy, breast cancer operation, amputation, thoracotomy and the like. Local anesthetics temporarily block local nerve conduction, thereby providing anesthesia. Common local anesthetics are procaine, lidocaine, bupivacaine, and ropivacaine. At present, the analgesia time of the clinically used water-soluble local anesthetic by single injection is too short, however, the time required for analgesia after laparotomy, breast cancer operation, amputation operation, thoracotomy and the like is generally from several days to more than ten days, so that the single injection administration cannot meet the clinical requirement. Clinically, pain is generally managed by placement of a continuous administration catheter, but this presents a costly treatment apparatus (pump) and a risk of infection. In order to solve the existing disadvantages, a safe and effective local anesthesia slow-release preparation is urgently needed to be developed.
The local anesthetic emulsion has the advantages that firstly, the emulsion has solubilization, and the oil phase in the emulsion can greatly increase the solubility of lipophilic drugs; secondly, the slow release effect is realized, and the drug can be gradually diffused and permeated after the emulsion layer is broken, so that the aim of slow release is fulfilled. The stable and accurate release of the local anesthetic sustained-release emulsion can meet the clinical requirement of 3-7 days of analgesic time after operation, and simultaneously, the problem of cardiovascular toxicity caused by drug accumulation due to excessive injection times is reduced.
The invention discloses a Chinese patent publication No. CN1318422A, which is named as a self-suction multi-channel phase dispersion extraction device, and the application scheme discloses a self-suction multi-channel phase dispersion device, and the device solves the problem of overlarge shearing force in the traditional emulsion preparation process. The disadvantage is that the device is mainly used for extraction technology, so the problem of uniform emulsion particle size is not considered.
Chinese patent publication No. CN100421775C, invents the name "a preparation facilities of the emulsion droplet of the self-priming type of uniform low shear", the apparatus utilizes the negative pressure produced under the low rotational speed, disperse the oil phase or aqueous phase in another phase evenly, the liquid is stressed the shearing force evenly, can prepare the emulsion droplet with homogeneous particle size. The disadvantages are that the device has less processing capacity and cannot realize continuous mechanized operation.
The invention discloses a Chinese patent publication No. CN100469426C, which discloses a high-flux continuous uniform emulsion droplet preparation device, and the device can continuously and uniformly disperse an oil phase or a water phase in another phase at a low rotating speed to prepare emulsion droplets with uniform particle sizes. The disadvantage is that the device is only suitable for preparing emulsion droplets with larger particle size.
Therefore, it is necessary to develop a local anesthetic-carrying emulsion with uniform particle size, high drug encapsulation rate, good sustained and controlled release effect, strong stability, simple preparation process, and easy realization of later-stage amplification production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a local anesthetic-carrying emulsion and a preparation method and application thereof, and particularly provides the local anesthetic-carrying emulsion which is uniform in particle size, high in drug encapsulation rate, good in sustained and controlled release effect and strong in stability, and the preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a local anesthetic-carrying emulsion, which is an O/W type emulsion prepared by using a local anesthetic and an auxiliary material as raw materials and combining an O/W type emulsion method with a rapid membrane emulsion method.
In clinical application, the local anesthetics such as ropivacaine, bupivacaine, mepivacaine and lidocaine can be frequently injected due to short half-life period, so that excessive drug concentration accumulation can cause cardiovascular and central nervous toxicity. On the premise of ensuring high drug loading, the achievement of the release behavior and burst release dosage to the ideal clinical expectation becomes one of the difficulties. The emulsion carrying the local anesthetic is prepared by creatively adopting an O/W type emulsification method and a rapid membrane emulsification method as preparation raw materials, is different from the traditional emulsion preparation method (mechanical stirring, ultrasound, homogenization and the like), and can be used for preparing the emulsion with uniform and controllable particle size, strong stability, high drug encapsulation efficiency and accurate and stable drug release by combining the O/W emulsification method and the rapid membrane emulsification method. The fast membrane emulsification technology is that the pre-emulsion passes through the membrane pores by pressurizing inert gas, so as to form a monodisperse emulsion with the pore diameter smaller than that of the membrane, and the technology can prepare the emulsion with uniform and controllable particle diameter by adjusting the pore diameter of the microporous membrane, thereby avoiding flocculation and delamination caused by the Oswald curing phenomenon brought by the traditional technology.
Preferably, the average particle size of the local anesthetic-loaded emulsion is 0.5-200 μm, such as 0.5 μm, 1 μm, 5 μm, 10 μm, 20 μm, 50 μm, 100 μm, 150 μm, 200 μm, and the like, and other specific values in the value range can be selected, which are not described in detail herein. Preferably 1 to 50 μm, and more preferably 5 to 20 μm.
Preferably, the particle size distribution coefficient Span value of the local anesthetic-loaded emulsion is 0.1-1.2, such as 0.1, 0.2, 0.4, 0.5, 0.6, 0.7, 0.8, 1.0, 1.1, 1.2, and the like, and other specific values in the numerical range can be selected, which is not described in detail herein. Preferably 0.1 to 1.0.
Preferably, the preparation raw materials comprise local anesthetics, emulsifiers, surfactants, isotonic regulators, thickeners, oil phase solvents and water.
The emulsion provided by the invention is prepared by combining and matching the preparation raw materials of local anesthetic, emulsifier, surfactant, isotonic regulator, thickener, oil phase solvent and water, and when the following specific mass ratio relationship is met, the prepared emulsion has uniform and controllable particle size, strong stability and high drug encapsulation rate, and can realize accurate and stable drug release.
Preferably, the local anesthetic is added to the emulsion in an amount of 0.5-40% (w/v), such as 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 37%, 40%, etc., and other specific values within this range can be selected, which is not described herein again. Every 1% (w/v) at w/v according to the present invention corresponds to 10 (g/L).
Preferably, the preparation raw materials comprise, by mass, 0.5-40 parts of local anesthetic, 0.5-20 parts of emulsifier, 1-50 parts of surfactant, 2.25-30 parts of isotonic regulator, 0.5-15 parts of thickener, 0.5-50 parts of oil phase solvent and 50-99.5 parts of water.
The local anesthetic can be selected from 0.5 part, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 37 parts, 40 parts and the like in parts by weight.
The emulsifier can be selected from 0.5 part, 1 part, 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, 18 parts, 20 parts and the like in parts by mass.
The surfactant can be selected from 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 37 parts, 40 parts, 45 parts, 50 parts and the like in parts by mass.
The isotonic regulator can be selected from 2.25 parts, 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, 18 parts, 20 parts, 25 parts, 30 parts and the like in parts by mass.
The mass parts of the thickening agent can be selected from 0.5 part, 1 part, 5 parts, 8 parts, 10 parts, 12 parts, 15 parts and the like.
The oil phase solvent can be selected from 0.5 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 50 parts and the like in parts by weight.
The water can be selected from 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 99.5 parts and the like in parts by mass.
Other specific values within the above ranges can be selected, and are not described in detail herein.
Further preferably, the preparation raw materials comprise, by mass, 0.5-20 parts of local anesthetic, 0.5-10 parts of emulsifier, 1-25 parts of surfactant, 2.25-15 parts of isotonic regulator, 0.5-10 parts of thickener, 0.5-50 parts of oil phase solvent and 50-99.5 parts of water.
More preferably, the preparation raw materials comprise, by mass, 0.5-10 parts of local anesthetic, 0.5-5 parts of emulsifier, 1-10 parts of surfactant, 2.25-5 parts of isotonic regulator, 0.5-2 parts of thickener, 0.5-50 parts of oil phase solvent and 50-99.5 parts of water.
In the present invention, the local anesthetic comprises any one or a combination of at least two of bupivacaine, levobupivacaine, tetracaine, ropivacaine, etidocaine, articaine, lidocaine, mepivacaine, prilocaine, etidocaine, buprenorphine, codeine, hydrocodone, hydromorphone, nalbuphine, oxycodone, oxymorphone, tapentadol, or meptazinol;
the combination of at least two of the foregoing combinations, for example, a combination of bupivacaine and levobupivacaine, a combination of tetracaine and ropivacaine, a combination of etidocaine and articaine, a combination of lidocaine and mepivacaine, and the like, may be selected from any other combination manners, and are not described in detail herein.
Preferably, the emulsifier comprises any one or a combination of at least two of tragacanth, lanolin, polyethylene lanolin, sucrose stearate, soya lecithin or lecithin;
the combination of at least two of the above-mentioned compounds, such as the combination of tragacanth and lanolin, the combination of polyethylene lanolin and sucrose stearate, the combination of soybean lecithin and lecithin, etc., can be selected in any combination manner, and will not be described in detail herein.
Preferably one or a combination of at least two of tragacanth, lanolin, sucrose stearate, soya lecithin or lecithin; further preferably one or a combination of at least two of tragacanth, lanolin, soybean lecithin or lecithin.
For the emulsion, when the emulsifier is selected from tragacanth, lanolin, soybean phospholipid or lecithin, the prepared emulsion has more uniform particle size and higher drug encapsulation rate, and further can realize more accurate and stable drug release.
In the present invention, the HLB value of the surfactant is 8-18, for example, HLB =8, HLB =9, HLB =10, HLB =12, HLB =13, HLB =14, HLB =15, HLB =16, HLB =17, HLB =18, and the like, and other specific values in the numerical range may be selected, which is not described in detail herein.
Preferably, the surfactant comprises any one of or a combination of at least two of polyoxypropylene mannitol dioleate, polyoxypropylene stearate, polyoxyethylene fatty acid, polyoxyethylene oxypropylene oleate, polyoxyethylene lauryl ether, polyoxyethylene monooleate, triethanolamine oleate, polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate;
the combination of at least two of the above-mentioned compounds, for example, the combination of polyoxypropylene mannitol dioleate and polyoxypropylene stearate, the combination of polyoxyethylene fatty acid and polyoxyethylene oxypropylene oleate, etc., may be selected in any combination manner, and thus, details are not repeated herein.
Further preferably, the surfactant is any one of polyoxyethylene fatty acid, polyoxyethylene oxypropylene oleate, polyoxyethylene lauryl ether, polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate or a combination of at least two of them.
More preferably, the surfactant is any one of polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate or a combination of at least two thereof.
For the emulsion related by the invention, when the surfactant is selected from polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate, the prepared emulsion has more uniform particle size and higher drug encapsulation rate, and further can realize more accurate and stable drug release.
In the present invention, the isotonic regulator includes any one or a combination of at least two of glycerin, mannitol, xylitol, sorbitol, sodium chloride solution or glucose; the combination of at least two of the above-mentioned compounds, such as the combination of glycerol and mannitol, the combination of xylitol and sorbitol, the combination of sodium chloride solution and glucose, etc., can be selected in any other combination manner, and thus, the details are not repeated herein.
Further preferably any one of glycerol, mannitol, xylitol, sodium chloride solution or glucose or a combination of at least two thereof.
More preferably any one or a combination of at least two of glycerol, xylitol, sodium chloride solution or glucose.
For the emulsion related by the invention, when glycerin, xylitol, sodium chloride solution or glucose is selected as the isotonic regulator, the prepared emulsion has more uniform grain diameter and higher drug encapsulation rate, and further more accurate and stable drug release can be realized.
In the present invention, the thickener includes any one or a combination of at least two of carbomer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, trehalose, tragacanth, hydroxyethyl cellulose ethyl ether or succinylated gelatin;
the combination of at least two of the above-mentioned materials, such as the combination of carbomer and hydroxypropyl methylcellulose, the combination of polyvinylpyrrolidone and sodium carboxymethylcellulose, the combination of trehalose and tragacanth, and the like, can be selected in any combination manner, and are not described in detail herein.
Further preferred is any one or a combination of at least two of sodium carboxymethylcellulose, carbomer, trehalose, tragacanth, hydroxyethylcellulose ethyl ether or succinylated gelatin.
More preferably any one or a combination of at least two of sodium carboxymethylcellulose, carbomer, trehalose, tragacanth or hydroxyethylcellulose.
For the emulsion related to the invention, when the thickening agent is selected from sodium carboxymethylcellulose, carbomer, trehalose, tragacanth or hydroxyethyl cellulose, the prepared emulsion has more uniform particle size and higher drug encapsulation rate, and further can realize more accurate and stable drug release.
In the present invention, the oil phase solvent includes any one or a combination of at least two of refined soybean oil, peanut oil, safflower oil, cottonseed oil, olive oil, coconut oil, sesame oil, fish oil, short chain triglycerides, medium chain triglycerides, long chain triglycerides, ethyl oleate, acetylated monoglycerol/propylene glycol diester, glyceryl linoleate, or glyceryl laureate polyethylene glycol;
the combination of at least two of the above-mentioned materials, such as the combination of refined soybean oil and peanut oil, the combination of safflower oil and cottonseed oil, the combination of coconut oil, sesame oil and fish oil, etc., can be selected in any combination manner, and thus, the details are not repeated herein.
Further preferably, the oil-soluble oil is one or a combination of at least two of refined soybean oil, peanut oil, olive oil, fish oil, short-chain triglycerides, medium-chain triglycerides, long-chain triglycerides, and ethyl oleate.
More preferably any one or a combination of at least two of refined soybean oil, medium chain triglycerides or olive oil.
For the emulsion related by the invention, when refined soybean oil, medium-chain triglyceride or olive oil is selected as the oil phase solvent, the prepared emulsion has more uniform particle size and higher drug encapsulation rate, and further can realize more accurate and stable drug release.
In a second aspect, the present invention provides a method for preparing the local anesthetic-loaded emulsion according to the first aspect, the method comprising:
(1) Mixing local anesthetic, emulsifier and oil phase solvent, and stirring to obtain oil phase; mixing a surfactant, an isotonic regulator, a thickening agent and water, and stirring to obtain a water phase;
(2) Mixing the oil phase and the water phase, and homogenizing to obtain a pre-emulsion;
(3) Under the protection of inert gas, a rapid membrane emulsifier is used to pass through a microporous membrane to obtain the local anesthetic-loaded emulsion.
The preparation process of the local anesthetic-carrying emulsion is simple, and the later-stage amplification production is easy to realize. The technological parameters of the preparation process can influence the uniformity of the particle size of the final product, and further influence the sustained and controlled release behaviors of the medicine, especially the pressure and times when the medicine passes through a microporous membrane. The rapid membrane emulsifier in the step (3) is preferably the equipment disclosed in the patent (application number is 200720103949. X).
Preferably, the mixing and stirring in step (1) are performed at 40-90 ℃, for example, 40 ℃, 45 ℃,50 ℃, 55 ℃,60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃,90 ℃ and the like, and other specific values in the numerical range can be selected, and are not described in detail herein. Preferably 40 to 70 ℃ and more preferably 40 to 60 ℃.
Preferably, the homogenizing rate in step (2) is 1000-30000rpm, such as 1000rpm, 2000rpm, 3000rpm, 5000rpm, 10000rpm, 15000rpm, 20000rpm, 25000rpm, 30000rpm, etc., and other specific values in the numerical range can be selected, which is not described herein again. Preferably 3000-20000rpm, more preferably 5000-10000rpm.
Preferably, the pore diameter of the microporous membrane in step (3) is 0.5-200 μm, such as 0.5 μm, 1 μm, 5 μm, 10 μm, 50 μm, 99 μm, 100 μm, 150 μm, 200 μm, etc., and other specific values in this numerical range can be selected, which is not described herein again. Preferably 5-99 μm.
Preferably, the Span of the pore size distribution of the microporous membrane is 1.2 or less, for example, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, etc., and other specific values within the numerical range can be selected, which is not described in detail herein. Preferably 1.0 or less.
Preferably, the microporous membrane of step (3) is carried out at 1-500kPa, such as 1kPa, 5kPa, 10kPa, 50kPa, 100kPa, 200kPa, etc., and other specific values in the value range can be selected, which is not described in detail herein. Preferably 10 to 200kPa, and more preferably 10 to 100kPa.
Preferably, the microporous membrane is passed in step (3) 1 to 10 times, for example, 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, preferably 1 to 5 times, and more preferably 1 to 3 times.
Compared with the prior art, the invention has the following beneficial effects:
in clinical application, local anesthetic ropivacaine, bupivacaine, mepivacaine, lidocaine and the like have short half-life and need frequent injection, so that excessive drug concentration accumulation can cause cardiovascular and central nervous toxicity. On the premise of ensuring high drug loading, the release behavior and burst release dosage reach the ideal clinical expectation, which becomes one of the difficulties. The emulsion carrying the local anesthetic is prepared by creatively adopting an O/W type emulsification method and a rapid membrane emulsification method as preparation raw materials, is different from the traditional emulsion preparation method (mechanical stirring, ultrasound, homogenization and the like), and can be used for preparing the emulsion with uniform and controllable particle size, strong stability, high drug encapsulation efficiency and accurate and stable drug release by combining the O/W emulsification method and the rapid membrane emulsification method.
Drawings
FIG. 1 is a schematic flow chart of the preparation of a local anesthetic-loaded emulsion according to the present invention;
FIG. 2 is a particle size distribution diagram of the emulsion prepared in example 1;
FIG. 3 is a graph of the in vitro release of the local anesthetic-loaded emulsion prepared in example 1;
FIG. 4 is a graph of the particle size distribution of the emulsion prepared in example 2;
FIG. 5 is a graph of the in vitro release of a local anesthetic-loaded emulsion prepared in example 2;
FIG. 6 is a graph of the particle size distribution of the emulsion prepared in example 3;
FIG. 7 is a graph of the in vitro release of the local anesthetic-loaded emulsion prepared in example 3;
FIG. 8 is a graph of the particle size distribution of the emulsion prepared in example 4;
FIG. 9 is a graph of the in vitro release of the local anesthetic-loaded emulsion prepared in example 4;
FIG. 10 is a graph of the particle size distribution of the emulsion prepared in example 5;
FIG. 11 is a graph of the in vitro release of a local anesthetic-loaded emulsion prepared in example 5;
FIG. 12 is a graph of the in vitro release of the local anesthetic-loaded emulsion prepared in example 6;
FIG. 13 is a graph of the in vitro release of the local anesthetic-loaded emulsion prepared in example 7;
FIG. 14 is a graph of the in vitro release of a local anesthetic-loaded emulsion prepared in example 8;
FIG. 15 is a chromatogram for HPLC determination of drug content in the local anesthetic-loaded emulsion prepared in example 1.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The prepared emulsion was measured by means of a laser particle sizer (Malvern Company, USA) and the Span value was calculated as follows:
Figure BDA0003093574840000111
wherein D is V,90％ ，D V,50％ And D V,10％ Represents the size of the emulsion particle size at 90%,50% and 10% by volume fraction, respectively. The Span value indicates the homogeneity of the emulsion, wherein a smaller Span value demonstrates a better homogeneity of the emulsion.
Determination of drug concentration and encapsulation efficiency: detection was performed by high performance liquid chromatography. Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler; phosphate buffer (1.3 mL of lmoL/L sodium dihydrogen phosphate solution, 32.5mL of 0.5mol/L disodium hydrogen phosphate solution, water to 1000mL, pH value to 8.0): acetonitrile = (50, v/v) as mobile phase, detection wavelength 240nm, column temperature 37 ℃, flow rate 1mL/min.
The method for measuring the concentration of the drug comprises the following steps: 1mL of a sample is accurately measured, the sample is placed in a 50mL Eppendorf low-adsorption centrifuge tube, 20mL of absolute ethyl alcohol is added for demulsification, the sample is transferred to a 25mL volumetric flask, and the volume is constant. Filtering with 0.45 μm organic filter membrane, and detecting the drug concentration by HPLC.
The method for measuring the encapsulation efficiency comprises the following steps: the content of drug in water phase is determined by high speed centrifugation method, 1mL is put into a centrifuge tube, and centrifuged for 30min at 15000rpm, and the lower layer thinner emulsion is centrifuged for 1h at 5000 rpm. Filtering the bottom layer clear water solution with a 0.2 μm microporous filter membrane, collecting the subsequent filtrate, and determining the encapsulation efficiency by HPLC method.
The envelope rate is calculated by the formula:
Figure BDA0003093574840000112
in the formula, C 0 Is the initial concentration of the drug in the emulsion, V 0 Is the total volume of the emulsion, C W Is the concentration of the drug in the aqueous phase, V W Is the volume of the aqueous phase.
The specific assay method for in vitro release is as follows: in vitro release experiments were performed using the forward osmosis method. 1mL of the emulsion was precisely measured and placed in a dialysis bag, sealed and placed in a 150mL Erlenmeyer flask, and 100mL of PBS buffer (pH = 7.4) was added as a release medium, and the mixture was fixed in a shaker at 200rpm (37. + -. 0.5) ℃ C. 5mL of phosphate buffer was removed from the Erlenmeyer flask at 0.5, 2, 4, 8, 12, 24, 30, 36, 48, 72 hour intervals, respectively, and an equal amount of release medium was added to keep the volume of the release system constant. Detecting the content by using a high performance liquid chromatograph, and determining the accumulative release amount of the medicament.
The fast membrane emulsifier referred to in the following examples all used the apparatus disclosed in the patent (application No. 200720103949. X).
The following examples refer to the following raw materials for the preparation as sources:
starting materials Purchasing merchants Model/make
Sodium carboxymethylcellulose Anhui mountain river pharmaceutical industry auxiliary materials GmbH Pharmaceutical grade croscarmellose sodium
Soybean lecithin Ai Wei Tuo medicine science and technology Co Ltd SY-SO-200801
Polyethylene lanolin Xian Tianzheng pharmaceutic adjuvant Co Ltd Lanolin
Polyvinylpyrrolidone Xian Tianzheng pharmaceutic adjuvant Co Ltd K30
Carbomer Wuhan Enison Biotech Ltd 19060802
Polyoxyethylene monostearate Xian Tianzheng pharmaceutic adjuvant Co Ltd HS15
Hydroxyethyl cellulose Shanxi brocade medicinal auxiliary materials Co Ltd 99 percent of medicinal grade
Polyoxyethylene fatty acid Xiantianzheng pharmaceutic adjuvant, inc Span 80
Sesame oil Xian Tianzheng pharmaceutic adjuvant Co Ltd Sesame oil for injection
Polyoxyethylene vegetable oil Xian jin Xiang pharmaceutic adjuvant Co., ltd Polyoxyethylene 40 hydrogenated castor oil
Example 1
This example provides a local anesthetic-loaded emulsion, which is prepared by the following steps (the preparation schematic diagram is shown in fig. 1):
(1) Precisely weighing 400mg of ropivacaine and 300mg of soybean lecithin, dissolving in 15mL of soybean oil, heating in a water bath at 50 ℃, and uniformly stirring to prepare an oil phase;
(2) Precisely weighing 80.25g of polysorbate, 562.5mg of glycerol and 250mg of sodium carboxymethylcellulose, dissolving in 35mL of water for injection, heating in a water bath at 50 ℃, and uniformly stirring to prepare a water phase;
(3) Adding the oil phase (O) into the water phase (W), and preparing pre-emulsion by a T18 homogenizer at 18000 rpm;
(4) Pouring the prepared pre-emulsion into a rapid membrane emulsifier provided with a 30-micron microporous membrane tube (hydrophilic porous membrane is soaked in water in advance to fully wet the surface of the membrane), and pressing the membrane through the microporous membrane for 10 times under the operation pressure of 60kPa to obtain the O/W emulsion.
Measuring the particle diameter and Span value of the emulsion by using a laser particle sizer, wherein the particle diameter is 23.497 μm and the Span value is 0.766 as shown in figure 2; the content of the determined drug is 7.24mg/mL (a chromatogram for detecting the content of the drug by HPLC is shown in figure 15), and the encapsulation efficiency is 93.42 percent; according to the in vitro release measurement, the cumulative release at 0.5h is 18.59%, and the sustained cumulative release within 3 days is 90.66%, as shown in fig. 3.
Example 2
This example provides a local anesthetic-loaded emulsion, which was prepared by the method different from example 1 only in that soybean phospholipid was replaced with the same amount of polyethylene lanolin, and the other conditions were kept unchanged. The particle size was determined to be 23.783 μm with a Span value of 0.810; the encapsulation efficiency of the drug was determined to be 92.13%.
Example 3
This example provides a local anesthetic-loaded emulsion that is prepared by the method described in example 1, except that the soy phospholipids are replaced with an equal amount of sucrose stearate, and the other conditions are maintained. The particle size is measured to be 22.672 mu m, and the Span value is 0.802; the encapsulation efficiency of the drug was determined to be 91.02%.
Example 4
This example provides a local anesthetic-loaded emulsion prepared by the method of example 1, except that the soybean oil was replaced with the same amount of peanut oil, and the other conditions were maintained. The particle size is determined to be 22.672 mu m, and the Span value is 0.835; the encapsulation efficiency of the drug was determined to be 91.12%.
Example 5
This example provides a local anesthetic-loaded emulsion prepared by the method different from that of example 1 only in that soybean oil was replaced with an equal amount of fish oil, and the other conditions were kept the same. The particle size is measured to be 20.769 μm, and the Span value is 0.816; the encapsulation efficiency of the drug was determined to be 92.33%.
Example 6
This example provides a local anesthetic-loaded emulsion that is prepared by the method described in example 1, except that polysorbate 80 is replaced with an equal amount of polyoxyethylene lauryl ether, and all other conditions are maintained. The particle size was measured to be 23.892 μm, the Span value was measured to be 0.829; the encapsulation efficiency of the drug was determined to be 90.39%.
Example 7
This example provides a local anesthetic-loaded emulsion that is prepared by the method described in example 1, except that glycerol is replaced with an equal amount of mannitol, and the other conditions are maintained. The particle size was determined to be 22.712 μm with a Span value of 0.783; the encapsulation efficiency of the drug was determined to be 93.02%.
Example 8
This example provides a local anesthetic-loaded emulsion prepared by the method different from example 1 only in that sodium carboxymethylcellulose was replaced with an equal amount of polyvinylpyrrolidone, and the other conditions were maintained. The particle size was determined to be 21.098 μm with a Span value of 0.793; the encapsulation efficiency of the drug was determined to be 92.18%.
Example 9
The embodiment provides a local anesthetic-loaded emulsion, which is prepared by the following steps:
(1) Precisely weighing 200mg of bupivacaine and 500mg of lecithin, dissolving in 15mL of olive oil, heating in a water bath at 60 ℃, and uniformly stirring to prepare an oil phase;
(2) Precisely weighing 25mg of sodium oleate, 112.5mg of mannitol and 500mg of carbomer, dissolving in 35mL of water for injection, heating in a water bath at 60 ℃, and uniformly stirring to prepare a water phase;
(3) Adding the oil phase (O) into the water phase (W), and preparing pre-emulsion at the speed of 10000rpm of a T18 homogenizer;
(4) Pouring the prepared pre-emulsion into a rapid membrane emulsifier provided with a 20-micron microporous membrane tube (hydrophilic porous membrane is soaked in water in advance to fully wet the membrane surface), and pressing the membrane through the microporous membrane under the operating pressure of 10kPa for 5 times to obtain the O/W emulsion.
Measuring the particle size and Span value of the emulsion by using a laser particle sizer, wherein the particle size is 16.858 mu m and the Span value is 0.763 as shown in figure 4; the content of the drug is 3.57mg/mL, and the encapsulation efficiency is 92.54%; according to the in vitro release assay, the cumulative release at 0.5h was 19.63% and the sustained cumulative release within 3 days was 88.27%, as shown in FIG. 5.
Example 10
The embodiment provides a local anesthetic-loaded emulsion, which is prepared by the following steps:
(1) Accurately weighing 300mg of etidocaine and 300mg of gelatin, dissolving in 15mL of soybean oil, heating in water bath at 60 ℃, and uniformly stirring to prepare an oil phase;
(2) 1.25g of polyoxyethylene monostearate, 562.5mg of xylitol and 250mg of polyvinylpyrrolidone are precisely weighed and dissolved in 35mL of water for injection, and the mixture is heated in a water bath and uniformly stirred at the temperature of 60 ℃ to prepare a water phase;
(3) Adding the oil phase (O) into the water phase (W) to prepare pre-emulsion at the speed of 22000rpm of a T18 homogenizer;
(4) Pouring the prepared pre-emulsion into a rapid membrane emulsifier provided with a 10-micron microporous membrane tube (hydrophilic porous membrane is soaked in water in advance to fully wet the surface of the membrane), and pressing the membrane through the microporous membrane under the operation pressure of 100kPa for 2 times to obtain the O/W type emulsion.
Measuring the particle size and Span value of the emulsion by using a laser particle sizer, wherein the particle size is 8.943 μm and the Span value is 0.802 as shown in FIG. 6; the content of the drug is 5.68mg/mL, and the encapsulation rate is 92.47%; according to the in vitro release measurement, the cumulative release at 0.5h was 23.55%, and the sustained cumulative release within 3 days was 86.47%, as shown in FIG. 7.
Example 11
The embodiment provides a local anesthetic-loaded emulsion, which is prepared by the following steps:
(1) Accurately weighing 133.5mg of articaine and 30mg of Arabic gum, dissolving in 5mL of soybean oil, heating in water bath at 60 ℃, and uniformly stirring to prepare an oil phase;
(2) Precisely weighing 2.25g of polyoxyethylene vegetable oil, 112.5mg of xylitol and 750mg of trehalose, dissolving in 45mL of water for injection, heating in a water bath at 60 ℃, and uniformly stirring to prepare a water phase;
(3) Adding the oil phase (O) into the water phase (W), and preparing pre-emulsion by a T18 homogenizer at 25000 rpm;
(4) Pouring the prepared pre-emulsion into a rapid membrane emulsifier provided with a 10-micron microporous membrane tube (hydrophilic porous membrane is soaked in water in advance to fully wet the membrane surface), and pressing through the microporous membrane under the operation pressure of 300kPa for 3 times to obtain the O/W emulsion.
Measuring the particle diameter and Span value of the emulsion by using a laser particle sizer, wherein the particle diameter is 8.299 μm and the Span value is 0.843 as shown in figure 8; the content of the drug is measured to be 2.45mg/mL, and the encapsulation efficiency is 94.55%; according to the in vitro release measurement, the cumulative release at 0.5h was 33.23%, and the sustained cumulative release within 3 days was 85.66%, as shown in FIG. 9.
Example 12
The embodiment provides a local anesthetic-loaded emulsion, which is prepared by the following steps:
(1) Precisely weighing 267mg of lidocaine and 1g of tragacanth, dissolving in 10mL of soybean oil, heating in water bath at 90 ℃, and stirring uniformly to obtain an oil phase;
(2) Precisely weighing 2.0g of polyoxyethylene lauryl ether, 900mg of sorbitol and 25mg of hydroxyethyl cellulose, dissolving in 40mL of water for injection, heating in a water bath at 90 ℃, and uniformly stirring to prepare a water phase;
(3) Adding the oil phase (O) into the water phase (W), and preparing pre-emulsion by a T18 homogenizer at a speed of 30000 rpm;
(4) Pouring the prepared pre-emulsion into a rapid membrane emulsifier provided with a 50-micron microporous membrane tube (hydrophilic porous membrane is soaked in water in advance to fully wet the membrane surface), and pressing the microporous membrane under the operation pressure of 300kPa for 8 times to obtain the O/W emulsion.
Measuring the particle size and Span value of the emulsion by using a laser particle sizer, wherein the particle size is 39.447 mu m and the Span value is 0.806 as shown in FIG. 10; the content of the drug is 5.04mg/mL, and the encapsulation rate is 95.13%; according to the in vitro release measurement, the cumulative release at 0.5h was 22.09%, and the sustained cumulative release within 3 days was 86.76%, as shown in FIG. 11.
Example 13
The embodiment provides a local anesthetic-loaded emulsion, which is prepared by the following steps:
(1) Accurately weighing 350mg of mepivacaine and 25mg of apricot gum, dissolving in 15mL of fish oil for injection, heating in water bath at 40 ℃, and uniformly stirring to prepare an oil phase;
(2) Accurately weighing 50mg of polyoxyethylene fatty acid, 787.5mg of glucose and 25mg of succinyl gelatin, dissolving in 35mL of water for injection, heating in a water bath at 40 ℃, and uniformly stirring to prepare a water phase;
(3) Adding the oil phase (O) into the water phase (W), and preparing pre-emulsion by a T18 homogenizer at the speed of 1000 rpm;
(4) Pouring the prepared pre-emulsion into a rapid membrane emulsifier provided with a 2.8-micron microporous membrane tube (hydrophilic porous membrane is soaked in water in advance to ensure that the surface of the membrane is fully wetted), pressing the pre-emulsion through the microporous membrane under the operation pressure of 60kPa, and passing the membrane for 4 times to obtain the O/W emulsion.
Measuring the particle diameter and Span value of the emulsion by using a laser particle sizer, wherein the particle diameter is 1.198 mu m, and the Span value is 0.786; the content of the drug is 6.79mg/mL, and the encapsulation efficiency is 96.48%; according to the in vitro release measurement, the cumulative release at 0.5h is 16.05%, and the sustained cumulative release within 3 days is 88.73%, as shown in fig. 12.
Example 14
The embodiment provides a local anesthetic-loaded emulsion, which is prepared by the following steps:
(1) Accurately weighing 250mg of proparacaine and 90mg of lecithin, dissolving in 15mL of ethyl oleate for injection, heating in a water bath at 40 ℃, and uniformly stirring to prepare an oil phase;
(2) Precisely weighing 1.75g of polyoxyethylene stearate, 45mg of sodium chloride and 350mg of hydroxypropyl methyl cellulose, dissolving in 35mL of water for injection, heating in a water bath at 40 ℃, and uniformly stirring to prepare a water phase;
(3) Adding the oil phase (O) into the water phase (W), and preparing pre-emulsion by a T18 homogenizer at 12000 rpm;
(4) Pouring the prepared pre-emulsion into a rapid membrane emulsifier provided with a 100-micron microporous membrane tube (hydrophilic porous membrane is soaked in water in advance to fully wet the membrane surface), and pressing the microporous membrane under the operating pressure of 40kPa for 1-time membrane crossing to obtain the O/W emulsion.
Measuring the particle diameter and Span value of the emulsion by using a laser particle sizer, wherein the particle diameter is 89.981 mu m, and the Span value is 0.829; determining the content of the medicine to be 4.58mg/mL; the encapsulation efficiency is 91.44%; according to the in vitro release assay, the cumulative release at 0.5h was 25.67%, and the sustained cumulative release within 3 days was 86.96%, as shown in fig. 13.
Example 15
The embodiment provides a local anesthetic-loaded emulsion, which is prepared by the following steps:
(1) Accurately weighing 150mg of meptazinol and 500mg of Arabic gum, dissolving in 15mL of sesame oil for injection, heating in water bath at 50 ℃, and uniformly stirring to prepare an oil phase;
(2) Precisely weighing 1g of polyoxyethylene vegetable oil, 550mg of glycerol and 650mg of tragacanth, dissolving in 35mL of water for injection, heating in water bath at 50 ℃, and uniformly stirring to prepare a water phase;
(3) Adding the oil phase (O) into the water phase (W), and preparing pre-emulsion by a T18 homogenizer at the speed of 5000 rpm;
(4) Pouring the prepared pre-emulsion into a rapid membrane emulsifier provided with a 1-micron microporous membrane tube (the hydrophilic porous membrane is soaked in water in advance to fully wet the membrane surface), and pressing through the microporous membrane for 3 times under the operation pressure of 50kPa to obtain the O/W emulsion.
Measuring the particle size and Span value of the emulsion by using a laser particle sizer, wherein the particle size is 0.548 mu m, and the Span value is 0.779; the content of the drug is measured to be 2.678mg/mL, and the encapsulation efficiency is 96.87%; according to the in vitro release assay, the cumulative release at 0.5h was 18.64%, and the sustained cumulative release over 3 days was 87.88%, as shown in fig. 14.
The applicant states that the present invention is described by the above examples to describe the local anesthetic-carrying emulsion and the preparation method thereof, but the present invention is not limited to the above examples, i.e., it is not meant to imply that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are all within the protection scope of the present invention.
It should be noted that, in the above embodiments, the various features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, the present invention does not separately describe various possible combinations.

Claims (10)

1. The emulsion carrying the local anesthetic is characterized in that the emulsion carrying the local anesthetic is an O/W type emulsion prepared by taking the local anesthetic and auxiliary materials as preparation raw materials and combining an O/W type emulsification method with a rapid membrane emulsification method.
2. The local anesthetic-loaded emulsion according to claim 1, wherein the average particle size of the local anesthetic-loaded emulsion is 0.5-200 μm, preferably 1-50 μm, and more preferably 5-20 μm;
preferably, the particle size distribution coefficient Span value of the local anesthetic-loaded emulsion is between 0.1 and 1.2, preferably between 0.1 and 1.0;
preferably, the preparation raw materials comprise local anesthetics, emulsifying agents, surfactants, isotonic regulators, thickening agents, oil phase solvents and water;
preferably, the local anesthetic is added to the emulsion in an amount of 0.5-40% (w/v).
3. The local anesthetic-loaded emulsion according to claim 2, wherein the preparation raw materials comprise, in parts by mass, 0.5 to 40 parts of the local anesthetic, 0.5 to 20 parts of an emulsifier, 1 to 50 parts of a surfactant, 2.25 to 30 parts of an isotonicity adjusting agent, 0.5 to 15 parts of a thickener, 0.5 to 50 parts of an oil-phase solvent, and 50 to 99.5 parts of water;
preferably, the preparation raw materials comprise, by mass, 0.5-20 parts of local anesthetic, 0.5-10 parts of emulsifier, 1-25 parts of surfactant, 2.25-15 parts of isotonic regulator, 0.5-10 parts of thickener, 0.5-50 parts of oil phase solvent and 50-99.5 parts of water;
preferably, the preparation raw materials comprise, by mass, 0.5-10 parts of local anesthetic, 0.5-5 parts of emulsifier, 1-10 parts of surfactant, 2.25-5 parts of isotonic regulator, 0.5-2 parts of thickener, 0.5-50 parts of oil phase solvent and 50-99.5 parts of water.
4. A local anaesthetic-loaded emulsion as claimed in claim 2 or 3 wherein the local anaesthetic comprises any one of or a combination of at least two of bupivacaine, levobupivacaine, tetracaine, ropivacaine, etidocaine, articaine, lidocaine, mepivacaine, prilocaine, etidocaine, buprenorphine, codeine, hydrocodone, hydromorphone, nalbuphine, oxycodone, oxymorphone, tapentadol or meptazinol;
preferably, the emulsifier comprises any one or a combination of at least two of tragacanth, lanolin, polyethylene lanolin, sucrose stearate, soya lecithin or lecithin; preferably one or a combination of at least two of tragacanth, lanolin, sucrose stearate, soya lecithin or lecithin; further preferred is any one or a combination of at least two of tragacanth, lanolin, soybean lecithin or lecithin.
5. The local anesthetic-bearing emulsion according to any one of claims 2-4, wherein the surfactant has an HLB value of 8-18;
preferably, the surfactant comprises any one of or a combination of at least two of polyoxypropylene mannitol dioleate, polyoxypropylene stearate, polyoxyethylene fatty acid, polyoxyethylene oxypropylene oleate, polyoxyethylene lauryl ether, polyoxyethylene monooleate, triethanolamine oleate, polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate;
preferably, the surfactant is any one or combination of at least two of polyoxyethylene fatty acid, polyoxyethylene oxypropylene oleate, polyoxyethylene lauryl ether, polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate;
preferably, the surfactant is any one of polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate or a combination of at least two of the polyoxyethylene vegetable oil, the polyoxyethylene monostearate, the polysorbate 80 and the sodium oleate.
6. The local anesthetic-loaded emulsion according to any one of claims 2-5, wherein the isotonic adjusting agent comprises any one or a combination of at least two of glycerol, mannitol, xylitol, sorbitol, sodium chloride solution, or glucose; preferably any one or the combination of at least two of glycerol, mannitol, xylitol, sodium chloride solution or glucose; further preferably any one or a combination of at least two of glycerol, xylitol, sodium chloride solution or glucose;
preferably, the thickening agent comprises any one or a combination of at least two of carbomer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, trehalose, tragacanth, hydroxyethylcellulose ethyl ether or succinylated gelatin; preferably any one or a combination of at least two of sodium carboxymethylcellulose, carbomer, trehalose, tragacanth, hydroxyethylcellulose ethyl ether or succinylated gelatin; further preferably one or a combination of at least two of sodium carboxymethylcellulose, carbomer, trehalose, tragacanth or hydroxyethylcellulose;
preferably, the oil phase solvent comprises any one or a combination of at least two of refined soybean oil, peanut oil, safflower oil, cottonseed oil, olive oil, coconut oil, sesame oil, fish oil, short chain triglycerides, medium chain triglycerides, long chain triglycerides, ethyl oleate, acetylated monoglycerol diester of propylene glycol, glycerol linoleate or glycerol laureate of polyethylene glycol; preferably any one or a combination of at least two of refined soybean oil, peanut oil, olive oil, fish oil, short chain triglycerides, medium chain triglycerides, long chain triglycerides or ethyl oleate; further preferred is any one or a combination of at least two of refined soybean oil, medium-chain triglyceride and olive oil.
7. The method of preparing a local anesthetic-loaded emulsion according to any of claims 1-6, wherein the method of preparation comprises:
(1) Mixing local anesthetic, emulsifier and oil phase solvent, and stirring to obtain oil phase; mixing a surfactant, an isotonic regulator, a thickening agent and water, and stirring to obtain a water phase;
(2) Mixing the oil phase and the water phase, and homogenizing to obtain a pre-emulsion;
(3) Under the protection of inert gas, a rapid membrane emulsifier is used to pass through a microporous membrane, and the emulsion carrying the local anesthetic is obtained.
8. The process for preparing a local anesthetic-loaded emulsion according to claim 7, wherein the mixing and stirring of step (1) are performed at 40-90 ℃, preferably 40-70 ℃, and more preferably 40-60 ℃;
preferably, the homogenization rate in step (2) is 1000-30000rpm, preferably 3000-20000rpm, and more preferably 5000-10000rpm.
9. The method for preparing a local anesthetic-loaded emulsion according to claim 7 or 8, wherein the pore size of the microporous membrane of step (3) is 0.5 to 200 μm, preferably 5 to 99 μm;
preferably, the microporous membrane has a pore size distribution Span value of 1.2 or less, preferably 1.0 or less.
10. The process for preparing a local anesthetic-loaded emulsion according to any of claims 7-9, wherein the microporous membrane of step (3) is performed at 1-500kPa, preferably 10-200kPa, more preferably 10-100kPa;
preferably, the microporous membrane is passed in step (3) 1 to 10 times, preferably 1 to 5 times, and more preferably 1 to 3 times.
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CN116139137A (en) * 2023-03-10 2023-05-23 上海市第四人民医院 Sustained-release anesthetic composition and preparation method thereof
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