DE10054919A1 - Topical analgesic and antipruritic medicament, useful e.g. for combating pain of injections, comprising local anesthetic in colloidal carrier system comprising lipophilic and hydrophobic phases - Google Patents

Abstract

A topically applied medicament (I), having a colloidal drug carrier system, for the treatment and prophylaxis of painful and pruritic states comprises: (a) up to 10 wt. % of a lipophilic phase, containing local anesthetic(s) in an amount of up to 30 wt. %; (b) up to 50 wt. % of a surfactant-cosurfactant mixture; and (c) 40-75 wt. % of a hydrophilic phase.

Description

This invention relates to drug formulations with Lo Kalanesthetics, which after topical application Skin and mucous membranes from local anesthesia fen and their use.

Local anesthesia of the intact skin is increasing Interest, not only because of the steadily increasing number of people number of minimally invasive surgical procedures. A Injection of local anesthetics is always with one additional pain connected by the needle insertion and harbors avoidable risks (e.g. infection) in yourself. The work was concerned with a formulation to develop a fast and sufficient strong local anesthesia after topical application of the skin. The application of egg is also conceivable  nes such preparation for pain reduction in Ve functions and at i.m. or s.c. Injections.

So far, these applications have been available on the German market only EMLA® cream available. This product contains the eutectic mixture as active ingredient (1: 1 m / m) of the two local anesthetics Lidocaine and Prilo cain in their base forms. This combination of at the substances reduce the melting point to 18 ° C, so that at normal application temperatures a liquid instead of crystalline solids lies. This results in an increased thermodynami the activity of the active ingredients that form the basis for forms a faster skin penetration. Lidocaine and Prilocaine are concentrated in EMLA® cream each contain 2.5%. Achieving an effective Local anesthesia with EMLA® cream is only under occlusion sion possible. There is an application period of at least 60 minutes necessary.

In WO 9633706 a locally anesthetically effective me presented cream, which is also 2.5% lidocaine and contains prilocaine. It is a O / W emulsion with a pH of 6.8.

A formulation of emulsion type W / 0 for topical Local anesthesia is described in WO 9922717. A paraffin-based vehicle system with water Content below 1% forms the basis in WO 9955287 was able to incorporate lidocaine and prilocaine in Ratio 3: 1 (m / m). Above all, it is advantageous here the high storage stability. The beginning of local anäs The theoretical effect is 45 to 60 minutes according to Appli cation specified.  

Another lipid-based basis is in the WO 9601637 presented. Thereby, with tetracaine in 5% concentration already 15 minutes after application anesthesia has been demonstrated in guinea pigs become.

A lipid carrier system consisting of a polar and a non-polar lipid, is WO 9319736 reasons. At 10% water content, 5% lidocaine incorporated and the effectiveness in the pin prick test demonstrated. A local anesthetic gel for Application on the oral mucosa is in the WO 9738675. The active ingredient is the eutectic mixture of lidocaine and prilocaine (each 2.5%) used. Another gel preparation on normal skin contains amethocaine in 4% - concentration and is ge in WO 9213533 teaches. The local anesthetic effect is said to already be pronounced after 40 min. In the UK it is the preparation is commercially available under the name Ametop® Gel.

In recent years, the number of examinations increased on colloidal drug delivery systems, because these vehicle systems have advantages over conventional Chen ointments and creams. To the particularly Formulations that have been thoroughly examined are among them Liposome products. So there are already some Versu che, local anesthetics encapsulated liposomally on the To apply skin. In US 4,937,078 could Pin-prick test significantly better local anesthesia of 0.5% tetracaine in liposomal preparation compared to ointments. A tetracaine containing liposome formulation is also in the US 5,718,914. However, here too the application under occlusion.  

Colloidal drug delivery systems with particle size are in the nanometer range (colloidal solutions) however, so far for local anesthetic use hardly been examined. However, they bid against conventional vehicles such as ointments have the great advantage that occlusion can largely be dispensed with, since the systems themselves have properties of penetration have senhancers.

The object of the present invention is therefore a new drug formulation for topical application for the therapy and prophylaxis of pain and Propose itching conditions that have these disadvantages eliminated.

The task is determined by the generic drug formulation with the characteristic features of the contract spell 1 solved. The respective subclaims advantageous developments. The usage the drug formulation is characterized by the characteristics of Claims 18 to 20 solved.

According to the invention, the pharmaceutical formulation is based on a colloidal drug carrier system which consists of at least three essential components:

• a) containing a lipophilic phase in an amount of up to 10% by weight
  at least one local anesthetic in an amount of up to 30% by weight
• b) a mixture of surfactant and cosurfactant in one Amount up to 50% by weight,
• c) a hydrophilic phase in an amount between 40 and 75% by weight.

The drug delivery system is colloidal Form before.

An important advantage of the medicament according to the invention formulation is that liquid components, like the eutectic mixture of lidocaine and prilo cain, in much higher concentrations leave as in ointments, in which a Bre Chen the emulsion can occur.

Pharmaceuticals are preferred as the lipophilic phase Oils, waxes or fats are used. Among them are especially triglyceride, isopropyl myristate, 2- Octyldodecanol, isopropyl palmitate, oleic acid and / or a mixture of these is preferred.

Polyoxyethylene sorbents are preferred as surfactants Tan fatty acid esters and polyoxyethylene glycol fat acid ester and selected as co-surfactant poloxamers. There have been mass relationships between the ten sid and the cosurfactant in an order of magnitude between 1: 3 and 3: 2 were found to be advantageous. Especially a surfactant-cosurfactant mixture showed good results made of polyoxyethylene 20 sorbitan monooleate and poloxamer 331 in a mass ratio of 2: 3.

As an advantageous further development of the pharmaceutical formulation the hydrophilic phase is selected from polyols, Water, aqueous NaOH or buffer or mixtures of Polyols with water, aqueous NaOH or buffer, such as z. B. a hydrophilic phase from a mixture Propylene glycol and aqueous NaOH in mass ratio from 1:10 to 10: 1. Has been particularly advantageous a hydrophilic phase from a mixture of propy lenglycol and 0.01N NaOH in a mass ratio of 2: 1 proved.  

For the local anesthetics used in the Pharmaceutical formulation according to the invention in a pre partial education lidocaine and / or a deri vat of that selected. You can also use Prilo cain and / or its derivative, bupivacaine and / or its derivatives and / or mixtures of these be set.

In addition, of course, other Active substances are present in the pharmaceutical formulation, such as B. a corticosteroid.

To get a fast and effective local anesthesia local anesthesia proved to be important table active substances in their lipophilic bases form to use. The water soluble hydrochloride form works well for injections, but it can the stratum corneum only as a barrier to penetration overcome badly.

In addition, 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 in their neutralized environment in their protonated, poorly detectable form. In alkaline, the unprotonated, lipophilic form predominates, which has a better penetration ability.

By adding penetration enhancers such. B. Dimethyl sulfoxide or short chain alcohols in one Concentration up to 20% by weight can penetration behavior of the drug formulation further improved become.  

The colloidal drug delivery system stands out characterized in that the disperse phase particle diameter ser in the order of 5 to 200 nm.

The medicament according to the invention is particularly suitable formulation for therapy and prophylaxis painful ter and / or itchy skin diseases and / or the mucous membrane and / or the appendages of the skin.

Likewise, the therapy and prophylaxis of physika and chemical injuries to the skin and / or the mucous membrane and / or the skin appendage form with the pharmaceutical formulation according to the invention respectively.

Furthermore, the drug formulation is preferred for the treatment of painful manipulations (e.g. Punctures, injections, dressing changes) application.

Based on the following examples, the Invention moderate drug formulation are explained in more detail.

example 1

Composition and manufacture of vehicle systems

A colloidal drug delivery system was developed wraps and then in various ways varied. This basic system consists of a ten sid mixture, a hydrophilic (NaOH / propylene glycol) and a lipophilic phase (local anesthetics and pharmaceutical oils)

The emulsifiers polyoxyethylene-20- sorbitan monooleate (Tween © 80) and Poloxamer 331 (Synperonic® PE / L 101) selected. For the manufacturer  The vehicle systems have a combination tion of both in a ratio of 2: 3 mass fractions proven particularly suitable. Mixtures of the two Surfactants and propylene glycol / NaOH were previously made from.

Powdered drugs (lidocaine, bupivacaine) were treated with pharmaceutical oils (isopropyl palmitate or oleic acid) carefully driven and then the Ten added sid mix. The eutectic mix of Lidocaine and Prilocaine, which be at room temperature is already liquid, was di without additional oil mixed right with the surfactants. Then followed the addition of the hydrophilic phase (propylene glycol kol / NaOH mixture) and stirring until clear.

Variations on this basic system were made by Ver Changes in the composition of the hydrophilic phase. So became part of the propylene glycol / NaOH mixture by ethanol in concentrations of 10 to 20% moved to the final salary replaced. Furthermore, the added hydrophilic phase dimethyl sulfoxide (DMSO). For comparison, surfactant-free systems were also tested stet, which is the eutectic mixture of lidocaine and Prilocaine in a solution of water, propylene glycol and contained ethanol.

The concrete composition of all tested formu Lations is shown in Tab. 1 to 3. there are the systems with the highest medication substance content (10% per drug :) compared. All formulations were also ge accordingly tested lower concentrations. For that the Proportion of the hydrophilic phase increased, while the Ten sid concentration was kept constant.  

DMSO and ethanol were promoted for their penetration derenden properties added. That out as a surfactant selected polyoxyethylene 20 sorbitan monooleate is in 100% concentration unresponsive to human skin tolerated and is well tolerated by mucous membranes.

Example 2 Characterization of the vehicle systems

The drug carrier systems have been u. a. with help characterized by dynamic laser light scattering. This procedure is more colloidal for sizing Particles suitable in liquid media. For the doctor Formulations free of non-toxic substances could pass through 20 nm.

Example 3 Liberation investigations

With the multi-layer membrane model system (according to Neubert) was the in vitro release of the drugs the above formulations depending on of time examined.

The individual cells of the model passed from base plate and cover plate, between which the mem were arranged. About a recess the cover plate was a defined amount of Formu application (10 mg) applied to the membranes. As Ak dodecanol-collodion membranes with egg served as a zeptor content of 2% dodecanol. About the determination of the Saturation solubility of the drugs in dodecanol was able to determine the acceptance capacity of the acceptor become. By using three on top of each other  Laying membranes were accepting sink conditions gate guaranteed.

During the test period (5, 10 and 30 minutes) de the model is tempered at 32 ± 1 ° C. After expiration the excess formulation became the trial period carefully removed, the membranes separated, with off extracted pure ethanol and a salary determination subjected to HPLC. The analytical para meters are summarized in Tab. 4. It was pro A five-fold determination was carried out during the test period.

Tab. 5 shows the payment results of all tested systems. From this it can be seen that all For a large proportion after just 5 minutes have released the active ingredients contained. To Depending on the system, 30 minutes are available between 54 and 93% bar and thus essentially the process of liberalization completed. This proves that the release of the Drugs from the vehicle in none of the tested systems limit the rapid effectiveness occurs.

Example 4 Testing clinical efficacy on the subject (pin Prick test)

The study re-examined several new blinds developed galenical preparations with already left local anesthetic agents in the Hin look at the timing of the effect and the Efficacy on volunteers.  

The goals of the study were:

• - assessment of the local anesthetic effects of new pharmaceutical preparations
• - Objectification of the time between application and onset of action
• - Objectification of the potency
• - Objectification of the duration of action

The course of the study included the following steps:

• - the recruitment of 20 volunteers who: met the inclusion criteria
• - the study was double-blind
• - random division of the 32 test preparations into 2 Groups of 16 investigational medicinal products each and additional 4 control preparations (a total of 20 test preparations tions)
• - Application of the test preparations on the back with the help of FCS Epicutan plasters (Finn Chambers on Scanpor®) by one, on the evaluation and assessment Exercise of study results not involved test person
• - Testing the local anesthetic effectiveness with Fine needle stitches after 5, 10, 30, 60, 120 min

The study was carried out in practice by February to March 2000.

The patients were selected according to the following Criteria:  

inclusion

• - only voluntary participation
• - adult subjects
• - The written consent form is available after participating in the study the education about nature, risks and consequences the testing
• - only based on the preliminary medical examination healthy subjects

exclusion criteria

Subjects with intolerance and / or Hypersensitivity to any of the following substances:

• - Local anesthetics
• - Tween 80
• - Synperonic PE L101
• - oleic acid
• - propylene glycol
• - ethanol
• - DMSO
• - isopropyl
• - Borate buffer (boric acid, sodium hydroxide solution)

Subjects on one of the following cranes kungen suffer:

• - neurological disorders
• - Diseases known to be associated with neurolo changes can go hand in hand
• - Skin diseases with a test area

Subjects who regularly or within the medication taken last 14 days or have been administered

• - Pregnant or nursing women  
• - Unreliability or lack of cooperation tion of the subject

The test preparations were made by a pharmacist as follows:

• - Weighing the drug
• - Add the mixture of Tween 80 and Synperonic PE L101 and rub the two components
• - Add the oil component (oleic acid or isopropyl palmitate)
• - Add the aqueous phase
• - Even mixing of the components
• - Add ethanol and rub up to one clear, homogeneous microemulsion

EMLA® cream was used as a positive reference substance used.

The test preparations were each at room temperature but not stored / stored above 30 ° C.

The test preparations were in plaster strips (Scanpor®) with 5 application chambers each (corresponds to 5 Test substances) applied epicutaneously. For everyone too un application time was therefore 4 Pfla ster strips (a total of 20 test substances) are used. These were so posi on the back of a subject tionier glued that 4 patches at each test time strips for a total of 20 test substances removed could become.

The investigator recruited 20 subjects, the Ein final criteria met and discussed this Aim, course and risk of the study. To written declaration of consent from each subject  was with the grouping, the investigations and the application of the test preparations started. All work steps were written in a pro band-related test protocol. After Ab At the end of the examination, a medical examination was carried out circuit-examination.

The application areas were covered with a Colored pencil thus marks a unique assignment the individual tests were secured. Testing the Anesthetic effectiveness was assessed using a fine needle stitch (pain stimulus - pin prick test), with a canoe lenhülle (touch stimulus) and visual (erythema as Degree of compatibility) checked. and by the pro tied in a scale of 0-5 in the strength of the rei zes classified. The comparison was always too given to an untreated neighboring area. The test was performed as a double-blind prospective Attempt. To ensure blindness, the Test substances from a second, on evaluation of results not involved investigator, appli decorated, removed and the remains of the test substances wiped. After the test was completed, a Disinfection of the stitches and a specialist Examination of the affected skin areas.

For comparison of the individual active substances and The therapeutic effect was determined Results of each parameter in a contingency entered in the table and with the chi-square test ana lysed.

Claims (20)

1. Pharmaceutical formulation for topical use for the therapy and prophylaxis of. Containing pain and itching conditions

• a) 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 and

wherein the drug carrier system is in colloidal form. 2. Pharmaceutical formulation according to claim 1, characterized ge indicates that the lipophilic phase is selected is made from pharmaceutical oils, waxes or fet th. 3. Drug formulation according to at least one of the before arising claims, characterized in that the lipophilic phase is selected from Triglycerides, isopropyl myristate, 2- Octyldodecanol, isopropyl palmitate or oleic acid.   4. Drug formulation according to at least one of the before arising claims, characterized in that the surfactants are selected from polyoxyethy lensorbitan fatty acid esters and polyoxyethylene glycerol fatty acid esters. 5. Drug formulation according to at least one of the before arising claims, characterized in that the cosurfactant is selected from poloxamers. 6. Drug formulation according to at least one of the before arising claims, characterized in that the surfactant-cosurfactant mixture in one mass ratio of 1: 3 to 3: 2 is present. 7. Drug formulation according to at least one of the before arising claims, characterized in that the surfactant-cosurfactant mixture of polyoxyethy len-20 sorbitan monooleate and Poloxamer 331 in one nem mass ratio of 2: 3. 8. Drug formulation according to at least one of the before arising claims, characterized in that the hydrophilic phase is selected from Po lyols, water, aqueous NaOH or buffer or Mixtures of polyols with water, aqueous NaOH and / or buffer.   9. Drug formulation according to at least one of the before arising claims, characterized in that the hydrophilic phase is a mixture of propy lenglycol and NaOH in a mass ratio of 1:10 up to 10: 1. 10. Drug formulation according to at least one of the before arising claims, characterized in that the hydrophilic phase is a mixture of propy lenglycol and 0.01N NaOH in a mass ratio of Is 2: 1. 11. Drug formulation according to at least one of the before arising claims, characterized in that as a local anesthetic lidocaine and / or a Derivative of which is included. 12. Drug formulation according to at least one of the before arising claims, characterized in that as a local anesthetic prilocaine and / or a Derivative of which is included. 13. Drug formulation according to at least one of the before arising claims, characterized in that as a local anesthetic bupivacaine and / or a Derivative of which is included.   14. Drug formulation according to at least one of the before arising claims, characterized in that in addition to local anesthetics further active ingredient, e.g. B. a corticosteroid and / or a derivative thereof. 15. Drug formulation according to at least one of the before arising claims, characterized in that the local anesthetic in the lipophilic Ba is present. 16. Pharmaceutical formulation according to at least one of the above arising claims, characterized in that in addition penetration enhancers such. B. Tue. methyl sulfoxide or short chain alcohols in one Concentration of 1-20% by weight are included. 17. Pharmaceutical formulation according to at least one of the above arising claims, characterized in that the disperse phase particle diameter in the Magnitude of 5 to 200 nm. 18. Use of the pharmaceutical formulation according to at least one of the preceding claims, for therapy and prophylaxis painful and / or itchy Skin and / or mucous membrane disorders and / or the skin appendages.   19. Use of the pharmaceutical formulation according to at least one of claims 1 to 18, for therapy and Prophylaxis of physical and / or chemical Injuries to the skin and / or mucous membrane and / or the skin appendages. 20. Use of the pharmaceutical formulation according to at least one of claims 1 to 18, for therapy and Prophylaxis of painful manipulations (e.g. Punctures, injections, dressing changes).