WO2003097010A1 - Formulation pharmaceutique sous forme colloidale pour application topique, servant a la therapie et a la prophylaxie d'etats douloureux et prurigineux - Google Patents

Formulation pharmaceutique sous forme colloidale pour application topique, servant a la therapie et a la prophylaxie d'etats douloureux et prurigineux Download PDF

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Publication number
WO2003097010A1
WO2003097010A1 PCT/EP2002/005356 EP0205356W WO03097010A1 WO 2003097010 A1 WO2003097010 A1 WO 2003097010A1 EP 0205356 W EP0205356 W EP 0205356W WO 03097010 A1 WO03097010 A1 WO 03097010A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
formulation according
prophylaxis
therapy
skin
Prior art date
Application number
PCT/EP2002/005356
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German (de)
English (en)
Inventor
Johannes Wohlrab
Reinhard Neubert
Annett Krause
Original Assignee
Johannes Wohlrab
Reinhard Neubert
Annett Krause
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Johannes Wohlrab, Reinhard Neubert, Annett Krause filed Critical Johannes Wohlrab
Priority to AU2002344968A priority Critical patent/AU2002344968A1/en
Priority to PCT/EP2002/005356 priority patent/WO2003097010A1/fr
Publication of WO2003097010A1 publication Critical patent/WO2003097010A1/fr

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Classifications

    • 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
    • A61K31/16—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
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics

Definitions

  • This invention relates to pharmaceutical formulations with local anesthetics, which cause local anesthesia after topical application to the skin and mucous membranes, and to the use thereof.
  • Local anesthesia of the intact skin is of increasing interest, not only because of the steadily increasing number of minimally invasive surgical interventions.
  • An injection of local anesthetics is always associated with additional pain due to the needle prick and entails avoidable risks (eg infection).
  • the aim of the work was to develop a formulation that achieved a fast and sufficiently strong local anesthesia after topical application on the skin. It is also conceivable to use a Such a preparation for pain reduction in venipuncture and in or sc injections.
  • the active ingredient of this product is the eutectic mixture (1: 1 m / m) of the two local anesthetics lidocaine and prilocaine in their base forms.
  • This combination of the two substances causes the melting point to be reduced to 18 ° C., so that a liquid is present instead of crystalline solids at normal application temperatures.
  • Lidocaine and prilocaine are contained in EMLA cream in a concentration of 2.5% each. Effective local anesthesia with EMLA cream can only be achieved with occlusion. This requires an application period of at least 60 minutes.
  • WO 9633706 presents a locally anesthetically active cream which also contains 2.5% lidocaine and prilocaine. It is an O / W emulsion with a pH of 6.8.
  • WO 9922717 A formulation of the emulsion type W / O for topical local anesthesia is described in WO 9922717.
  • a paraffin-based vehicle system with a water content of less than 1% forms the basis for incorporating lidocaine and prilocaine in a ratio of 3: 1 (m / m).
  • the high storage stability is particularly advantageous here.
  • the start of the local anesthetic effect is given as 45 to 60 min after application.
  • Another lipid-based basis is presented in WO 9601637. Anesthesia was detected in guinea pigs 15 minutes after application with tetracaine in a 5% concentration.
  • a lipid carrier system consisting of a polar and a non-polar lipid is based on WO 9319736. At 10% water content, 5% lidocaine was incorporated and the effectiveness was demonstrated in the pin prick test.
  • a locally anesthetically active gel for use on the oral mucosa is described in WO 9738675. The eutectic mixture of lidocaine and prilocaine (2.5% each) is used as the active ingredient.
  • Another gel preparation for use on normal skin contains amethocaine in a 4% concentration and is taught in WO 9213533. The local anesthetic effect should be pronounced after only 40 minutes. In the UK, the preparation is sold under the name Ametop Gel.
  • colloidal drug carrier systems with particle sizes in the nanometer range have so far hardly been investigated for local anesthetic use.
  • colloidal solutions with particle sizes in the nanometer range (colloidal solutions) have so far hardly been investigated for local anesthetic use.
  • conventional vehicles such as ointments, they offer the great advantage that occlusion can largely be dispensed with, since the systems themselves have properties of penetration enhancers.
  • the pharmaceutical formulation is based on a colloidal drug carrier system which consists of at least three essential components:
  • a lipophilic phase in an amount of up to 10% by weight, containing at least one local anesthetic in an amount of up to 30% by weight each b) a mixture of surfactant and cosurfactant in an amount of up to 50% by weight, c) a hydrophilic phase in an amount between 40 and 75% by weight.
  • the drug delivery system is in colloidal form.
  • liquid constituents such as the eutectic mixture of lidocaine and prilocaine, can be incorporated in much higher concentrations than in ointments in which the emulsion can easily break.
  • oils, waxes or fats are preferably used as the lipophilic phase.
  • triglyceride, isopropyl myristate, 2-octyldodecanol, isopropyl palmitate, oleic acid and / or a mixture thereof are particularly preferred.
  • Polyoxyethylene sorbitan fatty acid esters and polyoxyethylene glycerol fatty acid esters are preferably selected as surfactants and poloxamers as co-surfactants. Mass ratios between the surfactant and the cosurfactant in a range between 1: 3 and 3: 2 have been found to be advantageous. A surfactant-cosurfactant mixture of polyoxyethylene-20-sorbitan monooleate and Poloxamer 331 in a mass ratio of 2: 3 showed particularly good results.
  • the hydrophilic phase is selected from polyols, water, aqueous NaOH or buffer or mixtures of polyols with water, aqueous NaOH or buffer, such as a hydrophilic phase from a mixture of propylene glycol and aqueous NaoH in a mass ratio of 1: 10 to 10: 1.
  • a hydrophilic phase consisting of a mixture of propylene glycol and 0.01N NaOH in a mass ratio of 2: 1 has proven to be particularly advantageous.
  • lidocaine and / or a derivative thereof was selected for the local anesthetics used in the pharmaceutical formulation according to the invention.
  • prilocaine and / or its derivative, bupivacaine and / or its derivatives and / or mixtures thereof can also be used.
  • active ingredients can of course also be present in the pharmaceutical formulation, e.g. a corticosteroid.
  • the water-soluble hydrochloride form is well suited for injections, but it is difficult to overcome the stratum corneum as a penetration barrier.
  • the vehicle system should have a slightly alkaline pH. Since the local anesthetics used have pK a values between 7 and 9, they are predominantly present in their neutralized environment in their protonated, poorly penetrable form. In alkaline, the unprotonated, lipophilic form predominates, which has a better penetration ability.
  • the penetration behavior of the pharmaceutical formulation can be further improved by adding penetration enhancers, such as dimethyl sulfoxide or short-chain alcohols, in a concentration of up to 20% by weight.
  • penetration enhancers such as dimethyl sulfoxide or short-chain alcohols
  • the colloidal drug carrier system is characterized in that the disperse phase has particle diameters in the order of 5 to 200 nm.
  • the pharmaceutical formulation according to the invention is particularly suitable for the therapy and prophylaxis of painful and / or itchy diseases of the skin and / or the mucous membrane and / or the appendages of the skin.
  • the therapy and prophylaxis of physical and / or chemical injuries to the skin and / or the mucous membrane and / or the appendages of the skin can be carried out with the pharmaceutical formulation according to the invention.
  • the pharmaceutical formulation is preferably used for the treatment of painful manipulations (e.g. punctures, injections, dressing changes).
  • a colloidal drug delivery system was developed and then varied in various ways. This basic system consists of a surfactant mixture, a hydrophilic (NaOH / propylene glycol) and a lipophilic phase (local anesthetics and pharmaceutical oils)
  • Suitable surfactants of the emulsifiers of polyoxyethylene-20 sorbitan monooleate (Tween ® 80) and Poloxamer 331 were
  • Powdered drugs (lidocaine, bupivacaine) were carefully rubbed with pharmaceutical oils (isopropyl palmitate or oleic acid) and then added to the surfactant mixture.
  • pharmaceutical oils isopropyl palmitate or oleic acid
  • the eutectic mixture of lidocaine and prilocaine which is already liquid at room temperature, was mixed directly with the surfactants without any additional oil.
  • the hydrophilic phase propylene glycol / NaOH mixture
  • This basic system was varied by changing the composition of the hydrophilic phase. Part of the propylene glycol / NaOH mixture was replaced by ethanol in concentrations of 10 to 20% based on the final content. Dimethyl sulfoxide (DMSO) was also added to the hydrophilic phase. For comparison, surfactant-free systems were also tested which contained the eutectic mixture of lidocaine and prilocaine in a solution of water, propylene glycol and ethanol.
  • DMSO dimethyl sulfoxide
  • the drug delivery systems have been characterized with the help of dynamic laser light scattering. This method is suitable for determining the size of colloidal particles in liquid media. Particle diameters of approx. 20 nm could be determined for the drug-free formulations.
  • the multi-layer membrane model system (according to Neubert) was used to investigate the in vitro release of the drugs from the above-mentioned formulations as a function of time.
  • the individual cells of the model consisted of a base plate and cover plate, between which the membrane layers were arranged. A defined amount of formulation (10 mg) was applied to the membranes via a recess in the cover plate.
  • Dodecanol-collodion membranes with a content of 2% dodecanol served as acceptors. The absorption capacity of the acceptor was determined by determining the saturation solubility of the drugs in dodecanol. By using three on top of each other placed membranes were guaranteed sink conditions in the acceptor.
  • the model was tempered at 32 ⁇ 1 ° C during the test period (5, 10 and 30 minutes). After the test period, the excess formulation was carefully removed, the membranes separated, extracted with absolute ethanol and subjected to a content determination by means of HPLC.
  • the analytical parameters are summarized in Tab. 4. A five-fold determination was carried out for each test period.
  • Tab. 5 shows the payment results of all systems tested. It can be seen from this that all formulations have released a large proportion of the active ingredients contained after only 5 minutes. After 30 minutes, depending on the system, between 54 and 93% are available, which essentially completes the payment process. This proves that the release of the drugs from the vehicle is not a limitation for the rapid onset of action in any of the systems tested.
  • the study examined double-blind different newly developed galenical preparations with already approved local anesthetic active substances with regard to the temporal course of the effect and the potency of volunteers.
  • the goals of the study were:
  • Borate buffer (boric acid, sodium hydroxide solution) Subjects who suffer from one of the following diseases:
  • test preparations were made by a pharmacist as follows:
  • test preparations were not stored at room temperature above 30 ° C.
  • test preparations were applied epicutaneously in plaster strips (Scanpor ® ) with 5 application chambers each (corresponds to 5 test substances). For each application time to be examined, 4 plaster strips (a total of 20 test substances) were used. These were placed on the back of a test subject so that 4 plaster strips for a total of 20 test substances could be removed at each test time.
  • the investigator recruited 20 subjects who met the inclusion criteria and discussed the goal, schedule, and risk of the trial. After a written declaration of consent from each subject the grouping, the examinations and the application of the test preparations were started. All work steps were recorded in writing in a test-related test report. After the examination, a final medical examination was carried out.
  • the application areas were marked on the skin with a colored pencil so that a clear assignment of the individual tests was ensured.
  • the test of the anesthetic effectiveness was checked with a fine needle prick (pain stimulus - pin prick test), with a cannula sleeve (touch stimulus) and visually (Erythe as a measure of tolerance) and by the test person in a scale of 0-5 in strength of the stimulus. The comparison to an untreated neighboring area was always given.
  • the test was carried out as a double-blind prospective test. In order to ensure blindness, the test substances were applied and removed by a second test doctor who was not involved in the evaluation of the results, and the residues of the test substances were wiped off. After the test was completed, the punctures were disinfected and the skin areas concerned examined by a specialist.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dispersion Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des systèmes vecteurs de médicaments sous forme colloïdale, contenant des anesthésiques locaux, pour application topique sur la peau et les muqueuses. Les systèmes selon l'invention sont constitués d'un mélange tensioactif/co-tensioactif (monooléate de polyoxyéthylène-20-sorbitane et poloxamère 331), d'une phase hydrophile (par exemple, de mélanges propylèneglycol/NaOH aqueux), d'une phase lipophile (palmitate d'isopropyle ou acide oléique), ainsi que d'activateurs de pénétration.
PCT/EP2002/005356 2002-05-15 2002-05-15 Formulation pharmaceutique sous forme colloidale pour application topique, servant a la therapie et a la prophylaxie d'etats douloureux et prurigineux WO2003097010A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002344968A AU2002344968A1 (en) 2002-05-15 2002-05-15 Medicinal preparation in a colloid for topical application in the therapy and prophylaxis of states of pain and itching
PCT/EP2002/005356 WO2003097010A1 (fr) 2002-05-15 2002-05-15 Formulation pharmaceutique sous forme colloidale pour application topique, servant a la therapie et a la prophylaxie d'etats douloureux et prurigineux

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2002/005356 WO2003097010A1 (fr) 2002-05-15 2002-05-15 Formulation pharmaceutique sous forme colloidale pour application topique, servant a la therapie et a la prophylaxie d'etats douloureux et prurigineux

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WO2003097010A1 true WO2003097010A1 (fr) 2003-11-27

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AU (1) AU2002344968A1 (fr)
WO (1) WO2003097010A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4168308A (en) * 1976-03-12 1979-09-18 Apoteksvarucentralen Vitrum Ab Composition for enhancing the administration of pharmacologically active agents
WO1991018669A1 (fr) * 1990-06-08 1991-12-12 Affinity Biotech, Inc. Procede servant a preparer des microemulsions
DE19723308A1 (de) * 1997-06-04 1998-12-10 Wolfgang A Prof Dr Wohlrab Neue Mikroemulsionen zur topischen Anwendung von Arzneimittelwirkstoffen
WO1999048485A1 (fr) * 1998-03-20 1999-09-30 Caldwell Galer, Incorporated Procede pour traiter les douleurs liees a un nevrome
WO2000069471A1 (fr) * 1999-05-19 2000-11-23 The University Of Georgia Research Foundation, Inc. Anesthesie transcutanee amelioree au moyen d'agents anesthesiques locaux
DE10029404A1 (de) * 2000-06-15 2002-01-03 Johannes Wohlrab Arzneiformulierung enthaltend Ciclosporin und deren Verwendung

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4168308A (en) * 1976-03-12 1979-09-18 Apoteksvarucentralen Vitrum Ab Composition for enhancing the administration of pharmacologically active agents
WO1991018669A1 (fr) * 1990-06-08 1991-12-12 Affinity Biotech, Inc. Procede servant a preparer des microemulsions
DE19723308A1 (de) * 1997-06-04 1998-12-10 Wolfgang A Prof Dr Wohlrab Neue Mikroemulsionen zur topischen Anwendung von Arzneimittelwirkstoffen
WO1999048485A1 (fr) * 1998-03-20 1999-09-30 Caldwell Galer, Incorporated Procede pour traiter les douleurs liees a un nevrome
WO2000069471A1 (fr) * 1999-05-19 2000-11-23 The University Of Georgia Research Foundation, Inc. Anesthesie transcutanee amelioree au moyen d'agents anesthesiques locaux
DE10029404A1 (de) * 2000-06-15 2002-01-03 Johannes Wohlrab Arzneiformulierung enthaltend Ciclosporin und deren Verwendung

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KREILGAARD M ET AL: "NMR characterisation and transdermal drug delivery potential of microemulsion systems", JOURNAL OF CONTROLLED RELEASE, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, vol. 69, no. 3, 3 December 2000 (2000-12-03), pages 421 - 433, XP004221292, ISSN: 0168-3659 *
KREILGAARD MADS ET AL: "Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics.", PHARMACEUTICAL RESEARCH (NEW YORK), vol. 18, no. 5, May 2001 (2001-05-01), pages 593 - 599, XP009002863, ISSN: 0724-8741 *
KREILGAARD MADS: "Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis.", PHARMACEUTICAL RESEARCH (NEW YORK), vol. 18, no. 3, March 2001 (2001-03-01), pages 367 - 373, XP009002868, ISSN: 0724-8741 *
WOHLRAB J ET AL: "Lokalanästhetisch wirksame kolloidale Arzneistoffträgersysteme für die topische Therapie.", H+G ZEITSCHRIFT FÜR HAUTKRANKHEITEN, vol. 75, no. 7-8, 2000, GERMANY, pages 486, XP009002775 *

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