CN115252557B - Preparation method of ropivacaine polycystic liposome preparation - Google Patents
Preparation method of ropivacaine polycystic liposome preparation Download PDFInfo
- Publication number
- CN115252557B CN115252557B CN202211065311.7A CN202211065311A CN115252557B CN 115252557 B CN115252557 B CN 115252557B CN 202211065311 A CN202211065311 A CN 202211065311A CN 115252557 B CN115252557 B CN 115252557B
- Authority
- CN
- China
- Prior art keywords
- ropivacaine
- preparation
- liposome
- polycystic
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- 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
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Anesthesiology (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a ropivacaine polycystic liposome preparation, which comprises the following preparation steps: a) Mixing the first aqueous solution with a water-immiscible phase to form a water-in-oil first emulsion; b) Forming a second emulsion by online shearing the water-in-oil first emulsion and the second aqueous solution; c) Removing the volatile solvent from the second emulsion to form an aqueous suspension of ropivacaine encapsulated multivesicular liposomes; d) And carrying out displacement concentration on the aqueous suspension to obtain the ropivacaine multivesicular liposome preparation. The preparation method provided by the invention can effectively improve the encapsulation efficiency and stability of the ropivacaine polycystic liposome, reduce the breakage of the ropivacaine polycystic liposome and the generation of phospholipid fragments, and is more convenient, stable and controllable compared with the prior art in operation, and easy for large-scale industrialized production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of a ropivacaine polycystic liposome preparation.
Background
Clinically common local anesthetics can be divided into two categories according to chemical properties: amides and esters. The amide local anesthetics mainly comprise ropivacaine (Rop), bupivacaine, lidocaine, etidocaine and the like; the ester local anesthetic mainly comprises procaine, cocaine, tetracaine and the like. Ropivacaine hydrochloride belongs to BCS 1 medicine, has good water solubility, has double functions of anesthesia and analgesia, but has short half-life, and is usually developed into a liposome formulation in order to enable the injection to achieve the effect of long-acting slow release analgesia.
Liposomes can be classified into single-chamber liposomes, multi-chamber liposomes, and non-concentric Multivesicular Liposomes (MLV), depending on whether the liposomes are concentric or not. The microvesicular liposomes have a microstructure in which a plurality of liposomes are aggregated into a sphere, and there are many large and small vesicles separated by a lipid bilayer in the interior, and this unique structure imparts a strong rigidity to the liposomes. At present, the preparation of the polycystic liposome mainly adopts a multiple emulsion method.
Chinese patent application CN 110215435A discloses a method for preparing polycystic liposomes comprising the steps of: a) Mixing the inner water phase containing active substances and the volatile water-immiscible solvent phase, and emulsifying to prepare W/O type colostrum; b) Pressing the obtained W/O colostrum into an external water phase through a porous component to obtain W/O/W type compound emulsion; c) Removing volatile water-immiscible solvent in the multiple emulsion to obtain the polycystic liposome suspension. However, the ropivacaine multivesicular liposome prepared by the prior method has poor stability, the solution is agglomerated, broken and the like during the storage and transportation, and broken multivesicular liposome and broken phospholipid fragments are generated when observed under a microscope; meanwhile, the encapsulation efficiency of the sample is also required to be improved, the particle size distribution is wider, the particle size of the sample is reduced during the placement stability, and the stability of the sample is reduced. The long-acting slow release effect of the polycystic liposome is mainly realized by virtue of non-concentric honeycombs, and the polycystic liposome gradually breaks and releases the medicine from outside to inside during release, and the broken polycystic liposome can make the medicine difficult to achieve the expected long-acting slow release effect and influence the therapeutic effect of the medicine.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method of a ropivacaine polycystic liposome preparation. The preparation method provided by the invention can effectively improve the encapsulation efficiency and stability of the ropivacaine polycystic liposome, reduce the breakage of the ropivacaine polycystic liposome and the generation of phospholipid fragments, is more convenient, stable and controllable compared with the prior art, is easy to carry out large-scale manufacture, and solves the problems that the ropivacaine polycystic liposome is easy to generate broken phospholipid fragments, has low encapsulation efficiency, and has reduced stability during the placement period and the like in the prior preparation process.
The purpose of the present invention will be further explained by the following detailed description.
The invention provides a preparation method of a ropivacaine polycystic liposome preparation, which comprises the following preparation steps:
a) Mixing the first aqueous solution with a water-immiscible phase, and shearing at high speed to form a water-in-oil first emulsion; the first aqueous solution comprises phosphoric acid and glucose; the water-immiscible phase comprises a volatile solvent, ropivacaine, and a lipid mixture comprising at least one amphiphilic lipid and at least one neutral lipid;
b) Forming a second emulsion by online shearing the water-in-oil first emulsion and the second aqueous solution; the second aqueous solution comprises glucose and lysine;
c) Removing the volatile solvent from the second emulsion to form an aqueous suspension of ropivacaine encapsulated multivesicular liposomes;
d) And carrying out displacement concentration on the aqueous suspension to obtain the ropivacaine multivesicular liposome preparation.
Preferably, in the first aqueous solution, the mass fraction of glucose is 1-5%, and the mass concentration of phosphoric acid is 25-35mg/ml.
Preferably, in the second aqueous solution, the mass fraction of glucose is 1-5%, and the molar concentration of lysine is 25-35mmol/l.
Preferably, the volume ratio of the first aqueous solution to the water-immiscible mixture is (0.9-1.1): 1.
Preferably, the volume ratio of the water-in-oil first emulsion to the second aqueous solution is (0.2-1): 1.
Preferably, the water-in-oil first emulsion and the second aqueous solution are treated at a constant flow rate through an in-line shear to obtain the second emulsion.
The invention selects the phosphoric acid and the glucose with specific concentration in the first aqueous solution, and selects the phosphoric acid and the lysine with specific concentration in the second aqueous solution, thereby providing proper pH value and osmotic pressure and being beneficial to improving the encapsulation efficiency of the liposome. According to the invention, the ropivacaine medicine is added into the water-immiscible mixture, the mass fraction is not less than 65%, the medicine carrying capacity is remarkably improved, the generation of phospholipid blocks is effectively reduced, and the encapsulation rate is effectively improved.
Preferably, the volatile solvent comprises dichloromethane and/or chloroform.
More preferably, the lipid mixture comprises cholesterol, sinapis acyl lecithins (DEPC), dipalmitoyl phosphatidylglycerols (DPPG) and tricaprylin.
More preferably, the mole fraction of cholesterol in the lipid mixture is no more than 45.45%; the molar ratio of the sinapis acyl lecithin to the cholesterol is 0.5:1-1:1. The inventor found through experiments that: the addition of phospholipids and cholesterol plays a critical role in the preparation process of the liposome, and the particle size, oxidation stability and physical stability of the liposome are positively related to the addition of cholesterol within a certain range, but if the addition of cholesterol is out of range, the membrane load is exceeded, and partial liposome rupture can be caused.
Preferably, the aqueous suspension has an average particle size of 20-40 μm.
Preferably, in the step a), the high-speed shearing rotation speed is 5000-15000rpm; in the step b), the rotation speed of the on-line shearing is 3200-4000rpm.
Preferably, in said step d), the substitution is performed with a sodium chloride solution of 0.8-1.0% by mass concentration.
Correspondingly, the invention also provides the ropivacaine polycystic liposome preparation prepared by the preparation method of the ropivacaine polycystic liposome preparation.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention selects the phosphoric acid and the glucose with specific concentration in the first aqueous solution, controls the pH value of the first aqueous solution to be 1.0-3.0, the osmotic pressure to be 150-300mOsm/kg, selects the phosphoric acid and the lysine with specific concentration in the second aqueous solution, controls the pH value of the second aqueous solution to be 8.0-10.0, and the osmotic pressure to be 150-300mOsm/kg, thereby playing an important role in improving the encapsulation efficiency of the aqueous suspension and the liposome.
(2) According to the invention, ropivacaine is added into the water-immiscible phase, so that the drug loading rate is remarkably improved, the generation of phospholipid blocks is effectively reduced, and the encapsulation efficiency of the aqueous suspension and the quality stability of the liposome preparation are improved.
(3) The inventors found that the addition of phospholipids and cholesterol plays a critical role in the liposome preparation process of the present invention, and by controlling the mole fraction of cholesterol in the lipid mixture to be not more than 45.45%, and preferably the mole ratio of sinapis acyl lecithin to cholesterol, the disruption of the liposome is reduced, and the encapsulation efficiency of the aqueous suspension and the stability of the liposome preparation are further improved.
(4) According to the invention, the online shearing machine is selected to prepare the second emulsion, so that the uniformity of the particle size of the aqueous suspension is effectively improved.
Drawings
Fig. 1 is a photomicrograph of the aqueous suspension prepared by prescription 1 and prescription 4.
Fig. 2 particle size spectra of aqueous suspensions prepared in formulations 1 and 7.
Figure 3 is a graph showing the drug time profile of ropivacaine hydrochloride injection and ropivacaine multivesicular liposome formulations.
Fig. 4 is a graph showing the analgesic effect of ropivacaine hydrochloride injection and ropivacaine multivesicular liposome preparation.
Detailed Description
The invention will be described in further detail with reference to the drawings and examples.
In the present invention, the materials and reagents involved are conventional commercial products, or may be obtained by conventional means of techniques in the art.
Example 1 preparation of ropivacaine polycystic liposome preparation
The preparation method of the ropivacaine polycystic liposome preparation comprises the following preparation steps:
a) Mixing 250ml of the first aqueous solution with 250ml of the water-immiscible phase and shearing at high speed at 10000rpm to form a water-in-oil first emulsion; the first aqueous solution comprises phosphoric acid and glucose, wherein the mass fraction of the glucose is 3%, and the mass concentration of the phosphoric acid is 30mg/ml; the water-immiscible phase comprises volatile solvents of dichloromethane, ropivacaine and a lipid mixture, wherein the mass concentration of the ropivacaine is 60mg/ml, and the lipid mixture comprises 9.4mg/ml of cholesterol, 16.4mg/ml of sinapis acyl lecithin, 1.8mg/ml of dipalmitoyl phosphatidylglycerol and 4.0mg/ml of tricaprylin;
b) Forming a second emulsion by online shearing the water-in-oil first emulsion and 1500mL of second aqueous solution, wherein the online shearing rotating speed is 3600rpm; the second aqueous solution comprises glucose and lysine, wherein the mass fraction of the glucose is 3%, and the molar concentration of the lysine is 30mmol/l;
c) Removing dichloromethane from the second emulsion by purging with nitrogen to form an aqueous suspension of multivesicular liposomes having ropivacaine encapsulation;
d) And (3) carrying out displacement concentration on the aqueous suspension by adopting a sodium chloride solution with the mass concentration of 0.9% to obtain the ropivacaine polycystic liposome preparation.
EXAMPLE 2 investigation of the Effect of different factors on ropivacaine polycystic liposome formulations
The influence of different factors on the ropivacaine polycystic liposome preparation is examined in the embodiment, and the preparation method of the ropivacaine polycystic liposome preparation comprises the following steps:
1) Preparation of the first emulsion: preparing a first aqueous solution of 3wt% glucose and 30mg/ml phosphoric acid, mixing 250ml of the first aqueous solution with 250ml of water-immiscible phases (methylene dichloride is used as a solvent) in which ropivacaine, cholesterol, sinapis acyl lecithin, dipalmitoyl phosphatidylglycerol and tricaprylin are dissolved, and shearing at a high speed to obtain a first emulsion;
2) Preparation of a second emulsion: glucose and lysine are dissolved in water to prepare 1500ml of a second aqueous solution of 3wt% glucose and 30mmol/L phosphoric acid; passing the first emulsion and the second aqueous solution through an online shearing machine at a constant flow rate to obtain a second emulsion;
3) The second aqueous emulsion was purged with nitrogen to remove volatile methylene chloride and form an aqueous suspension of the encapsulated multivesicular liposomes with ropivacaine.
4) Then 0.9wt% sodium chloride solution is used for replacement and concentration, thus obtaining the ropivacaine liposome preparation.
(1) Effect of different first aqueous solutions on ropivacaine polycystic liposome formulations
Prescriptions 1-3 as shown in table 1, prescriptions 1, 2 differ from prescription 3 only in that: the first aqueous solution is different. As can be seen from table 1, the encapsulation efficiency of the aqueous suspension prepared in formulation 1 is significantly higher than that of formulations 2 and 3; therefore, the first aqueous solution contains glucose and phosphoric acid with certain concentration, which is favorable for better wrapping ropivacaine in the process of preparing liposome and plays a vital role in improving the encapsulation rate of the aqueous suspension.
Table 1 ropivacaine liposome formulations and encapsulation efficiency for different first aqueous solutions
(2) Effects of ropivacaine addition to different relative ropivacaine polycystic liposome formulations
Table 2 ropivacaine liposome formulations and encapsulation rates with different phases of ropivacaine addition
As can be seen from table 2, the addition of ropivacaine to the water-immiscible phase significantly improves the encapsulation efficiency of the aqueous suspension, and the first aqueous solution formulation is simpler and more convenient to operate, stable and controllable, and easier to mass production; as can be seen from FIG. 1, the aqueous suspension prepared in formulation 1 had better particle rounding and significantly less phospholipid cake.
(3) Effect of different lipid mixtures on ropivacaine polycystic liposome formulations
Table 3 ropivacaine liposome formulations and encapsulation efficiency for different lipid mixtures
From table 3, it can be seen that the ratio of sinapis acyl lecithin to cholesterol is critical in the liposome preparation process; when the molar ratio of the sinapis acyl lecithin to the cholesterol is 0.75:1, the encapsulation efficiency and the stability of the aqueous suspension are optimal; when the molar ratio of the sinapis acyl lecithin to the cholesterol is 2:1, the encapsulation efficiency is not ideal.
(4) Influence of the preparation Process of the second emulsion on the preparation of ropivacaine polycystic liposomes
Table 4 comparison of second emulsion preparation on-line shear and agitation
As can be seen from table 4 and fig. 2, the use of the in-line shear to prepare the second emulsion effectively improves the encapsulation efficiency and uniformity of particle size of the aqueous suspension.
EXAMPLE 3 pharmacokinetic Studies of ropivacaine polycystic liposome formulations
The ropivacaine hydrochloride injection and ropivacaine polycystic liposome preparation are subjected to pharmacokinetics study in rats. Ropivacaine multivesicular liposome formulations were prepared according to prescription 1 in example 2, and ropivacaine hydrochloride injection was obtained by dissolving ropivacaine hydrochloride in 0.9wt% sodium chloride. Ropivacaine hydrochloride injection and ropivacaine multivesicular liposome formulations were subcutaneously administered to each group of rats (6 rats per group) at a ropivacaine dose of 20.0 mg/kg rat body weight to compare the pharmacokinetic profile of each group of rats. Blood samples were collected 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours and 96 hours after injection, respectively, and centrifuged to obtain plasma samples, which were immediately stored at-80 ℃ until the detection analysis. Pharmacokinetic data obtained from plasma samples were analyzed using WinNonlin software and specific pharmacokinetic parameters are shown in table 5.
Table 5 rat pharmacokinetics parameters for single subcutaneous different ropivacaine formulations
As can be seen from Table 5, C obtained with ropivacaine hydrochloride injection group max In contrast, ropivacaine polycystic liposome formulation group C max The probability of adverse reaction is greatly reduced for 62 percent. T obtained by ropivacaine hydrochloride injection group 1/2 In contrast, ropivacaine polycystic liposome formulation group T 1/2 The time for maintaining the drug effect is prolonged obviously longer. The results of the drug profile are shown in fig. 3, and a certain concentration of ropivacaine can be detected in the plasma sample collected from the ropivacaine polycystic liposome preparation group (curve 1) at 48 hours after the administration of the ropivacaine polycystic liposome preparation group (rat), however, the ropivacaine hydrochloride injection group (curve 2) has difficulty in detecting ropivacaine in the plasma sample collected after 12 hours.
Example 4 pimple needle penetration model of percutaneous injection evaluation of anesthetic effect of drugs
The analgesic effect of ropivacaine hydrochloride injection and ropivacaine multivesicular liposome preparation in guinea pig body was evaluated by adopting a guinea pig intradermal rash method. Healthy adult male guinea pigs, weighing 700+ -20 g, were 6 in total. Raising in separate cages, taking water and food freely, and circularly illuminating for 12 hr at 24 deg.C and humidity of 20-30%. The day before administration, mao Ti of the 3×3cm area of the back skin was cleaned and concentric circles were made with r=0.5 cm, r=1.0 cm and r=2.0 cm, respectively. The drug was formed into intradermal pimples by back intradermal injection, and the inside (r=0.5 cm), the pimples (r=1.0 cm), the pimples and the outside (r=2.0 cm) of the pimples were stimulated with needles 5, 12, 16 times each at 3-5s intervals before and at different time points after administration, with the muscle contraction at the place of guinea pig fizzing or stimulation as a pain manifestation, and the number of painless reactions was recorded. The stimulation time points after administration are 15min, 1h, 3h, 6h, 12h, 18h, 24h, 30h and 36h. If the group of drugs is given two time points with zero painless response times, the group of acupuncture stimulation is terminated. The narcotic analgesic effect of ropivacaine hydrochloride injection and ropivacaine multivesicular liposome formulation administered at the same dose is shown in fig. 4, wherein fig. 4-a refers to the inside of pimple (r=0.5 cm), fig. 4-B refers to pimple (r=1.0 cm), and fig. 4-C refers to pimple and beyond (r=2.0 cm). As can be seen from fig. 4, the ropivacaine hydrochloride injection has reduced analgesic effect at 3h after administration, and no analgesic effect begins at 6h; the ropivacaine multivesicular liposome preparation has the continuous efficacy for 36 hours; the ropivacaine polycystic liposome preparation data in the area outside the pimple (r=2.0) show that the analgesic effect starts to decrease at 3h after administration, and a certain analgesic effect is achieved until 36h.
The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.
Claims (8)
1. A method for preparing a ropivacaine polycystic liposome preparation, which is characterized in that: the preparation method comprises the following preparation steps:
a) Mixing the first aqueous solution with a water-immiscible phase, and shearing at high speed to form a water-in-oil first emulsion; the first aqueous solution comprises phosphoric acid and glucose; the water-immiscible phase comprises a volatile solvent, ropivacaine, and a lipid mixture comprising at least one amphiphilic lipid and at least one neutral lipid;
the lipid mixture includes cholesterol, sinapis acyl lecithin, dipalmitoyl phosphatidylglycerol, and tricaprylin; the mole fraction of cholesterol in the lipid mixture is no greater than 45.45%; the molar ratio of the sinapis acyl lecithin to the cholesterol is 0.5:1-1:1;
b) Forming a second emulsion by online shearing the water-in-oil first emulsion and the second aqueous solution; the second aqueous solution comprises glucose and lysine;
c) Removing the volatile solvent from the second emulsion to form an aqueous suspension of ropivacaine encapsulated multivesicular liposomes;
d) And carrying out displacement concentration on the aqueous suspension to obtain the ropivacaine multivesicular liposome preparation.
2. A process for the preparation of ropivacaine polycystic liposome formulation according to claim 1, characterized in that: in the first aqueous solution, the mass fraction of glucose is 1-5%, and the mass concentration of phosphoric acid is 25-35mg/ml.
3. A process for the preparation of ropivacaine polycystic liposome formulation according to claim 1, characterized in that: in the second aqueous solution, the mass fraction of glucose is 1-5%, and the molar concentration of lysine is 25-35mmol/l.
4. A process for the preparation of ropivacaine multivesicular liposome formulations according to any one of claims 1 to 3, characterized in that: the volatile solvent comprises dichloromethane and/or chloroform.
5. A process for the preparation of ropivacaine multivesicular liposome formulations according to any one of claims 1 to 3, characterized in that: the average particle size of the aqueous suspension is 20-40 μm.
6. A process for the preparation of ropivacaine multivesicular liposome formulations according to any one of claims 1 to 3, characterized in that: in the step a), the rotating speed of high-speed shearing is 5000-15000rpm; in the step b), the rotation speed of the on-line shearing is 3200-4000rpm.
7. A process for the preparation of ropivacaine multivesicular liposome formulations according to any one of claims 1 to 3, characterized in that: in step d), the substitution is carried out by using a sodium chloride solution with the mass concentration of 0.8-1.0%.
8. Ropivacaine multivesicular liposome preparation prepared by the method for preparing a ropivacaine multivesicular liposome preparation according to any one of claims 1 to 7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211065311.7A CN115252557B (en) | 2022-09-01 | 2022-09-01 | Preparation method of ropivacaine polycystic liposome preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211065311.7A CN115252557B (en) | 2022-09-01 | 2022-09-01 | Preparation method of ropivacaine polycystic liposome preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115252557A CN115252557A (en) | 2022-11-01 |
| CN115252557B true CN115252557B (en) | 2023-06-02 |
Family
ID=83754449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211065311.7A Active CN115252557B (en) | 2022-09-01 | 2022-09-01 | Preparation method of ropivacaine polycystic liposome preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115252557B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113171343A (en) * | 2021-05-14 | 2021-07-27 | 成都大学 | Amikacin sulfate multivesicular liposome for local injection and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6780849B2 (en) * | 2000-12-21 | 2004-08-24 | Scimed Life Systems, Inc. | Lipid-based nitric oxide donors |
| CN104606129B (en) * | 2015-01-21 | 2018-05-04 | 中国人民解放军广州军区武汉总医院 | Ropivacaine long-acting injection thermo-sensitive gel and preparation method thereof |
| CN110215435B (en) * | 2018-05-09 | 2024-01-09 | 广东嘉博制药有限公司 | Method for preparing polycystic liposome |
| 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 |
| CN113171354B (en) * | 2021-04-13 | 2022-12-16 | 华南理工大学 | Sodium alginate modified ropivacaine hydrochloride multi-vesicular liposome microsphere and preparation method and application thereof |
-
2022
- 2022-09-01 CN CN202211065311.7A patent/CN115252557B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113171343A (en) * | 2021-05-14 | 2021-07-27 | 成都大学 | Amikacin sulfate multivesicular liposome for local injection and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115252557A (en) | 2022-11-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11839685B2 (en) | Composition of matter comprising liposomes embedded in a polymeric matrix and methods of using same | |
| US8834921B2 (en) | Sustained-release liposomal anesthetic compositions | |
| CN108379269B (en) | Sustained-release preparation for postoperative analgesia and preparation method thereof | |
| AU5559799A (en) | Liposomal bupivacaine compositions prepared using an ammonium sulfate gradient | |
| JP2006502233A (en) | Platinum aggregate and method for producing the same | |
| US9579261B2 (en) | Method and apparatus for preparing novel liposome | |
| US11819572B2 (en) | Treatment of pain by administration of sustained-release liposomal anesthetic compositions | |
| US11931459B2 (en) | Treatment of pain in pediatric patients by administration of sustained-release liposomal anesthetic compositions | |
| US20220273568A1 (en) | Multivesicular liposome formulations of dexmedetomidine | |
| CN109983013A (en) | Meloxicam zinc complexes particle multivesicular liposome preparation and preparation method thereof | |
| CN115252557B (en) | Preparation method of ropivacaine polycystic liposome preparation | |
| CN110496103B (en) | Docetaxel palmitate liposome and preparation method thereof | |
| TWI391149B (en) | Nanopegylated liposome and method for making the same | |
| WO2023064464A1 (en) | Bupivacaine multivesicular liposome formulations and uses thereof | |
| CN112773776A (en) | Drug-loaded nanoparticle system | |
| CN113827566A (en) | Chlorogenic acid-lipid complex liposome and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |