CN113797168A - Preparation method of bupivacaine multivesicular liposome - Google Patents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil
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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
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
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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
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
Abstract
The invention provides a preparation method of bupivacaine multivesicular liposome, which comprises the following steps: taking a phosphoric acid aqueous solution with the concentration of 15-30 mg/mL as an internal water phase; mixing bupivacaine, lipid components and dichloromethane to form an organic phase, wherein the concentration of the bupivacaine is 35-45 mg/mL; mixing glucose, L-lysine and sodium chloride solution to form an outer water phase, mixing an inner water phase with an organic phase to form a first phase W/O, mixing the first phase W/O with a certain volume of the outer water phase, and stirring to form W/OW primary emulsion; and mixing the W/OW primary emulsion with external water with a certain volume again, stirring to form W/OW multiple emulsion, and removing the organic solvent to obtain the stable multivesicular liposome. The method is a stable and reliable preparation method of multivesicular liposome, which can be used for commercial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical equipment, and particularly relates to a preparation method of bupivacaine multivesicular liposome.
Background
The bupivacaine multivesicular liposome is in a non-concentric circular honeycomb shape, is a preparation which is similar to a sphere and is formed by extruding a plurality of small chambers together, and because the bupivacaine multivesicular liposome can be accumulated at an injection part, the small chambers are gradually broken to release the medicament wrapped in an inner cavity, thereby achieving the purpose of good slow release, improving the medicament carrying capacity of the traditional liposome medicaments and prolonging the medicament release time. The multivesicular liposome is prepared by mixing an inner water phase containing a medicament with an organic phase to prepare a first phase W/O, then dispersing the first phase W/O into an outer water phase to obtain a stable dispersed W/OW emulsion, forming a multivesicular structure by quickly removing an organic solvent, and gradually increasing the hardness of multivesicules along with the gradual removal of the organic solvent to finally form the stable multivesicular liposome. Therefore, the ability to form stable W/OW emulsions is a critical step in the formation of multivesicular. And improper process control in the liquid preparation process can easily cause the phospholipid to be broken and agglomerated to generate floccules which float in the solution.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of bupivacaine multivesicular liposome, which can obtain stable multivesicular liposome.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of bupivacaine multivesicular liposome comprises the following steps:
A. preparation of three-phase solution
Taking a phosphoric acid aqueous solution with the concentration of 15-30 mg/mL as an internal water phase;
mixing bupivacaine, lipid components and dichloromethane to form an organic phase, wherein the concentration of the bupivacaine is 35-45 mg/mL;
mixing glucose, L-lysine and sodium chloride solution to form an external water phase;
B. mixing the internal aqueous phase with the organic phase to form a first phase W/O;
C. mixing the first phase W/O with a certain volume of external water, and stirring to form W/OW colostrum;
D. mixing the W/OW primary emulsion with external water with a certain volume again, stirring to form W/OW multiple emulsion, and removing the organic solvent to obtain the multivesicular liposome.
The multivesicular vesicles contain negatively charged phospholipid components, so that the multivesicular globules are charged with an appropriate amount of charge to stabilize the multivesicular dispersion against multivesicular aggregation, clumping and flocculation, but the surface charge is affected by the concentration of electrolytes in the solution environment and by the volume of the environmental liquid. The concentration of electrolytes in the external aqueous phase is therefore particularly important for the formation of stable W/OW emulsions.
The invention adds L-lysine and electrolyte sodium chloride in the external water phase after the formation of the multi-capsules, and is used for adjusting the surface charge of the multi-capsules. L-lysine in the external water phase has positive charges and forms electrostatic potential with phospholipid globules with negative charges, and the acting force acts on the surfaces of the globules, so that the effect of stabilizing the globules is achieved. Because the potential on the surface of the small ball has important influence on the stability of the small ball, the charge quantity in the solution is adjusted by adjusting the adding quantity of the sodium chloride, and the mutual collision, aggregation and flocculation of the multiple capsules in the forming process can be avoided.
In the step B, the volume ratio of the internal water phase to the organic phase is 0.9-1.1: 1.1 to 0.9, and forming a first phase W/O under high shear at 8000 to 10000 rpm. In the volume ratio range and the high shear speed, the W/O viscosity of the formed first phase is proper, the first phase is not easy to disperse due to agglomeration caused by excessive viscosity in the dilution and dispersion of the external water phase in the next step, and the situation that the multi-capsule particle size is smaller due to the lack of the agglomeration force for forming the multi-capsule caused by low viscosity is avoided.
In the step C, the volume ratio of the first phase W/O to the external water phase is 1: 1.5-2.5, and the first phase W/O and the external water phase are stirred at a low speed of 450-500 rpm to form W/O/W primary emulsion.
Adding external water for carrying out primary dilution on the organic phase is a key for forming a multi-capsule, the particle size of the multi-capsule is influenced, if the rotating speed is high, the first phase W/O with high viscosity is rapidly dispersed and demulsified, the volume ratio of the first phase W/O to the external water phase of the primary dilution is controlled to be 1: 1.5-2.5, the electrostatic attraction and the molecular distance are proper, and the primary diluted W/OW colostrum is most stable.
And D, stirring the W/OW primary emulsion and the external water phase at a volume ratio of 1: 5-6 at a low speed of 150-200 rpm to form W/O/W multiple emulsion.
And controlling the volume ratio of the W/OW colostrum to the external aqueous phase to be 1: 5-6 during the second dilution, wherein the distance between the phospholipid globules is influenced by the volume of the solution, the distance between the globules with larger liquid volume is increased, the electrostatic acting force caused by surface charge is weakened, the density of the multi-vesicle globules is larger, the globules gradually sink in the absence of electrostatic force, and finally the globules are stacked, agglomerated and crushed. When the liquid volume is less, the probability of collision among the small balls is increased, and the small balls are gathered and finally flocculated.
In the second dilution process, the multivesicular is gradually hardened along with the removal of the organic solvent, and the breaking of the multivesicular is directly caused by the excessively high stirring speed, so that the stirring is performed at a low speed of 150-200 rpm.
The temperature of the external water phase is 10-15 ℃, and the W/OW multiple emulsion at low temperature is more stable.
The lysine concentration in the external water phase is 0.6-3 mg/mL, and the glucose concentration is 40-60 mg/mL; the concentration of sodium chloride is 1-2.5 mg/mL. The surface charge quantity is influenced by the positive charge of L-lysine, and also influenced by the ion concentration in the solution environment, the concentration of the substances directly influences the stability of the polycycle, the osmotic pressure is influenced by glucose, the globules with unbalanced osmotic pressure inside and outside the globules can be split, and the concentrations of the lysine and the sodium chloride are used for adjusting the charges.
The lipid component of the present invention consists of triolein, neutral phospholipids, cholesterol, and negatively charged phospholipids.
The invention has the beneficial effects that:
1. on the basis of the components of the original research product, the bupivacaine medicament and the lipid component form an organic phase and then are mixed with the internal water phase, which is different from the traditional method that the medicament is firstly dissolved in the internal water phase, and is more beneficial to the stability of colostrum; sodium chloride electrolyte is added into the external water phase, and the addition amount is strictly controlled to form a stable charge system, so that the surface charge is stable in the process of generating the multi-vesicular globules, the aggregation and flocculation of the globules are prevented, and the stable multi-vesicular liposome is obtained. The method is a stable and reliable preparation method of the multivesicular liposome, and can be applied to actual commercial scale-up production.
2. The invention carries out deep research on the dilution volume, the dilution times, the concentration of L-lysine, the concentration of sodium chloride and the concentration of glucose in the liquid preparation process, ensures that the concentration of phospholipid globules dispersed in the solution is proper, the surface charge amount is moderate, controls the interaction force among globules to balance the globule-solution dispersion system, and further improves the stability in the globule forming process.
Drawings
FIG. 1 is a morphological diagram of the bupivacaine polycystic lipid observed under an optical microscope; a) is the observation of example 4, b) is the observation of the comparative example.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to the accompanying drawings.
Example 1
A preparation method of bupivacaine multivesicular liposome comprises the following steps:
A. preparation of three-phase solution
Taking a phosphoric acid aqueous solution with the concentration of 15mg/mL as an internal water phase;
mixing bupivacaine, lipid components and dichloromethane to form an organic phase, wherein the concentration of the bupivacaine is 35 mg/mL;
mixing glucose, L-lysine and sodium chloride solution to form an external water phase;
B. mixing the internal aqueous phase with the organic phase to form a first phase W/O;
C. mixing the first phase W/O with a certain volume of external water, and stirring to form W/OW colostrum;
D. mixing the W/OW primary emulsion with external water with a certain volume again, stirring to form W/OW multiple emulsion, and removing the organic solvent to obtain the multivesicular liposome.
The concentration of L-lysine in the external water phase is 3mg/mL, the concentration of glucose is 60mg/mL, and the concentration of sodium chloride is 2 mg/mL.
The lipid component consists of triolein, neutral phospholipids, cholesterol and negatively charged phospholipids.
Example 2
A preparation method of bupivacaine multivesicular liposome comprises the following steps:
A. preparation of three-phase solution
Phosphoric acid aqueous solution with the concentration of 30mg/mL is used as an internal water phase;
mixing bupivacaine, lipid components and dichloromethane to form an organic phase, wherein the concentration of the bupivacaine is 45 mg/mL;
mixing glucose, L-lysine and sodium chloride solution to form an external water phase;
B. mixing the internal aqueous phase with the organic phase to form a first phase W/O;
C. mixing the first phase W/O with a certain volume of external water, and stirring to form W/OW colostrum;
D. mixing the W/OW primary emulsion with external water with a certain volume again, stirring to form W/OW multiple emulsion, and removing the organic solvent to obtain the multivesicular liposome.
The concentration of L-lysine in the external water phase is 2mg/mL, and the concentration of glucose is 50 mg/mL; the sodium chloride concentration was 1.5 mg/mL.
The lipid component consists of triolein, neutral phospholipids, cholesterol and negatively charged phospholipids.
Example 3
A preparation method of bupivacaine multivesicular liposome comprises the following steps:
A. preparation of three-phase solution
Phosphoric acid aqueous solution with the concentration of 20mg/mL is used as an internal water phase;
mixing bupivacaine, lipid components and dichloromethane to form an organic phase, wherein the concentration of the bupivacaine is 40 mg/mL;
mixing glucose, L-lysine and sodium chloride solution to form an external water phase;
B. mixing the internal aqueous phase with the organic phase to form a first phase W/O;
C. mixing the first phase W/O with a certain volume of external water, and stirring to form W/OW colostrum;
D. mixing the W/OW primary emulsion with external water with a certain volume again, stirring to form W/OW multiple emulsion, and removing the organic solvent to obtain the multivesicular liposome.
The inner aqueous phase also contains glucose.
The concentration of L-lysine in the external water phase is 1mg/mL, and the concentration of glucose is 50 mg/mL; the sodium chloride concentration was 2 mg/mL.
The lipid component consists of triolein, neutral phospholipids, cholesterol and negatively charged phospholipids.
Example 4
In this example, a 50L batch of the chemical solution was processed based on example 1:
and B, the volume ratio of the internal water phase to the organic phase is 0.9: 1.1 and shearing at 8000rpm to form the first phase W/O.
And C, stirring at low speed of 450rpm to form W/O/W primary emulsion, wherein the volume ratio of the first phase W/O to the external water phase is 1: 1.5.
And D, stirring at a low speed of 150rpm to form W/O/W multiple emulsion, wherein the volume ratio of the W/OW primary emulsion to the external water phase is 1:5.
The temperature of the external aqueous phase was 15 ℃.
Example 5
In this example, a 70L batch of the chemical solution was processed based on example 2:
and B, the volume ratio of the internal water phase to the organic phase is 1.1: 0.9 and sheared at 10000rpm to form the first phase W/O.
And C, stirring at a low speed of 500rpm to form W/O/W colostrum, wherein the volume ratio of the first phase W/O to the external water phase is 1: 2.5.
And D, stirring at a low speed of 200rpm to form W/O/W multiple emulsion, wherein the volume ratio of the W/OW primary emulsion to the external water phase is 1: 6.
The temperature of the external aqueous phase was 10 ℃.
Example 6
In this example, an 80L batch of the chemical solution was processed in addition to example 3:
and B, the volume ratio of the internal water phase to the organic phase is 1:1 and sheared at 9000rpm to form the first phase W/O.
And C, stirring at a low speed of 480rpm to form W/O/W primary emulsion, wherein the volume ratio of the first phase W/O to the external water phase is 1: 2.
And D, stirring at a low speed of 180rpm to form W/O/W multiple emulsion, wherein the volume ratio of the W/OW primary emulsion to the external water phase is 1: 5.5.
The temperature of the external aqueous phase was 12 ℃.
Design of experiments
Preparation of three-phase solution:
inner water phase components: 25mg/mL phosphoric acid aqueous solution;
external water phase: the concentration of L-lysine is 0.6mg/mL, the concentration of glucose is 55mg/mL, and the concentration of sodium chloride is 2.25 mg/mL;
organic phase: bupivacaine, a lipid component and dichloromethane were added, and the concentration of bupivacaine was 25 mg/mL.
Mixing the internal aqueous phase with the organic phase to form a first phase W/O; mixing the first phase W/O with a certain volume of external water, and stirring to form W/OW colostrum; and mixing the W/OW primary emulsion with external water with a certain volume again, stirring to form W/OW multiple emulsion, and removing the organic solvent by adopting nitrogen purging to obtain the multivesicular liposome.
TABLE 1 comparison of appearance at different formulation volumes
As can be seen from Table 1, the volume ratio of the internal aqueous phase to the organic phase is 0.9-1.1: 1.1-0.9, the primary emulsion has good fluidity; when the volume ratio of the first phase W/O to the external water phase is 1: 1.5-2.5, the multiple capsules of the liposome are regular; when the volume ratio of the W/OW colostrum to the external water phase is 1: 5-6, the multiple capsules of the liposome are regular and dense. After the volume of the prepared solution is determined, the following comparative experiments are carried out to determine the optimal component formula of the liposome.
Comparative experiment 1
Preparation of three-phase solution: taking a phosphoric acid aqueous solution with the concentration of 15mg/mL as an internal water phase; mixing bupivacaine, lipid components and dichloromethane to form an organic phase, wherein the concentration of the bupivacaine is 35 mg/mL; mixing glucose and L-lysine solution to form an external water phase, wherein the concentration of L-lysine in the external water phase is 3mg/mL, and the concentration of glucose is 60 mg/mL.
Liquid preparation method A liquid medicine in an amount of 200ml was treated in accordance with the method of example 4, to give a comparative example.
FIGS. 1a) and 1b) are the morphology of the multivesicular liposomes prepared in example 4 and comparative example, respectively, observed under an optical microscope. It can be seen that the vesicles formed in example 4 were dense and regular in shape after the addition of sodium chloride to the external aqueous phase, whereas the vesicles obtained in comparative example 1 were less numerous and irregular in shape without sodium chloride.
Comparative experiment 2
Preparation of three-phase solution: taking a phosphoric acid aqueous solution with the concentration of 15mg/mL as an internal water phase; mixing bupivacaine, lipid components and dichloromethane to form an organic phase, wherein the concentration of the bupivacaine is 35 mg/mL; mixing L-lysine, glucose and sodium chloride solution to form an external water phase.
15 sets of the three-phase solution were prepared, and 200ml of each solution was prepared by taking different concentrations of L-lysine, glucose and sodium chloride in the external aqueous phase according to the method of example 4. The external aqueous phase components of each group are shown in Table 2.
TABLE 2 external Water phase Components of the groups
TABLE 3 appearance of multivesicular liposomes prepared from each group
As can be seen from tables 2 and 3, when the concentration of L-lysine in the external water phase is 0.6 mg/mL-3 mg/mL, the concentration of glucose is 40 mg/mL-60 mg/mL and the concentration of sodium chloride is 1-2.5 mg/mL, the concentration of dispersed phospholipid globules in the solution is appropriate, the surface charge amount is moderate, the interaction force among globules enables the globule-solution dispersion system to reach balance, the multivesicular is complete without flocculation, and the encapsulation rate is more than 90%, so that the stable multivesicular liposome is obtained.
The above-mentioned embodiments only express the specific embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (7)
1. A preparation method of bupivacaine multivesicular liposome is characterized by comprising the following steps:
A. preparation of three-phase solution
Taking a phosphoric acid aqueous solution with the concentration of 15-30 mg/mL as an internal water phase;
mixing bupivacaine, lipid components and dichloromethane to form an organic phase, wherein the concentration of the bupivacaine is 35-45 mg/mL;
mixing glucose, L-lysine and sodium chloride solution to form an external water phase;
B. mixing the internal aqueous phase with the organic phase to form a first phase W/O;
C. mixing the first phase W/O with a certain volume of external water, and stirring to form W/OW colostrum;
D. mixing the W/OW primary emulsion with external water with a certain volume again, stirring to form W/OW multiple emulsion, and removing the organic solvent to obtain the multivesicular liposome.
2. The method for preparing bupivacaine multivesicular liposomes according to claim 1, wherein in the step B, the volume ratio of the internal aqueous phase to the organic phase is 0.9-1.1: 1.1 to 0.9, and forming a first phase W/O under high shear at 8000 to 10000 rpm.
3. The preparation method of bupivacaine multivesicular liposomes according to claim 1, wherein in the step C, the volume ratio of the first phase W/O to the external aqueous phase is 1: 1.5-2.5, and the first phase W/OW colostrum is formed by stirring at low speed of 450-500 rpm.
4. The preparation method of bupivacaine multivesicular liposomes according to claim 1, wherein in the step D, the W/OW colostrum and the external aqueous phase are stirred at a low speed of 150-200 rpm and form W/OW multiple emulsion, and the volume ratio of the W/OW colostrum to the external aqueous phase is 1: 5-6.
5. The method for preparing bupivacaine multivesicular liposomes according to claim 1 wherein the temperature of the external aqueous phase is 10 ℃ to 15 ℃.
6. The method for preparing bupivacaine multivesicular liposomes according to claim 1, wherein the L-lysine concentration in the external aqueous phase is 0.6 to 3mg/mL, and the glucose concentration is 40 to 60 mg/mL; the concentration of sodium chloride is 1-2.5 mg/mL.
7. The method of preparing bupivacaine multivesicular liposomes according to claim 1 wherein said lipid component is comprised of triolein, neutral phospholipids, cholesterol and negatively charged phospholipids.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108078929A (en) * | 2017-12-28 | 2018-05-29 | 广州玻思韬控释药业有限公司 | A kind of preparation method of Bupivacaine multivesicular liposome and Bupivacaine multivesicular liposome preparation |
| CN110215435A (en) * | 2018-05-09 | 2019-09-10 | 广东嘉博制药有限公司 | A method of preparing multivesicular liposome |
| US20190314281A1 (en) * | 2018-04-11 | 2019-10-17 | Xi'an Libang Biomedical Technology Co.,Ltd. | Local anesthetic analgesic sustained-release drug delivery system, preparation method and application thereof |
| US11033495B1 (en) * | 2021-01-22 | 2021-06-15 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108078929A (en) * | 2017-12-28 | 2018-05-29 | 广州玻思韬控释药业有限公司 | A kind of preparation method of Bupivacaine multivesicular liposome and Bupivacaine multivesicular liposome preparation |
| US20190314281A1 (en) * | 2018-04-11 | 2019-10-17 | Xi'an Libang Biomedical Technology Co.,Ltd. | Local anesthetic analgesic sustained-release drug delivery system, preparation method and application thereof |
| CN110215435A (en) * | 2018-05-09 | 2019-09-10 | 广东嘉博制药有限公司 | A method of preparing multivesicular liposome |
| US11033495B1 (en) * | 2021-01-22 | 2021-06-15 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
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