KR100343125B1 - lipo-mixture of local anesthetics and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a liposome type mixed topical anesthetic for improving the surface anesthetic effect and a method for preparing the same, among lidocaine, tetracaine, ropivacaine and cocaine. 0.5-10% by weight of selected local anesthetic, phosphatidylcholine (lecithin), phosphatidyldioleoyl, phosphatidylpalmitoyl, phosphatidylethanolamine, phosphatidyldylglycerol (phosphatidylseryl glycerol) 20-50% by weight of mixed lipid of phospholipid and cholesterol and 50-80% by weight of pH 7.0-8.2 are added. It is long and has a wide range of clinical applications, especially in dermatological procedures, venous intubation, and blood sampling. Four is effective in patients with pain and resolve the reluctance caused by the needle or catheter.

Description

Liposomal mixed topical anesthetics for coating and method for manufacturing the same {lipo-mixture of local anesthetics and manufacturing method

The present invention relates to a liposome-type mixed topical anesthetic for application and improvement of the surface anesthetic effect, and more particularly, lidocaine, tetracaine, ropivacaine and cocaine 0.5-10% by weight of local anesthetic such as phosphatidylcholine (lecithin), phosphatidyldioleoyl, phosphatidylpalmitoyl, phosphatidylethanolamine, phosphatidyldilserine or phosphatidylserine The present invention relates to a liposome type mixed topical anesthetic comprising 20-50 wt% of mixed phospholipid such as (phosphatidylglycerol) and cholesterol (cholesterol) and a buffer solution of 50-80 wt% having a pH of 7.0-8.2 and a method for preparing the same.

Everyone goes to the hospital and suffers physical and psychological pain during the injection. In particular, children are more serious. For example, growth hormone may be rejected because of pain that must be met every day. There is a need to easily and effectively alleviate the pain caused by relatively local skin, such as infusion of catheters, injection of acupuncture needles for blood collection, as well as local dermatological procedures including laser treatment.

In general, methods for resolving pain include passive methods such as analgesic injection and oral administration or central nervous system inhibitors, and light surgery to temporarily block neurotransmission through local anesthesia to treat childbirth or chronic pain. There is an active way.

EMLA (Eutectic Mixture of Local Anesthetics) cream, the most commonly used surface anesthetic in the clinic, is a combination of lidocaine and prilocaine topical anesthetics. Anesthesia only occurs after a while, and all of the production from Sweden's Astra is being imported.

As such, conventional surface anesthetics are too late to start working, and the anesthetic effect is not strong. Therefore, it is not suitable to generalize to anesthetics on the skin surface except in special circumstances. It is in a required state.

It is an object of the present invention to provide a liposome-type mixed topical anesthetic that is shortened to within 1 hour of action, its effect is strong, and is applicable for long application time.

Another object of the present invention is to provide a method for preparing a liposome type mixed topical anesthetic for application.

The liposome type mixed topical anesthetic for application of the present invention for achieving the above object is characterized by comprising 0.5 to 10% by weight of local anesthetics and 20 to 50% by weight of mixed lipids of phospholipids and cholesterol.

The liposome-type mixed topical anesthetic for application is dissolved in 0.5 to 10% by weight of local anesthetics and 20 to 50% by weight of mixed lipids of phospholipids and cholesterol with chloroform, and then formed into a thin film using a rotary evaporator, followed by pH 7.2-8.2. It is characterized in that it is formulated by hydration in the buffer solution of several times repeated freezing and thawing.

1 is a graph evaluating the effects of liposome type mixed local anesthetics (lipo-MLA (Mixture of Local Anesthetics)) obtained in Example 1 compared to EMLA (Eutectic Mixture of Local Anesthetics) for each action time.

Figure 2 is a graph evaluating the effect of the liposome-type mixed topical anesthetic (lipo-MLA) of the present invention obtained in Example 2 compared to EMLA for each action time,

Figure 3 is a graph evaluating the effect of the liposome type mixed topical anesthetic (lipo-MLA) of the present invention obtained in Example 3 compared to EMLA by action time,

Figure 4 is a graph evaluating the effect of the liposome-type mixed topical anesthetic (lipo-MLA) of the present invention obtained in Example 4 compared to EMLA by action time,

Figure 5 is a graph evaluating the effect of the liposome type mixed topical anesthetic (lipo-MLA) of the present invention obtained in Example 5 by action time compared with EMLA.

In the present invention, among the currently used topical anesthetics, keratin absorbency, anesthesia is strong, and percutaneous absorption fast tetracaine (tetracaine) and excellent drug stability, including the mixing of lidocaine (lidocaine) fast drug efficacy in solution state, including Local anesthetics with different performances can be mixed and then encapsulated with lipids to obtain synergistic effects of the drug, as well as to control lipophilicity, the composition of the cream base, the choice of enhancers and conditions. Optimization improves the skin penetration of the drug to speed up the onset of action, increase the depth of anesthesia and extend the duration.

The present invention relates to a liposome-type mixed topical anesthetic for improving the surface anesthetic effect and a method for preparing the same, wherein the topical anesthetic in the present invention is lidocaine, tetracaine, and ropivacaine ) And cocaine (cocaine) can be used, preferably using a combination of high safety lidocaine (lidocaine) and high potency tetracaine (tetracaine), but in the art Any conventionally used local anesthetic may be used.

The amount of such local anesthetics is preferably 0.5 to 10% by weight in the entire formulation. If the amount of local anesthetics is less than 0.5% by weight, the effect of local anesthesia is lowered. ) There is a risk of problems.

In order to prepare a liposome form containing a local anesthetic, the local anesthetic is encapsulated with a lipid. The lipid used is a mixed lipid of phospholipids and cholesterol. selected from the group consisting of phosphatidyldioleoyl, phosphatidypalmitoyl, phosphatidylethanolamine, phosphatidylserine and phosphatidylglycerol, cholesterol for the purpose of improving the safety of the structure ) Together.

The amount of such mixed lipids is 20 to 50% by weight of the total formulation, if the amount is less than 20% by weight, there is a problem of forming into liposomes, and if more than 50% by weight, lipophilic properties are inadequate. There is.

In addition, the mixing ratio of phospholipid and cholesterol is preferably 3: 1 to 1: 1.

Since lipid is one of the major constituents of a living body, it is a highly biocompatible material for drug carriers. Lipids can be a carrier of various drugs because they are diverse and form various dispersion states with water according to their physical and chemical properties.

In general, liposomes are composed of lipid bimolecular membranes and internal phases (aqueous phase), which are morphologically three types: multilamellar vesicles (MLVs), small unilamellar vesicles (SUVs), and large It is largely divided into single membrane liposomes (largeunilamellar vesicles (LUV)). Liposomes can include both water-soluble and fat-soluble drugs. Generally, liposomes include water-soluble drugs in the water phase and fat-soluble drugs in the lipid membrane.

The liposome type of the mixed topical anesthetic of the present invention is MLV, which is most commonly used as a vesicle having a diameter of several hundred to several thousand nm having a structure in which two layers of lipids overlap each other.

The preparation method of the liposome type mixed local anesthetic according to the present invention is as follows; First, lipids dissolved in organic solvents such as a local anesthetic and chloroform are put in a round bottom flask to evaporate the organic solvent to form a lipid thin film. As the organic solvent, conventional ones capable of dissolving lipids other than chloroform, for example, methanol, ethanol, diethyl ether or a mixed solvent thereof can be used.

Evaporation of the organic solvent is carried out using a rotary evaporator, specifically, it is carried out at 50 to 100rpm at 0.5 to 3 hours at 20 to 40 ℃.

Then, buffer is added thereto to hydrate the lipid to prepare MLV. At this time, the pH of the buffer solution is preferably 7.0 ~ 8.2 in consideration of the stabilization of the drug and skin absorption.

On the other hand, liposome-type mixed topical anesthetics formulated to compensate for the unstable lipids at room temperature allow for long-term storage by lyophilization.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the Examples.

(1) liposome formulation

Local anesthetics such as tetracaine, lidocaine, and cocaine are mixed with lipids such as egg yolk phosphatidylcholine (lecithin), cholesterol, and phosphatidylcholine dioleyl dissolved in chloroform to evaporate the organic solvent in the rotary evaporator to evaporate the lipid membrane. After forming, the resultant was hydrated with Tris-EDTA buffer (pH 7.2) and the like, followed by freezing and thawing to prepare a liposome formulation.

(2) Test subject and evaluation

20 to 40 healthy adult males and females who agreed to the experiment were compared with EMLA (Astrasa Products), followed by a pinprick test (5g weighted) at 30g intervals up to 3 hours. needle) to measure pain. The pain score was assessed by setting a 10-scaled pain score of 10 for pain at the normal site without drug and 0 for no pain at all.

(3) Statistical processing

The results of the effects of the liposome type mixed topical anesthetic and EMLA according to the present invention were analyzed by repeated measures ANOVA and paired comparison test (p <0.05).

Example 1

Buchi Rotavapor R with 5: 3: 2 egg yolk phosphatidylcholine (lecithin), cholesterol and phosphatidylcholine dioleyl 24 wt% dissolved in 0.5 wt% tetracaine and 2.5 wt% lidocaine in 2 ml of chloroform. -114, manufactured by Buchi Co., Ltd., evaporated the organic solvent at 60 to 80 rpm at 26 ° C. for 1 hour to form a lipid film on the surface of the local anesthetic, and then hydrated with Tris-EDTA buffer solution (pH 7.2), and then freezing and thawing were repeated. Liposome formulations were made.

The prepared liposome type mixed topical anesthetic agent and EMLA of the present invention were compared by applying 50 ± 2 mg in each square of 1 cm 2 of the forearm oyster. After a certain time, the drug was wiped off and the pain was measured by a pinprick test (5 g weighted needle) every 30 minutes until 3 hours.

The pain index was set to a 10-point pain index of which the pain at the normal part without applying the drug was set to 10 and the pain was not felt at all, which was 0, and the results are shown in FIG. 1.

The results in Fig. 1 is a result of wiping the drug after applying the drug for 60 minutes and evaluating it through a pinprick test (5g weighted needle) for 3 hours at an interval of 30 minutes, the left index of the pain index of the liposome type mixed topical anesthetic according to the present invention. The bar on the right shows the pain index of EMLA.

Example 2

A liposome type local anesthetic was prepared in the same composition and method as in Example 1, except that 50 ± 2 mg of liposomes and EMLA were applied and occluded in a square of 1 cm 2 of the forearm oyster, respectively. Evaluation in the same manner as in Example 1 shown in Figure 2 the results.

The result of FIG. 2 is a result of wiping the drug after applying the drug for 60 minutes and evaluating it through a pinprick test (5g weighted needle) for 3 hours at an interval of 30 minutes. The left bar shows the pain index of the liposome type mixed topical anesthetic. The bar on the right represents the pain index of EMLA.

Example 3

Liposomes were prepared in the same manner as in Example 1, except that 1% by weight of tetracaine and 4% by weight of lidocaine were used, and 50 ± 2 mg of liposomes and EMLA in a square of 1 cm 2 of the forearm oyster. Were applied and evaluated in the same manner as in Example 1, and the results are shown in FIG.

3 shows that after applying the drug for 60 minutes, the drug was wiped off and evaluated through a pinprick test (5 g weighted needle) for 3 hours at an interval of 30 minutes. The left bar shows the pain index of the liposome type mixed topical anesthetic. The bar on the right represents the pain index of EMLA.

Example 4

Liposomes were prepared in the same manner as in Example 1, using 0.5% by weight of tetracaine, 2.5% by weight of lidocaine, 1% by weight of tetracaine, and 4% by weight of lidocaine. Next, the evaluation was performed in the same manner as in Example 3, and the results are shown in FIG. 4.

4 is a result of wiping the drug after applying the drug for 60 minutes and evaluated by pinprick test (5g weighted needle) for 3 hours at an interval of 30 minutes, the left bar is liposome type mixed topical anesthetic with a total local anesthetic weight of 3% Pain index of the, and the bar on the right represents the pain index of the liposome-type mixed topical anesthetic of 5% of the total local anesthetic weight.

Example 5

Liposomes were prepared in the same manner as in Example 1 using 2.5% by weight of lidocaine and 0.5% by weight of tetracaine as a local anesthetic, followed by 0.5 to 2 minutes before and after application of the drug. The evaluation was carried out in the same manner as in Example 1, except that heating was performed at 38 to 40 ° C. using infrared rays for 5 to 10 minutes, and the results are shown in FIG. 5.

The results of FIG. 5 were pre-heated for 0.5 to 2 minutes before applying the drug, and after applying the drug, the application site was heated through a pinprick test (5g wighted needle) for 3 hours at 30 minute intervals after 5 to 10 minutes of heating. As a result, the left bar represents the pain index of liposome-type mixed topical anesthetics, and the right bar represents the pain index of EMLA.

As can be seen from the results of Examples 1 to 5, specifically, as shown in the results of FIGS. 1 to 5, the liposome type mixed topical anesthetic was found to be significantly more effective in anesthetic drug expression time and duration than EMLA. In contrast, the anesthetic drug expression time was 1 to 2 hours in the case of EMLA, whereas the anesthetic drug expression time of the liposome type mixed topical anesthetic according to the present invention was shortened to within 1 hour. In the case of 120 minutes after application, the pain index gradually increased to 5 or more. The liposome type mixed topical anesthetic according to the present invention exhibited an average pain index of 2 to 4 up to 240 minutes after application.

In addition, EMLA showed an effect after 1 to 2 hours after occlusion, whereas the liposome type local anesthetic according to the present invention showed a better effect without occlusion, and the drug was applied after 0.5 to 2 minutes of preheating. When heated for 5 to 10 minutes again, it can be seen that the drug expression time is shortened to within 30 minutes. In this way, the drug expression time is shortened by heating before or after the application is believed to be due to the improved skin permeability of the drug by relaxing and expanding the dense molecular spacing of the stratum corneum, which is a barrier to drug absorption.

In addition, all subjects did not exhibit any unusual side effects such as erythema and itching after the experiment, as well as long-term stable use of the local anesthetic of the prepared liposome formulation.

As a result, the liposome-type mixed topical anesthetic according to the present invention has a wide range of clinical applications due to its keratin permeability and a long duration of medicinal effects, especially due to needles or catheters during procedures including dermatological procedures, venous intubation, and blood collection. It is effective in resolving patient's rejection and pain.

Claims (11)

A liposome type mixed topical anesthetic for application comprising 0.5 to 10% by weight of local anesthetics and 20 to 50% by weight of mixed lipids of phospholipids and cholesterol. The method of claim 1, Local anesthetics are from the group consisting of lidocaine, tetracaine, ropivacaine, cocaine, divecaine, prilocaine and pontocaine. Liposomal mixed topical anesthetic for application, characterized in that mixing at least two. delete The method of claim 1, Phospholipids used in formulating liposomes to promote transdermal absorption of local anesthetics include phosphatidylcholine (lecithin), phosphatidyldioleoyl, phosphatidypalmitoyl, phosphatidylethanolamine, and phosphatidylethanolamine. Liposome type mixed topical anesthetic for application, characterized in that selected from the group consisting of phosphatidylserine, polyoxyethylene and phosphatidylglycerol. 0.5-10% by weight of local anesthetic and 20-50% by weight of mixed lipid of phospholipid and cholesterol are dissolved in organic solvent, and then evaporated organic solvent using a rotary evaporator to form a thin lipid membrane film, and then in buffer solution of pH 7.0-8.2. Method for producing a liposome type mixed topical anesthetic for application, characterized in that the hydration (freezing) and thawing by repeating several times. The method of claim 5, Local anesthetics are from the group consisting of lidocaine, tetracaine, ropivacaine, cocaine, divecaine, prilocaine and pontocaine. Method for producing a liposome type mixed topical anesthetic for application, characterized in that mixing at least two. The method of claim 5, Phospholipids used in formulating liposomes to promote transdermal absorption of local anesthetics include phosphatidylcholine (lecithin), phosphatidyldioleoyl, phosphatidypalmitoyl, phosphatidylethanolamine, and phosphatidylethanolamine. A process for preparing a liposome type mixed topical anesthetic for application, characterized in that selected from the group consisting of patyldyserine, polyoxyethylene and phosphatidylglycerol. The method of claim 5, An organic solvent is selected from the group consisting of chloroform, methanol, ethanol and diethyl ether, or a mixed solvent thereof is used. The method of claim 5, Evaporation of the organic solvent is a method for producing a liposome type mixed topical anesthetic for application, characterized in that is carried out at 50 to 100rpm for 0.5 to 3 hours at 20 to 40 ℃. delete delete