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

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

A kind of emulsion loaded with local anesthetic and preparation method thereof

technical field

The invention belongs to the technical field of biomedicine, relates to a local anesthetic-loaded emulsion and a preparation method thereof, in particular to a local anesthetic-loaded emulsion with uniform particle size, high drug encapsulation rate, good slow and controlled release effect and strong stability emulsion and its preparation method.

Background technique

With the improvement of living standards, people's demand for painless surgery is becoming more and more urgent. Local anesthetics can be used to control acute or chronic postoperative pain, mainly including laparotomy, breast cancer surgery, amputation, and open chest surgery. Local anesthetics will temporarily block the local nerve conduction, thus playing an anesthesia effect. Commonly used local anesthetics are procaine, lidocaine, bupivacaine, and ropivacaine. At present, the analgesic time of a single injection of water-soluble local anesthetics in clinical use is too short, but the time required for postoperative analgesia such as laparotomy, breast cancer surgery, amputation, and thoracotomy is generally several days to ten years. Several days, so a single injection can not meet the clinical requirements. Clinically, pain is generally controlled by placing a continuous drug delivery catheter, but it has the risk of expensive treatment equipment (pump) and susceptibility to infection. In order to solve the existing drawbacks, it is urgent to develop a safe and effective sustained-release preparation for local anesthesia.

The advantages of local anesthetic emulsions are firstly the solubilization effect, the oil phase in the emulsion can greatly increase the solubility of lipophilic drugs; secondly, the slow release effect, the drug will gradually diffuse and penetrate after the emulsified layer is broken to achieve the purpose of slow release . The stable and precise release of the local anesthetic sustained-release emulsion can meet the clinical needs of postoperative analgesia for 3-7 days, and at the same time reduce the cardiovascular toxicity caused by drug accumulation caused by too many injections.

Chinese Patent Publication No. CN1318422A, invented and created the name "self-priming multi-channel phase dispersion extraction device". The problem of excessive force. The disadvantage is that the device is mainly used for extraction technology, so the problem of uniform emulsion particle size is not taken into consideration.

Chinese Patent Publication No. CN100421775C, invented and created the name "a uniform low-shear self-priming emulsion droplet preparation device", which uses the negative pressure generated at low speed to evenly disperse the oil phase or water phase in another In the phase, the liquid is subjected to uniform shear force, and emulsion droplets with uniform particle size can be prepared. The disadvantage is that the processing capacity of the device is small, and continuous mechanized operation cannot be realized.

Chinese Patent Publication No. CN100469426C, invented and created the name "a high-throughput continuous uniform emulsion droplet preparation device". In this process, emulsion droplets with uniform particle size were prepared. The disadvantage is that the device is only suitable for preparing emulsion droplets with larger particle size.

Therefore, it is very necessary to develop a local anesthetic-loaded emulsion with uniform particle size, high drug encapsulation rate, good slow and controlled release effect, strong stability, simple preparation process, and easy to realize later scale-up production.

Contents of the invention

Aiming at the deficiencies of the prior art, the object of the present invention is to provide a local anesthetic-loaded emulsion and its preparation method and application, especially to provide a uniform particle size, high drug encapsulation rate, good slow and controlled release effect and stability Potent local anesthetic-loaded emulsions and methods for their preparation and use.

To achieve this purpose of the invention, the present invention adopts the following technical solutions:

In the first aspect, the present invention provides a local anesthetic-loaded emulsion. The local anesthetic-loaded emulsion is prepared from local anesthetics and auxiliary materials, and is prepared by O/W emulsification combined with rapid membrane emulsification. /W type emulsion.

In clinical application, local anesthetics such as ropivacaine, bupivacaine, mepivacaine, and lidocaine require frequent injections due to their short half-lives. toxicity. On the premise of ensuring high drug loading, making the release behavior and burst release dose meet the ideal clinical expectations has become one of the difficulties. The local anesthetic-loaded emulsion involved in the present invention is prepared by using local anesthetic and pharmaceutical excipients as raw materials, creatively adopting an O/W emulsification method combined with a rapid membrane emulsification method, which is different from the traditional emulsion preparation method ( mechanical stirring, ultrasonic, homogenization, etc.), the present invention combines O/W emulsification method and rapid membrane emulsification method, can prepare uniform and controllable particle size, strong stability, high drug encapsulation rate, and realize precise and stable drug release emulsion. The rapid membrane emulsification technology is to make the pre-emulsion pass through the membrane pores by pressurizing the inert gas to form a monodisperse emulsion smaller than the membrane aperture. Flocculation and stratification caused by the Oswald ripening phenomenon brought about by traditional techniques.

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, etc. Other specific point values within this numerical range All can be selected, so I won’t repeat them one by one here. It is preferably 1-50 μm, more preferably 5-20 μm.

Preferably, the particle size distribution coefficient Span value of the emulsion loaded with local anesthetic 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, etc., within this value range Other specific point values can be selected, and will not be repeated here. Preferably it is 0.1-1.0.

Preferably, the preparation raw materials include local anesthetics, emulsifiers, surfactants, isotonic regulators, thickeners, oil phase solvents and water.

The emulsion involved in the present invention specifically selects local anesthetics, emulsifiers, surfactants, isotonic regulators, thickeners, oil phase solvents and water for combination and matching, and meets the following specific quality formulations: When the relationship between ratio and ratio, the prepared emulsion has uniform and controllable particle size, strong stability, high drug encapsulation efficiency, and can realize precise and stable drug release.

Preferably, the added amount of the local anesthetic in the emulsion is 0.5-40% (w/v), such as 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30% %, 35%, 37%, 40%, etc., other specific point values within this value range can be selected, and will not be repeated here. In terms of w/v involved in the present invention, every 1% (w/v) is equivalent to 10 (g/L).

Preferably, the preparation raw materials include 0.5-40 parts of local anesthetics, 0.5-20 parts of emulsifiers, 1-50 parts of surfactants, 2.25-30 parts of isotonic regulators, and 0.5-30 parts of thickeners in parts by mass. 15 parts, 0.5-50 parts of oil phase solvent and 50-99.5 parts of water.

The mass parts of the local anesthetic can be selected from 0.5 parts, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 37 parts, 40 parts, etc.

The mass parts of the emulsifier can be selected from 0.5 parts, 1 part, 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, 18 parts, 20 parts, etc.

The mass parts of 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, etc.

The mass parts of 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, etc.

The mass parts of the thickener can be selected from 0.5 parts, 1 part, 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, etc.

The mass parts of the oil phase solvent can be selected from 0.5 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 50 parts, etc.

The mass parts of 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, etc.

Other specific point values within the above numerical ranges can be selected, and details will not be repeated here.

Further preferably, the preparation raw materials include 0.5-20 parts of local anesthetics, 0.5-10 parts of emulsifiers, 1-25 parts of surfactants, 2.25-15 parts of isotonic regulators, and 0.5 parts of thickeners in parts by mass. -10 parts, 0.5-50 parts of oil phase solvent and 50-99.5 parts of water.

More preferably, the preparation raw materials include 0.5-10 parts of local anesthetics, 0.5-5 parts of emulsifiers, 1-10 parts of surfactants, 2.25-5 parts of isotonic regulators, and 0.5 parts of thickeners in parts by mass. -2 parts, 0.5-50 parts of oil phase solvent and 50-99.5 parts of water.

In the present invention, the local anesthetics include bupivacaine, levobupivacaine, tetracaine, ropivacaine, etidocaine, articaine, lidocaine, mepivacaine, Any of prilocaine, hydroxyepicaine, buprenorphine, codeine, hydrocodone, hydromorphone, nalbuphine, oxycodone, oxymorphone, tapentadol, or meprotamol one or a combination of at least two;

The combination of at least two such as the combination of bupivacaine and levobupivacaine, the combination of tetracaine and ropivacaine, the combination of etidocaine and articaine, lidocaine and mepivacaine The combination of caine, etc., any other combination can be selected, and will not be repeated here.

Preferably, the emulsifier includes any one or a combination of at least two of tragacanth gum, lanolin, polyethylene lanolin, sucrose stearate, soybean lecithin or lecithin;

The combination of at least two such as the combination of tragacanth gum and lanolin, the combination of polyethylene lanolin and sucrose stearate, the combination of soybean lecithin and lecithin, etc., any other combination can be selected. This will not repeat them one by one.

Preferably it is any one or a combination of at least two of tragacanth gum, lanolin, sucrose stearate, soybean lecithin or lecithin; more preferably tragacanth gum, lanolin, soybean lecithin or lecithin Any one or a combination of at least two.

For the emulsion involved in the present invention, when the emulsifier is selected from tragacanth gum, lanolin, soybean lecithin or lecithin, the particle size of the prepared emulsion is more uniform, the drug encapsulation rate is higher, and more accurate and stable can be achieved. drug release.

In the present invention, the HLB value of the surfactant is 8-18, such as HLB=8, HLB=9, HLB=10, HLB=12, HLB=13, HLB=14, HLB=15, HLB=16 , HLB=17, HLB=18, etc., other specific point values within this value range can be selected, and will not be repeated here.

Preferably, the surfactant includes polyoxypropylene mannitol dioleate, polyoxypropylene stearate, polyoxyethylene fatty acid, polyoxyethylene oxypropylene oleate, polyoxyethylene lauryl ether, polyoxyethylene Any one or a combination of at least two of monooleate, triethanolamine oleate, polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate;

The combination of the at least two kinds, such as the combination of polyoxypropylene mannitol dioleate and polyoxypropylene stearate, the combination of polyoxyethylene fatty acid and polyoxyethylene oxypropylene oleate, etc., other arbitrary combinations All can be selected, so I won’t repeat them one by one here.

Further preferably, the surfactant is polyoxyethylene fatty acid, polyoxyethylene oxypropylene oleate, polyoxyethylene lauryl ether, polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or oil Any one or a combination of at least two of sodium bicarbonates.

More preferably, the surfactant is any one or a combination of at least two of polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate.

For the emulsion involved in the present invention, when the surfactant is selected from polyoxyethylene vegetable oil, polyoxyethylene monostearate, polysorbate 80 or sodium oleate, the particle size of the prepared emulsion is more uniform and the drug encapsulation The higher the rate, the more precise and stable drug release can be achieved.

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 such as The combination of glycerin and mannitol, the combination of xylitol and sorbitol, the combination of sodium chloride solution and glucose, etc., any other combination can be selected, and will not be repeated here.

More preferably, it is any one or a combination of at least two of glycerin, mannitol, xylitol, sodium chloride solution or glucose.

More preferably, it is any one or a combination of at least two of glycerin, xylitol, sodium chloride solution or glucose.

For the emulsion involved in the present invention, when glycerin, xylitol, sodium chloride solution or glucose is selected as the isotonic regulator, the particle size of the prepared emulsion is more uniform, the drug encapsulation rate is higher, and more accurate Smooth drug release.

In the present invention, the thickener includes carbomer, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, trehalose, tragacanth gum, hydroxyethylcellulose, hydroxyethylcellulose Any one or a combination of at least two of cellulose ethyl ether or succinylated gelatin;

The combination of at least two such as the combination of carbomer and hydroxypropyl methylcellulose, the combination of polyvinylpyrrolidone and sodium carboxymethylcellulose, the combination of trehalose and tragacanth gum, etc., other arbitrary combinations The methods can be selected, and will not be repeated here.

Further preferred is any one or at least two of carboxymethylcellulose sodium, carbomer, trehalose, tragacanth gum, hydroxyethylcellulose, hydroxyethylcellulose ethyl ether or succinylated gelatin combination.

More preferably, it is any one or a combination of at least two of sodium carboxymethylcellulose, carbomer, trehalose, tragacanth or hydroxyethylcellulose.

For the emulsion involved in the present invention, when the thickener selects sodium carboxymethyl cellulose, carbomer, trehalose, tragacanth gum or hydroxyethyl cellulose, the particle size of the emulsion obtained is more uniform, and the drug The encapsulation rate is higher, which can achieve more precise and stable drug release.

In the present invention, the oil phase solvent includes 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 Any one or a combination of at least two of esters, ethyl oleate, acetylated propylene glycol monoglyceride, glyceryl linoleate or polyethylene glycol laurate;

The combination of the at least two kinds, 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., any other combination can be selected, and will not be repeated here. A repeat.

Further preferred is 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.

More preferably, it is any one or a combination of at least two of refined soybean oil, medium-chain triglycerides or olive oil.

For the emulsion involved in the present invention, when the oil phase solvent is refined soybean oil, medium-chain triglyceride or olive oil, the particle size of the prepared emulsion is more uniform, the drug encapsulation rate is higher, and more accurate and stable can be achieved. drug release.

In a second aspect, the present invention provides a method for preparing the local anesthetic-loaded emulsion as described in the first aspect, the preparation method comprising:

(1) mix local anesthetic, emulsifier, oil phase solvent, stir to obtain oil phase; surfactant, isotonic regulator, thickener and water are mixed, stir to obtain 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, use a fast membrane emulsifier to pass through a microporous membrane to obtain the emulsion loaded with local anesthetic.

The preparation process of the emulsion loaded with local anesthetic involved in the present invention is simple, and it is easy to realize the enlarged production in the later stage. The process parameters of the preparation process will affect the uniformity of the particle size of the final product, and then affect the slow and controlled release behavior of the drug, especially the pressure and times when passing through the microporous membrane. The fast membrane emulsifier described in step (3) is preferably the equipment disclosed in the patent (Application No. 200720103949.X).

Preferably, the mixing and stirring in step (1) is carried out at 40-90°C, such as 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C , 90°C, etc. Other specific point values within this value range can be selected, and will not be repeated here. Preferably it is 40-70°C, more preferably 40-60°C.

Preferably, the homogenization rate in step (2) is 1000-30000rpm, such as 1000rpm, 2000rpm, 3000rpm, 5000rpm, 10000rpm, 15000rpm, 20000rpm, 25000rpm, 30000rpm, etc. Other specific point values in this numerical range can be selected , which will not be repeated here. 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. can be selected, and will not be described in detail here. Preferably it is 5-99 μm.

Preferably, the pore size distribution Span value of the microporous membrane is less than 1.2, such as 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, etc. Other specific point values within this numerical range All can be selected, so I won’t repeat them one by one here. Preferably it is 1.0 or less.

Preferably, the microporous membrane described in step (3) is carried out at 1-500kPa, such as 1kPa, 5kPa, 10kPa, 50kPa, 100kPa, 200kPa, etc. Other specific point values within this numerical range can be selected, and here I won't repeat them one by one. Preferably it is 10-200 kPa, more preferably 10-100 kPa.

Preferably, the number of microporous membranes described in step (3) is 1-10 times, such as 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times times, preferably 1-5 times, more preferably 1-3 times.

Compared with the prior art, the present invention has the following beneficial effects:

In clinical application, local anesthetics such as ropivacaine, bupivacaine, mepivacaine, and lidocaine require frequent injections due to their short half-lives. toxicity. On the premise of ensuring high drug loading, making the release behavior and burst release dose meet the ideal clinical expectations has become one of the difficulties. The local anesthetic-loaded emulsion involved in the present invention is prepared by using local anesthetic and pharmaceutical excipients as raw materials, creatively adopting an O/W emulsification method combined with a rapid membrane emulsification method, which is different from the traditional emulsion preparation method ( mechanical stirring, ultrasonic, homogenization, etc.), the present invention combines O/W emulsification method and rapid membrane emulsification method, can prepare uniform and controllable particle size, strong stability, high drug encapsulation rate, and realize precise and stable drug release emulsion.

Description of drawings

Fig. 1 is the preparation flow diagram of the emulsion that carries local anesthetic involved in the present invention;

Fig. 2 is the particle size distribution figure of the emulsion prepared by embodiment 1;

Fig. 3 is the in vitro release figure of the load local anesthetic emulsion prepared in embodiment 1;

Fig. 4 is the particle size distribution figure of the emulsion prepared by embodiment 2;

Fig. 5 is the in vitro release figure of the load local anesthetic emulsion prepared in embodiment 2;

Fig. 6 is the particle size distribution figure of the emulsion prepared by embodiment 3;

Fig. 7 is the in vitro release figure of the load local anesthetic emulsion prepared in embodiment 3;

Fig. 8 is the particle size distribution figure of the emulsion prepared by embodiment 4;

Fig. 9 is the in vitro release figure of the emulsion loaded with local anesthetic prepared in Example 4;

Fig. 10 is the particle size distribution figure of the emulsion prepared by embodiment 5;

Fig. 11 is the in vitro release figure of the emulsion loaded with local anesthetic prepared in Example 5;

Fig. 12 is the in vitro release figure of the emulsion loaded with local anesthetic prepared in Example 6;

Fig. 13 is the in vitro release figure of the emulsion loaded with local anesthetic prepared in Example 7;

Fig. 14 is the in vitro release figure of the emulsion loaded with local anesthetic prepared in Example 8;

FIG. 15 is a chromatogram of the drug content in the local anesthetic-loaded emulsion prepared in Example 1 determined by HPLC.

Detailed ways

The technical solutions of the present invention will be further described below through specific embodiments. It should be clear to those skilled in the art that the embodiments are only for helping to understand the present invention, and should not be regarded as specific limitations on the present invention.

Utilize laser particle size analyzer (Malvern Company, USA) to measure the emulsion prepared, the calculation method of its Span value is as follows:

Among them, _DV,90% , _DV,50% and _DV,10% represent the size of the emulsion particle size when the volume fraction is 90%, 50% and 10%, respectively. The Span value indicates the uniformity of the emulsion, and the smaller the Span value, the better the uniformity of the emulsion.

Determination of drug concentration and encapsulation efficiency: detection by high performance liquid chromatography. Chromatographic conditions: Octadecylsilane bonded silica gel as filler; phosphate buffer (take 1.3mL of 1moL/L sodium dihydrogen phosphate solution, 32.5mL of 0.5mol/L disodium hydrogen phosphate solution, add water to 1000mL, adjust pH value to 8.0): acetonitrile = (50:50, v/v) as the mobile phase, the detection wavelength is 240nm, the column temperature is 37°C, and the flow rate is 1mL/min.

Drug concentration determination method: Accurately measure 1 mL of the sample, place it in a 50 mL Eppendorf low-absorption centrifuge tube, add 20 mL of absolute ethanol to break the emulsion, transfer to a 25 mL volumetric flask, and constant volume. The 0.45μm organic filter membrane is filtered, and the filtrate is sent to HPLC to detect the drug concentration.

Determination of encapsulation efficiency: The drug content in the aqueous phase was determined by high-speed centrifugation, 1 mL was placed in a centrifuge tube, centrifuged at 15,000 rpm for 30 min, and the lower layer of the thinner emulsion was centrifuged at 5,000 rpm for 1 h. Take the clear aqueous solution at the bottom, filter it with a 0.2 μm microporous membrane, take the subsequent filtrate, and measure the encapsulation efficiency by HPLC.

The formula for calculating the encapsulation rate is:

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 drug concentration in the water phase, and V _W is the volume of the water phase.

The specific method for measuring the release in vitro is: use the forward osmosis method to perform the release test in vitro. Precisely measure 1mL of the emulsion and place it in a dialysis bag, seal it and place it in a 150mL conical flask, add 100mL of PBS buffer (pH=7.4) as the release medium, and fix it at 200rpm, (37±0.5)°C in the shaker. Take 5 mL of phosphate buffer solution from the Erlenmeyer flask at intervals of 0.5, 2, 4, 8, 12, 24, 30, 36, 48, and 72 hours, and add an equal amount of release medium to maintain the volume of the release system constant. Use a high-performance liquid chromatography to detect the content, and determine the cumulative release of the drug.

The rapid membrane emulsifiers involved in the following examples all adopt the equipment disclosed in the patent (Application No. 200720103949.X).

The preparation raw material sources involved in following examples are as follows:

raw material buy business Model/grade Sodium carboxymethyl cellulose Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Pharmaceutical grade croscarmellose sodium Soy lecithin Aiweituo Pharmaceutical Technology Co., Ltd. SY-SO-200801 polyethylene lanolin Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd. lanolin Polyvinylpyrrolidone Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd. K30 carbomer Wuhan Ainuosen Biotechnology Co., Ltd. 19060802 Polyoxyethylene monostearate Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd. HS15 Hydroxyethyl cellulose Shanxi Jinyang Pharmaceutical Excipients Co., Ltd. Pharmaceutical grade 99% polyoxyethylene fatty acid Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd. Span 80 sesame oil Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd. sesame oil for injection polyoxyethylene vegetable oil Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd. Polyoxyethylene 40 Hydrogenated Castor Oil

Example 1

This embodiment provides a kind of emulsion loaded with local anesthetic, and its preparation method is (its preparation schematic diagram is as shown in Figure 1):

(1) Precisely weigh 400 mg of ropivacaine and 300 mg of soybean lecithin and dissolve in 15 mL of soybean oil, heat in a water bath at 50°C and stir evenly to form an oil phase;

(2) Precisely weigh 1.25g of polysorbate 80, 562.5mg of glycerin, and 250mg of sodium carboxymethylcellulose, dissolve them in 35mL of water for injection, heat in a water bath at 50°C and stir evenly to form a water phase;

(3) Add the oil phase (O) to the water phase (W), and make a pre-emulsion at the speed of T18 homogenizer at 18000 rpm;

(4) Pour the prepared pre-emulsion into a fast membrane emulsifier equipped with a 30 μm microporous membrane tube (the hydrophilic porous membrane has been soaked in water in advance to make the membrane surface fully wet), and press it under an operating pressure of 60kPa. Pass through the microporous membrane and pass through the membrane 10 times to obtain an O/W emulsion.

Utilize laser particle size analyzer to measure emulsion particle diameter and Span value, as shown in Figure 2, particle diameter is 23.497 μ m, and Span value is 0.766; Measuring drug content is 7.24mg/mL (HPLC detects the chromatogram of drug content as shown in Figure 15 ), the encapsulation efficiency is 93.42%; according to the determination of in vitro release, its 0.5h cumulative release is 18.59%, and the sustained cumulative release within 3 days is 90.66%, as shown in Figure 3.

Example 2

This example provides an emulsion loaded with local anesthetics. The difference between its preparation method and Example 1 is that soybean lecithin is replaced by an equivalent amount of polyethylene lanolin, and other conditions remain unchanged. The particle size was determined to be 23.783 μm, and the Span value was 0.810; the encapsulation efficiency of the drug was determined to be 92.13%.

Example 3

This example provides an emulsion loaded with local anesthetics. The difference between its preparation method and Example 1 is that soybean lecithin is replaced by an equivalent amount of sucrose stearate, and other conditions remain unchanged. The particle size was determined to be 22.672 μm, and the Span value was 0.802; the encapsulation efficiency of the drug was determined to be 91.02%.

Example 4

This example provides an emulsion loaded with a local anesthetic, the difference between its preparation method and Example 1 is that soybean oil is replaced by an equivalent amount of peanut oil, and other conditions remain unchanged. The particle size was determined to be 22.672 μm, and the Span value was 0.835; the encapsulation efficiency of the drug was determined to be 91.12%.

Example 5

This example provides an emulsion loaded with local anesthetics. The difference between its preparation method and Example 1 is that soybean oil is replaced by an equivalent amount of fish oil, and other conditions remain unchanged. The particle size was determined to be 20.769 μm, and the Span value was 0.816; the encapsulation efficiency of the drug was determined to be 92.33%.

Example 6

This example provides an emulsion loaded with local anesthetics. The difference between its preparation method and Example 1 is that polysorbate 80 is replaced by an equivalent amount of polyoxyethylene lauryl ether, and other conditions remain unchanged. The particle size was determined to be 23.892 μm, and the Span value was 0.829; the encapsulation efficiency of the drug was determined to be 90.39%.

Example 7

This example provides an emulsion loaded with a local anesthetic. The difference between its preparation method and Example 1 is that glycerin is replaced by an equivalent amount of mannitol, and other conditions remain unchanged. The particle size was determined to be 22.712 μm, and the Span value was 0.783; the encapsulation efficiency of the drug was determined to be 93.02%.

Example 8

This example provides an emulsion loaded with local anesthetics. The difference between its preparation method and Example 1 is that sodium carboxymethylcellulose is replaced by an equivalent amount of polyvinylpyrrolidone, and other conditions remain unchanged. The particle size was determined to be 21.098 μm, and the Span value was 0.793; the encapsulation efficiency of the drug was determined to be 92.18%.

Example 9

The present embodiment provides a kind of emulsion that loads local anesthetic, and its preparation method is:

(1) Precisely weigh 200mg of bupivacaine and 500mg of lecithin and dissolve in 15mL of olive oil, heat in a water bath at 60°C and stir evenly to form an oil phase;

(2) Precisely weigh 25 mg of sodium oleate, 112.5 mg of mannitol, and 500 mg of carbomer, dissolve them in 35 mL of water for injection, heat in a water bath at 60°C, and stir evenly to form an aqueous phase;

(3) Add the oil phase (O) to the water phase (W), and make a pre-emulsion under the speed of T18 homogenizer at 10,000 rpm;

(4) Pour the prepared pre-emulsion into a fast membrane emulsifier equipped with a 20 μm microporous membrane tube (the hydrophilic porous membrane has been soaked in water in advance to make the membrane surface fully wetted), and press it under an operating pressure of 10kPa. Pass through the microporous membrane and pass through the membrane 5 times to obtain an O/W emulsion.

Utilize laser particle size analyzer to measure emulsion particle diameter and Span value, as shown in Figure 4, particle diameter is 16.858 μ m, and Span value is 0.763; Measure drug content to be 3.57mg/mL, encapsulation efficiency is 92.54%; According to the determination of in vitro release , the cumulative release in 0.5h is 19.63%, and the cumulative release within 3 days is 88.27%, as shown in Figure 5.

Example 10

The present embodiment provides a kind of emulsion that loads local anesthetic, and its preparation method is:

(1) Precisely weigh 300 mg of etidocaine and 300 mg of gelatin, dissolve in 15 mL of soybean oil, heat in a water bath at 60°C and stir evenly to form an oil phase;

(2) Precisely weigh 1.25g of polyoxyethylene monostearate, 562.5mg of xylitol, and 250mg of polyvinylpyrrolidone, dissolve them in 35mL of water for injection, heat in a water bath at 60°C and stir evenly to form an aqueous phase;

(3) Add the oil phase (O) to the water phase (W), and make a pre-emulsion at the speed of T18 homogenizer at 22000 rpm;

(4) Pour the prepared pre-emulsion into a fast membrane emulsifier equipped with a 10 μm microporous membrane tube (the hydrophilic porous membrane has been soaked in water in advance to make the membrane surface fully wet), and press it under an operating pressure of 100kPa. Pass through the microporous membrane and pass through the membrane twice to obtain an O/W emulsion.

Utilize the laser particle size analyzer to measure emulsion particle diameter and Span value, as shown in Figure 6, particle diameter is 8.943 μ m, and Span value is 0.802; Measure drug content to be 5.68mg/mL, encapsulation efficiency is 92.47%; According to the determination of in vitro release , its 0.5h cumulative release is 23.55%, and the continuous cumulative release within 3 days is 86.47%, as shown in Figure 7.

Example 11

The present embodiment provides a kind of emulsion that loads local anesthetic, and its preparation method is:

(1) Precisely weigh 133.5 mg of articaine and 30 mg of gum arabic and dissolve in 5 mL of soybean oil, heat in a water bath at 60°C and stir evenly to form an oil phase;

(2) Precisely weigh 2.25g of polyoxyethylene vegetable oil, 112.5mg of xylitol, and 750mg of trehalose, dissolve them in 45mL of water for injection, heat in a water bath at 60°C and stir evenly to form a water phase;

(3) Add the oil phase (O) to the water phase (W), and make a pre-emulsion at the speed of T18 homogenizer at 25000 rpm;

(4) Pour the prepared pre-emulsion into a fast membrane emulsifier equipped with a 10 μm microporous membrane tube (the hydrophilic porous membrane has been soaked in water in advance to make the membrane surface fully wet), and press it under an operating pressure of 300kPa. Pass through a microporous membrane and pass through the membrane 3 times to obtain an O/W emulsion.

Utilize the laser particle size analyzer to measure emulsion particle diameter and Span value, as shown in Figure 8, particle diameter is 8.299 μ m, and Span value is 0.843; Measure drug content to be 2.45mg/mL, encapsulation efficiency is 94.55%; According to the determination of in vitro release , the cumulative release in 0.5h is 33.23%, and the cumulative release within 3 days is 85.66%, as shown in Figure 9.

Example 12

The present embodiment provides a kind of emulsion that loads local anesthetic, and its preparation method is:

(1) Precisely weigh 267 mg of lidocaine and 1 g of tragacanth gum and dissolve in 10 mL of soybean oil, heat in a water bath at 90°C and stir evenly to form an oil phase;

(2) Precisely weigh 2.0 g of polyoxyethylene lauryl ether, 900 mg of sorbitol, and 25 mg of hydroxyethyl cellulose, dissolve them in 40 mL of water for injection, heat in a water bath at 90°C and stir evenly to form a water phase;

(3) Add the oil phase (O) to the water phase (W), and make a pre-emulsion at the speed of T18 homogenizer at 30000rpm;

(4) Pour the prepared pre-emulsion into a fast membrane emulsifier equipped with a 50 μm microporous membrane tube (the hydrophilic porous membrane has been soaked in water in advance to make the membrane surface fully wet), and press it under the operating pressure of 300kPa. Pass through the microporous membrane and pass through the membrane 8 times to obtain O/W emulsion.

Utilize the laser particle size analyzer to measure emulsion particle diameter and Span value, as shown in Figure 10, particle diameter is 39.447 μ m, and Span value is 0.806; Measure drug content to be 5.04mg/mL, encapsulation efficiency is 95.13%; According to the determination of in vitro release , the cumulative release in 0.5h is 22.09%, and the cumulative release within 3 days is 86.76%, as shown in Figure 11.

Example 13

The present embodiment provides a kind of emulsion that loads local anesthetic, and its preparation method is:

(1) Precisely weigh 350 mg of mepivacaine and 25 mg of apricot gum, dissolve in 15 mL of fish oil for injection, heat in a water bath at 40°C and stir evenly to form an oil phase;

(2) Precisely weigh 50 mg of polyoxyethylene fatty acid, 787.5 mg of glucose, and 25 mg of succinylated gelatin, dissolve them in 35 mL of water for injection, heat in a water bath at 40°C and stir evenly to form a water phase;

(3) Add the oil phase (O) to the water phase (W), and make a pre-emulsion at the speed of T18 homogenizer at 1000 rpm;

(4) Pour the prepared pre-emulsion into a fast membrane emulsifier equipped with a 2.8 μm microporous membrane tube (the hydrophilic porous membrane has been soaked in water in advance to make the membrane surface fully wetted), under the operating pressure of 60kPa Press through the microporous membrane and pass through the membrane 4 times to obtain an O/W emulsion.

The particle size and Span value of the emulsion were measured by a laser particle size analyzer, the particle size was 1.198 μm, and the Span value was 0.786; the drug content was determined to be 6.79 mg/mL, and the encapsulation rate was 96.48%; according to the determination of in vitro release, the cumulative release in 0.5 h is 16.05%, and the sustained cumulative release within 3 days is 88.73%, as shown in Figure 12.

Example 14

The present embodiment provides a kind of emulsion that loads local anesthetic, and its preparation method is:

(1) Precisely weigh 250 mg of prilocaine and 90 mg of lecithin, dissolve in 15 mL of ethyl oleate for injection, heat in a water bath at 40°C and stir evenly to form an oil phase;

(2) Precisely weigh 1.75g of polyoxyethylene stearate, 45mg of sodium chloride, and 350mg of hydroxypropyl methylcellulose, dissolve them in 35mL of water for injection, heat in a water bath at 40°C and stir evenly to make a water phase ;

(3) Add the oil phase (O) to the water phase (W), and make a pre-emulsion at the speed of T18 homogenizer at 12000 rpm;

(4) Pour the prepared pre-emulsion into a fast membrane emulsifier equipped with a 100 μm microporous membrane tube (the hydrophilic porous membrane has been soaked in water in advance to make the membrane surface fully wet), and press it under the operating pressure of 40kPa. Pass through a microporous membrane and pass through the membrane once to obtain an O/W emulsion.

The particle size and Span value of the emulsion were measured by a laser particle size analyzer, the particle size was 89.981 μm, and the Span value was 0.829; the drug content was determined to be 4.58 mg/mL; the encapsulation rate was 91.44%; according to the measurement of in vitro release, the cumulative release in 0.5 h is 25.67%, and the sustained cumulative release within 3 days is 86.96%, as shown in Figure 13.

Example 15

The present embodiment provides a kind of emulsion that loads local anesthetic, and its preparation method is:

(1) Precisely weigh 150 mg of mebutamol and 500 mg of gum arabic, dissolve in 15 mL of sesame oil for injection, heat in a water bath at 50°C and stir evenly to form an oil phase;

(2) Precisely weigh 1 g of polyoxyethylene vegetable oil, 550 mg of glycerin, and 650 mg of tragacanth gum, dissolve them in 35 mL of water for injection, heat in a water bath at 50°C, and stir evenly to form a water phase;

(3) Add the oil phase (O) to the water phase (W), and make a pre-emulsion at the speed of T18 homogenizer at 5000 rpm;

(4) Pour the prepared pre-emulsion into a fast membrane emulsifier equipped with a 1 μm microporous membrane tube (the hydrophilic porous membrane has been soaked in water in advance to make the membrane surface fully wet), and press it under an operating pressure of 50kPa. Pass through a microporous membrane and pass through the membrane 3 times to obtain an O/W emulsion.

The particle size and Span value of the emulsion were measured by laser particle size analyzer, the particle size was 0.548 μm, and the Span value was 0.779; the drug content was determined to be 2.678 mg/mL, and the encapsulation rate was 96.87%; according to the measurement of in vitro release, the cumulative release in 0.5 h is 18.64%, and the sustained cumulative release within 3 days is 87.88%, as shown in Figure 14.

The applicant declares that the present invention illustrates a local anesthetic-loaded emulsion of the present invention and its preparation method through the above examples, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must rely on the above examples can be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention. These simple modifications All belong to the protection scope of the present invention.

In addition, it should be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable way if there is no contradiction. The combination method will not be described separately.

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.

Images