WO2001019403A1 - Liposomal mixture of local anesthetics and manufacturing method thereof - Google Patents

Liposomal mixture of local anesthetics and manufacturing method thereof Download PDF

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Publication number
WO2001019403A1
WO2001019403A1 PCT/KR2000/000490 KR0000490W WO0119403A1 WO 2001019403 A1 WO2001019403 A1 WO 2001019403A1 KR 0000490 W KR0000490 W KR 0000490W WO 0119403 A1 WO0119403 A1 WO 0119403A1
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Prior art keywords
local anesthetic
liposomal
application
mixture
emla
Prior art date
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PCT/KR2000/000490
Other languages
French (fr)
Inventor
Jung-Ok Lim
Woon-Yi Baek
Do-Won Kim
Jeung-Soo Huh
Soo-Hyun Park
Original Assignee
Lim Jung Ok
Baek Woon Yi
Kim Do Won
Huh Jeung Soo
Park Soo Hyun
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Application filed by Lim Jung Ok, Baek Woon Yi, Kim Do Won, Huh Jeung Soo, Park Soo Hyun filed Critical Lim Jung Ok
Priority to AU52518/00A priority Critical patent/AU5251800A/en
Publication of WO2001019403A1 publication Critical patent/WO2001019403A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics

Definitions

  • EMLA topical anaesthesia
  • Liposomes are known to deliver more drugs into the dermis by increasing the rate of dermal penetration of drug as described by Adrienn et al., Anesthesia and Analgesia 67:1079-81(1988).
  • Tetracaine was considered the most suitable drug candidate for topical anesthetic for its high permeability coefficient in vitro. While lidocaine is the most widely used local anesthetic due to its safe property.
  • Tetracaine base(Sigma Chemical Co.) 1 wt%, lidocaine base(Sigma Chemical Co.) 4wt% were encapsulated into multilamellar phospholipid vesicles.
  • the lipid phase consisting of 2:5:3 egg yolk phosphatidylcholine (Sigma Chemical Co.), poly oxyethylene( Sigma Chemical Co.) and cholesteroKSigma Chemical Co.) was dissolved in 2ml chloroform (Sigma Chemical Co. ) in a pear-shape flask. The solvent was evaporated to dryness in a rotary evaporator under reduced pressure at 10-20 torr for 2 hours until a smooth, thin lipid film was obtained on the surface of the flask.
  • the dried thin film lipid was hydrated in lml(0.1wt%) Tris-EDTA (pH 7.4 Sigma Chemical Co.) buffer on a vortex mixer and sonicated for 30 minutes in ultra- sonicator at 25 ° C . Then it was followed by freezing and thawing three times. All chemicals purchased from Sigma Chemical Co., were used as received.
  • Tetracaine base(Sigma Chemical Co.) 0.5 -l%, lidocaine base(Sigma Chemical Co.) 2.5%-4% were encapsulated into multilamellar phospholipid vesicles.
  • the lipid phase consisting of different types of phospholipids and cholesterol was dissolved in chloroform in a pear- shape flask. The solvent was evaporated to dryness in a rotary evaporator under reduced pressure for 2 hours until a smooth, thin lipid film was obtained on the surface of the flask.
  • the dried thin film lipid was hydrated in Tris-EDTA (pH 7.4) buffer on a vortex mixer and sonicated for 30 minutes in ultra- sonicator at 25 ° C . Then it was followed by freezing and thawing three times.
  • Pinprick testing (as described by Chan AW et al, J Neurol Neurosurg Psychiat 1992 ; 55; 56-594) was used to assess the topical anesthesia.
  • the needle weighed 5g was used to produce pinprick stimulus.
  • the test was performed at 30, 60, 90, 120, 180, and 240 minutees following application of test preparations.
  • the 10-scaled pain score (as described by Jong Young et al, The Kor. J. of Occup. Med. 1994;6;2; 342-347) was applied to quantitatively evaluate the topical anesthetic effect indicating complete topical anesthesia as 0, intact sensory 10.
  • the pinprick apparatus was applied three times to each test area on the volar forearms.
  • Liposomal mixture of local anestheics was found to produce long lasting anesthesia and of the intact skin and the depth of anesthesia of lipo-MLA was stronger than EMLA.
  • Anesthesia was present after application of liposomal mixture of local anesthetics for shorter than one hour. Pain score analysis indicated that onset time of reliably deep anesthesia was between thirty and one hour. By mild heating the applied site for a few minutes, the onset time can be reduced to less than thirty minutes.
  • the difference between the anesthetic effects of lipo-MLA and EMLA were statistically significant at every time point. The anesthetic effect lasted upto 4 hours. In fact volunteers reported that the numbness at the test sites persisted a few hours after the testing had been completed. In the case of high concentration, the depth and duration of analgesia were found to be deeper and longer than lower concentration. EMLA cream was less effective. The whole volunteers were entirely recovered with no side effect.
  • lipid film After forming a lipid film with 0.5% of tetracaine, 2.5% of lidocaine, 5:3:2 egg yolk phosphatidylcholine( lecithin), cholesterol and phosphatidylcholine dioleoyl, the lipid film was hydrated with the Tris-EDTA buffer. Subsequently, liposome was obtained by repeatedly freezing and thawing the hydrated lipid film. A comparison was made after applying 50 ⁇ 2mg of liposome and EMLA, respectively, to an square test site of lcm J on the flexural part of a forearm. After a specific time elapsed, the applied agent was wiped off from the test site.
  • Fig. 1 the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours after applying the agent for 60 minutes and wiping off it.
  • the left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.
  • the liposome was prepared in a manner similar to that of Example 1 with 0.5% of tetracaine, 2.5% of lidocaine, 5:3:2 egg yolk phosphatidylcholine (lecithin), cholesterol and phosphatidylcholine dioleoyl. 50 ⁇ 2mg of liposome and EMLA, respectively, were applied to the square test sites of lc ⁇ on the flexural part of a forearm. The pain was measured in a manner similar to that of Example 1 except that occlusion was performed. The results were illustrated in Fig. 2.
  • Fig. 2 the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours after applying the agent for 60 minutes and wiping off it.
  • the left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.
  • Example 3 The liposome was prepared in a manner similar to that of Example 1 except that 1% of tetracaine and 4% of lidocaine were used. 50 ⁇ 2 g of liposome and EMLA, respectively, were applied to the square test sites of 1 cm 2 on the flexural part of a forearm. The pain was measured in a manner similar to that of Example 1. The results were illustrated in Fig. 3.
  • Fig. 3 the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours after applying the agent for 60 minutes and wiping off it.
  • the left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.
  • the liposome was prepared in a manner similar to that of Example 1 with one group containing 0.5% of tetracaine, 2.5% of lidocaine, 5:3:2 egg yolk phosphatidylcholine (lecithin), cholesterol and phosphatidylcholine dioleoyl, and the other group containing 1% of tetracaine, 4% of lidocaine, 5:3:2 egg yolk phosphatidylcholine (lecithin), cholesterol and phosphatidylcholine dioleoyl.
  • 50 ⁇ 2mg of liposome and EMLA, respectively, were applied to the square test sites of lcitf on the flexural part of a forearm. The pain was measured in a manner similar to that of Example 3. The results were illustrated in Fig. 4.
  • Fig. 4 the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours.
  • the left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.
  • the liposome was prepared in a manner similar to that of Example 1, using 0.5% of tetracaine and 2.5% of lidocaine. The pain was measured in a manner similar to that of Example 1 except that the test site was heated for 5 to 10 minutes. The results were illustrated in Fig. 5.
  • the test site was preheated for 0.5 to 2 minutes before application of the agent, and subsequently heated for 2 to 10 minutes after application of the agent.
  • the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours.
  • the left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Anesthesiology (AREA)
  • Dispersion Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

An improved topical anesthetics cream consisting of mixture of local anesthetics such as lidocaine, tetracaine and cocaine and lipids including phosphotidylcholine, phosphatidyldioleoyl and cholesterol which provide faster effectiveness and long lasting anesthesia, and convenient administration and a method for the manufacture thereof, are disclosed. The lipids and the method of manufacture used to form the effective topical anesthesia are selected on the basis of their skin penetration and effect duration characters. The topical anesthetic effects of the liposomal mixture of local anesthetics and EMLA as a control was evaluated by pinprick test. Liposomal mixture of local anesthetics under no occlusion appeared to be improved formulation for topical anesthetics which lasted up to four hours after one hour application and exhibited fast onset time as approximately thirty minutes. EMLA was comparatively ineffective; it takes at least an hour to be effective and the duration lasted around two hours.

Description

Liposomal mixture of local anesthetics and
manufacturing method thereof
Technical Field
• Transdermal delivery of local anesthetics which became effective in thirty minutes and prolong the duration upto four hours
• Formulation and evaluation of liposomal mixture of local anesthetics for topical anesthesia
Background Art
Patients undergoing venipuncture or intraveneous characterization often experience pain which makes minor procedures difficult for both the patient and the health care personnel. For patients compliance it is necessary to have effective topical anesthesia. Currently the most widely used topical anaesthesia is EMLA. It is a eutectic mixture of lidocaine and prilocaine and has been introduced clinically for surface anesthesia of intact skin. Although it is considered to be effective, the onset of anesthesia is slow. For administration EMLA should be occluded at least for an hour to be effective. The depth of penetration and degree of topical anesthesia attained following EMLA application depends on the duration of the application.
Liposomes are known to deliver more drugs into the dermis by increasing the rate of dermal penetration of drug as described by Adrienn et al., Anesthesia and Analgesia 67:1079-81(1988). Tetracaine was considered the most suitable drug candidate for topical anesthetic for its high permeability coefficient in vitro. While lidocaine is the most widely used local anesthetic due to its safe property.
Accordingly it is the object of the present invention to provide a method for manufacturing effective topical anesthesia by formulating liposomes containing mixture of local anesthetics such as tetracaine and lidocaine.
Disclosure of Invention
Tetracaine base(Sigma Chemical Co.) 1 wt%, lidocaine base(Sigma Chemical Co.) 4wt% were encapsulated into multilamellar phospholipid vesicles. The lipid phase, consisting of 2:5:3 egg yolk phosphatidylcholine (Sigma Chemical Co.), poly oxyethylene( Sigma Chemical Co.) and cholesteroKSigma Chemical Co.) was dissolved in 2ml chloroform (Sigma Chemical Co. ) in a pear-shape flask. The solvent was evaporated to dryness in a rotary evaporator under reduced pressure at 10-20 torr for 2 hours until a smooth, thin lipid film was obtained on the surface of the flask.
The dried thin film lipid was hydrated in lml(0.1wt%) Tris-EDTA (pH 7.4 Sigma Chemical Co.) buffer on a vortex mixer and sonicated for 30 minutes in ultra- sonicator at 25 °C . Then it was followed by freezing and thawing three times. All chemicals purchased from Sigma Chemical Co., were used as received.
Brief Description of Drawings
Figure I- topical anesthetic effect of lipo-MLA(Mixture of Local
Anesthetics) and EMLA(Eutectic Mixture of Local Anesthetics) as control from trial 1.
Figure 2: topical anesthetic effect of lipo-MLA(Mixture of Local
Anesthetics) and EMLA(Eutectic Mixture of Local Anesthetics) as control from trial 2.
Figure 3: topical anesthetic effect of lipo-MLA( Mixture of Local
Anesthetics) and EMLA(Eutectic Mixture of Local Anesthetics) as control from trial 3.
Figure 4- topical anesthetic effect of lipo-MLA( Mixture of Local
Anesthetics) and EMLA(Eutectic Mixture of Local Anesthetics) as control from trial 4.
Figure 5: topical anesthetic effect of lipo-MLA( Mixture of Local
Anesthetics) and EMLA(Eutectic Mixture of Local Anesthetics) as control from trial 5.
Best Mode for Carrying out the Invention
Preparation of Liposomes
Tetracaine base(Sigma Chemical Co.) 0.5 -l%, lidocaine base(Sigma Chemical Co.) 2.5%-4% were encapsulated into multilamellar phospholipid vesicles. The lipid phase, consisting of different types of phospholipids and cholesterol was dissolved in chloroform in a pear- shape flask. The solvent was evaporated to dryness in a rotary evaporator under reduced pressure for 2 hours until a smooth, thin lipid film was obtained on the surface of the flask.
The dried thin film lipid was hydrated in Tris-EDTA (pH 7.4) buffer on a vortex mixer and sonicated for 30 minutes in ultra- sonicator at 25 °C . Then it was followed by freezing and thawing three times.
In vivo study
This study was carried out in accordance with human research standards in Kyungpook National University Hospital ethics committee. Thirty healthy adult volunteers ( 20 male, 10 female) participated in the trial after giving written informed consent. Liposomal preparation was compared to a commercial preparation, EMLA (Astra Pharma Inc, Mississauga. Ontario). Following the obtainment of informed consent, volunteers' forearms were cleaned with alcohol swab and allowed to dry. A template having two open area of 1cm x 1cm square was placed on the volar forearms. 50mg of liposomal preparation and EMLA respectively were spread over the skin surface within the open area using a clean spatula. The test preparations were left on the forearms for specific period of 30 and 60 minutes. Following the application period, the test preparations were wiped from the skin with clean dry gauze.
Pinprick testing (as described by Chan AW et al, J Neurol Neurosurg Psychiat 1992 ; 55; 56-594) was used to assess the topical anesthesia. The needle weighed 5g was used to produce pinprick stimulus. The test was performed at 30, 60, 90, 120, 180, and 240 minutees following application of test preparations. The 10-scaled pain score(as described by Jong Young et al, The Kor. J. of Occup. Med. 1994;6;2; 342-347) was applied to quantitatively evaluate the topical anesthetic effect indicating complete topical anesthesia as 0, intact sensory 10. During the test procedure, the pinprick apparatus was applied three times to each test area on the volar forearms.
Data analysis
All data were expressed as mean± SEM. Data were analyzed using the repeated measured ANOVA and multiple comparison t-test. Values of *p<0.05 versus control(EMLA) was considered statistically significant.
Results
Liposomal mixture of local anestheics was found to produce long lasting anesthesia and of the intact skin and the depth of anesthesia of lipo-MLA was stronger than EMLA. Anesthesia was present after application of liposomal mixture of local anesthetics for shorter than one hour. Pain score analysis indicated that onset time of reliably deep anesthesia was between thirty and one hour. By mild heating the applied site for a few minutes, the onset time can be reduced to less than thirty minutes. The difference between the anesthetic effects of lipo-MLA and EMLA were statistically significant at every time point. The anesthetic effect lasted upto 4 hours. In fact volunteers reported that the numbness at the test sites persisted a few hours after the testing had been completed. In the case of high concentration, the depth and duration of analgesia were found to be deeper and longer than lower concentration. EMLA cream was less effective. The whole volunteers were entirely recovered with no side effect.
Example 1
After forming a lipid film with 0.5% of tetracaine, 2.5% of lidocaine, 5:3:2 egg yolk phosphatidylcholine( lecithin), cholesterol and phosphatidylcholine dioleoyl, the lipid film was hydrated with the Tris-EDTA buffer. Subsequently, liposome was obtained by repeatedly freezing and thawing the hydrated lipid film. A comparison was made after applying 50±2mg of liposome and EMLA, respectively, to an square test site of lcmJ on the flexural part of a forearm. After a specific time elapsed, the applied agent was wiped off from the test site. Subsequently the pain was measured by carrying out the weighted needle pinprick test(5g) at an interval of 30 minutes for 3 hours. The 10- scaled pain score was adopted where the state of pain on a normal site to which no agent was applied is 10 and the state of anesthesia is 0(zero). The results were illustrated in Fig. 1.
In Fig. 1, the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours after applying the agent for 60 minutes and wiping off it. The left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.
Example 2
The liposome was prepared in a manner similar to that of Example 1 with 0.5% of tetracaine, 2.5% of lidocaine, 5:3:2 egg yolk phosphatidylcholine (lecithin), cholesterol and phosphatidylcholine dioleoyl. 50± 2mg of liposome and EMLA, respectively, were applied to the square test sites of lcπ on the flexural part of a forearm. The pain was measured in a manner similar to that of Example 1 except that occlusion was performed. The results were illustrated in Fig. 2.
In Fig. 2, the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours after applying the agent for 60 minutes and wiping off it. The left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.
Example 3 The liposome was prepared in a manner similar to that of Example 1 except that 1% of tetracaine and 4% of lidocaine were used. 50± 2 g of liposome and EMLA, respectively, were applied to the square test sites of 1 cm2 on the flexural part of a forearm. The pain was measured in a manner similar to that of Example 1. The results were illustrated in Fig. 3.
In Fig. 3, the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours after applying the agent for 60 minutes and wiping off it. The left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.
Example 4
The liposome was prepared in a manner similar to that of Example 1 with one group containing 0.5% of tetracaine, 2.5% of lidocaine, 5:3:2 egg yolk phosphatidylcholine (lecithin), cholesterol and phosphatidylcholine dioleoyl, and the other group containing 1% of tetracaine, 4% of lidocaine, 5:3:2 egg yolk phosphatidylcholine (lecithin), cholesterol and phosphatidylcholine dioleoyl. 50±2mg of liposome and EMLA, respectively, were applied to the square test sites of lcitf on the flexural part of a forearm. The pain was measured in a manner similar to that of Example 3. The results were illustrated in Fig. 4.
In Fig. 4, the pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours. The left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.
Example 5
The liposome was prepared in a manner similar to that of Example 1, using 0.5% of tetracaine and 2.5% of lidocaine. The pain was measured in a manner similar to that of Example 1 except that the test site was heated for 5 to 10 minutes. The results were illustrated in Fig. 5.
In Fig. 5, the test site was preheated for 0.5 to 2 minutes before application of the agent, and subsequently heated for 2 to 10 minutes after application of the agent. The pain was measured by carrying out the needle pinprick test(5g weighted needle) at an interval of 30 minutes for 3 hours. The left-hand bar indicates the pain score of liposomal local anesthetic, and the right-hand bar does that of EMLA.

Claims

WHAT IS CLAIMED IS:
1. A liposomal local anesthetic for application containing 0.5~10 weight percent of local anesthetic and 20~50 weight percent of lipid compound with a mixture of phospholipid and cholesterol.
2. A liposomal local anesthetic for application as in claim 1 wherein said local anesthetic is selected from a group comprising lidocaine, tetracaine, ropivacaine, cocaine, and pontocaine.
3. A liposomal local anesthetic for application as in claim 1 or 2 wherein said local anesthetic is a mixture of lidocaine and tetracaine.
4. A liposomal local anesthetic for application as in claim 1 wherein said phospholipid is selected from a group comprising phosphatidylcholine(lecithin), phosphatidyldioleoyl, phosphatidypalmitoyl, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and polyoxyethylene.
5. A process for preparing a liposomal local anesthetic for application; said process comprising dissolving 0.5~10 weight percent of local anesthetic and 20~50 weight percent of lipid compound with a mixture of phospholipid and cholesterol in organic solvent, subsequently forming a thin lipid film by evaporating said organic solvent by means of a rotary evaporator, subsequently hydrating said thin lipid film in pH 7.0~8.2 of buffer, and lastly repeatedly freezing and thawing said hydrated thin lipid film.
6. A process for manufacturing a liposomal local anesthetic for application as in claim 5 wherein said local anesthetic is selected from a group comprising lidocaine, tetracaine, ropivacaine, cocaine, and pontocaine.
7. A process for preparing a liposomal local anesthetic for application as in claim 5 wherein said phospholipid is selected from a group comprising phosphatidylcholine(lecithin), phosphatidyldioleoyl, phosphatidypalmitoyl, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and polyoxyethylene,
8. A process for preparing a liposomal local anesthetic for application as in claim 5 wherein said organic solvent is selected from a group comprising chloroform, methanol, ethanol, and diethyl ether or a mixture of these solvents.
9. A process for preparing a liposomal local anesthetic for application as in claim 5 wherein said organic solvent is evaporated at 10-20 torr for 0.5~3 hours at 20~40°C .
10. A method of applying said liposomal local anesthetic of claim 1 to a site of application without occlusion.
11. A method of applying said liposomal local anesthetic to a site of application as in claim 10 in order to reduce the anesthesia onset time as less than thirty minutes wherein said liposomal local anesthetic is heated at 38~40°C for 0.5~2 minutes and for 2~10 minutes, respectively before and after applying said liposomal local anesthetic to a site of application.
PCT/KR2000/000490 1999-09-14 2000-05-19 Liposomal mixture of local anesthetics and manufacturing method thereof WO2001019403A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010090030A (en) * 2001-08-09 2001-10-18 임정옥 Manufacturing and synergic effect of topical anesthetic formula consisted of mixed local anesthetics
WO2008051889A1 (en) * 2006-10-24 2008-05-02 The Johns Hopkins University Rapid release mini-tablets provide analgesia in laboratory animals
WO2013168172A1 (en) * 2012-05-10 2013-11-14 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
US8808715B1 (en) * 2004-11-23 2014-08-19 Georgia Regents Research Institute, Inc Methods and compositions for modulating keratinocyte function
WO2019226599A1 (en) * 2018-05-22 2019-11-28 Alkalidx, Inc. Diagnostics and treatments of anesthetic insensitive subjects
CN113116823A (en) * 2019-12-30 2021-07-16 江苏恒瑞医药股份有限公司 Liposome and preparation method thereof
CN113597316A (en) * 2019-04-15 2021-11-02 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical preparation and application thereof

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Cited By (15)

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KR20010090030A (en) * 2001-08-09 2001-10-18 임정옥 Manufacturing and synergic effect of topical anesthetic formula consisted of mixed local anesthetics
US8808715B1 (en) * 2004-11-23 2014-08-19 Georgia Regents Research Institute, Inc Methods and compositions for modulating keratinocyte function
WO2008051889A1 (en) * 2006-10-24 2008-05-02 The Johns Hopkins University Rapid release mini-tablets provide analgesia in laboratory animals
US8093261B2 (en) 2006-10-24 2012-01-10 The Johns Hopkins University Rapid release mini-tablets provide analgesia in laboratory animals
US8461173B2 (en) 2006-10-24 2013-06-11 The Johns Hopkins Univeristy Rapid release mini-tablets provide analgesia in laboratory animals
US9668974B2 (en) 2012-05-10 2017-06-06 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
WO2013168172A1 (en) * 2012-05-10 2013-11-14 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
US9849088B2 (en) 2012-05-10 2017-12-26 Painreform Ltd. Depot formulations of a hydrophobic active ingredient and methods for preparation thereof
RU2664700C2 (en) * 2012-05-10 2018-08-21 Пейнреформ Лтд. Depot formulations of local anesthetic and methods for preparation thereof
US10206876B2 (en) 2012-05-10 2019-02-19 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
WO2019226599A1 (en) * 2018-05-22 2019-11-28 Alkalidx, Inc. Diagnostics and treatments of anesthetic insensitive subjects
CN113597316A (en) * 2019-04-15 2021-11-02 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical preparation and application thereof
CN113597316B (en) * 2019-04-15 2023-11-24 湖州依诺唯新药物制剂有限公司 Lipid pharmaceutical formulation and use thereof
CN113116823A (en) * 2019-12-30 2021-07-16 江苏恒瑞医药股份有限公司 Liposome and preparation method thereof
CN113116823B (en) * 2019-12-30 2024-02-20 江苏恒瑞医药股份有限公司 Liposome and preparation method thereof

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