Local anesthetic mixture for topical application, and process for its preparation

Start of patent duration: 1981 03 15 Longest possible duration:

t Issued on: 1981 10 27

Inventor: BRQBERG BERNDT FREDRIK JULIUS

SÖOERTXLJE »SWEDEN EVERS HANS CHRISTER ARVID SÖOERTXLJE. SWEDEN © Dependency: '

AT 3Ö4 4Ö1 © References which have been considered as delimiting from the state of the art:

OE-AS 1299796 GB-PS 889225

Nr.364451

The invention relates to a process for the preparation of locally anesthetically effective combination preparations in which the active component is present as an oil.

With the combination preparations obtainable according to the invention, surface anesthesia is achieved through the skin.

The aim of the invention is to find a way to use locally anesthetically active compounds in base form and to achieve a maximum concentration of the active substance when applied to the skin in order to achieve a local anesthetic with the lowest possible dose.

It is already known, for example, from SE-PS No. 352239, to produce a lidocaine in a crystal-clear, microdispersed, locally-anesthetically active film. The film is to be used for the anesthesia of mucous membranes, especially in the oral cavity to block the nerves around the teeth in order to facilitate smaller incisions. Lidocaine is present in the film at 2 to 40% mass. The disadvantage of this solid support is that it is not possible to penetrate a precisely set dose, because in one case it is not possible to judge how much lidocaine is left in the film carrier. As can be readily understood, the concentration of lidocaine also can not become too high, with the result that higher doses must be used as necessary.

Furthermore, it is known to combine two or more local anesthetics in the form of acid addition salts in aqueous solutions for injection (see GB-PS No. 1,360,820). In this case, the active agents are present in water-soluble form and do not form a homogeneous oil.

So far, it has also been a problem, locally anesthetically effective compounds in the form of their

Bases are used because they are crystalline at room temperature and when using the substance in crystalline form no acceptable effect can be achieved.

In GB-PS No. 889.225 and in DE-AS 1299796 a local anesthetic mixture with low toxicity is described, which consists of a combination of

a) an injectable local anesthetic as free base or its salt and

b) a local anesthetic called thesit.

The compounds mentioned under a) are relatively less toxic relative to the compound according to b), whereby the total amount of local anesthetics can be increased without the risk of dermatological damage by b). Furthermore, the penetration of b) can be improved by the addition of a).

Such a combination of only a local anesthetic with a poly (oxyethylene) alcohol does not form a eutectic mixture; each compound compounded in this way must be dissolved in a solvent.

"Thesit" is a surfactant with a certain local anesthetic effect. However, its cross section is not comparable to that of a true local anesthetic.

Thus, there was a desire to obtain an oil which consists of a large amount of local anesthetics and which can be easily applied to the desired surface by means of a simple carrier.

Surprisingly, it has now been found that it is possible to obtain such a form by means of the invention, wherein in addition a deeper penetration and an improved local anesthesia are achieved, and wherein the method according to the invention gekenn45 is characterized in that

a) a locally anesthetically active compound from the group prilocaine, tetracaine, Butanilicain and Trimecain, in base form, with

b) another locally anesthetically active compound from the group of benzocaine, lidocaine, bupivacaine, dihucaine, mepivacaine, etidocaine, tetracaine, butane silicate and trimecaine, in

Basenform, is melted together in such proportions that the resulting mixture has a melting point of below 40 ° C.

The compounds mentioned under a) have a melting point of 30 to 50 ° C, the compounds mentioned under b) have a melting point of about 30 ° C, preferably above 40 ° C.

Nr.364451

According to a preferred embodiment of the invention, prilocaine or tetracaine, in

Base form, with benzocaine, lidocaine, bupivacaine, mepivacaine, etidocaine or tetracaine, in base form, fused together. Of course, when tetracaine is used as the first base, it can not be used as the second base.

Particularly suitably, the mixing ratios are chosen so that the resulting

Mixture has a melting point of less than 25 ° C.

According to a preferred embodiment, prilocaine and benzocaine are in a weight ratio of 63: 37 to 96; 4, preferably from 65: 35 to 80: 20 and especially 70: 30 melted together.

According to a preferred embodiment, prilocaine and lidocaine are fused together in a weight ratio of from 42:58 to 80:20, preferably from 47:53 to 62:38 and especially 55:45.

According to a further preferred embodiment, prilocaine and etidocaine are in a weight ratio of 55: 45 to 95: 5, preferably 60: 40 to 80: 20, and in particular

70: 30 melted together.

According to another preferred embodiment, prilocaine and mepivacaine are present in a weight ratio of 80:20 to 97; 3, preferably from 85: 15 to 90: 10 and in particular 87: 13 melted together.

According to another, further preferred embodiment, prilocaine and bupivacaine 20 are melted together in a weight ratio of from 72:28 to 97: 3, preferably from 78:22 to 88:12 and especially 85:15.

According to yet another preferred embodiment of the invention, tetracaine and lidocaine are melted together in their base form in a weight ratio of 40:60 to 70:30, preferably 45:55 to 55:45, especially 50:50.

If the local anesthetics of the groups mentioned under a) or b) mixed and heated in base and crystalline form, the resulting mixture must have a melting temperature of below 40 ° C and form a homogeneous oil when they are exceeded. When the mixture is heated to the melting point, the oil is completely reformed, even after long term storage at low temperature.

The weight ratios given above give mixtures which melt at temperatures below 40 ° C and are then present in the form of an oil.

According to a preferred embodiment, the mixture prepared according to the invention is in a dose of 0.5 to 10 mg / cm² Applied to the skin.

The term skin used above refers to mucous as well as intact or injured

Skin.

A combination preparation produced according to the invention will have an effective clinical application, since the effect starts faster and / or the local anesthetic effect lasts longer than in known preparations of this type.

The above compounds except benzocaine and tetracaine are represented by the general formula

<img file="AT364451B_D0001.tif" />

wherein

Nr.364451

CH 3

CH₂CH₂CH₂CH₃ /

\.

./ \ \ _ /, CH₂CH₃ , CH₂CH₃

-CHNHCH₂ CH₂ CH₃; -CH₂ N or -CHN

CH, ^sCH₂CH₃ 'CH₂CH₃

CH₂CH₃ is and

R² Is hydrogen or methyl, where R² Hydrogen is when R^l -CHNHCH₂CH₂CH₃ means.

CH_a

Benzocaine, 4-aminobenzoic acid ethyl ester, has the formula h₂Tetracaine, 2- (dimethylamino) -äthyIester of p-butylaminobenzoic acid has the formula

CH₃(CH₂)₃NH

C00CH₂CH₂N (CH₃)₂ L-methyl-2- (2,6-xylylcarbamoyl) -piperidine is known by the general name mepivacaine be10.

1-Butyl-2- (2,6-xylylcarbamoyl) -piperidine is known by the general name bupivacaine.

2-Propylamino-N- (2-tolyl) -propionamide is known by the general name prilocaine.

Diethylaminoacet-2,6-xylidide is known by the general name lidocaine.

2-Ethylpropylamino-2,6-n-butyroxylidide is known by the generic name etidocaine.

Prilocaine has a melting point of 38 ° C; Lidocaine has a melting point of 68 ° C; Etidocaine has a melting point of 88 ° C; Mepivacaine has a melting point of 155 ° C; Bupivacaine has a melting point of 110 ° C; Benzocaine has a melting point of 89 ° C; Tetracaine has a melting point of 41 ° C; Butanilicain a melting point of 45 to 46 ° C; Trimecain has a melting point of 44 ° C and

Dibucaine has a melting point of 65 ° C.

The above-mentioned mixtures have a melting point minimum within the ranges indicated. The mixtures form eutectic mixtures with eutectic minima.

The oil formed by the locally anesthetically active compounds in the form of their bases at a flash point below 40 ° C may be administered as such, or transferred to a carrier, such as paper, or into a liquid carrier to form an emulsion or as an emulsion be placed in an ointment base. The different forms of preparation depend on where one wants to effect anesthesia.

After anesthesia through the skin, the following incisions can be made:

Mucosa: Performing a punch biopsy, minor incisions in the underlying

Mucous membrane, eg curettage, or gingival resection or calculus removal, elimination of

Nr.364451

Pinprick pain at injection. Otolaryngological incision in the nose and throat, eg biopsy or trepanation.

Paracentesis of the eardrum.

Trial excisions in the urogenital area.

Cervical local anesthesia at delivery.

Intact skin: minor skin incisions, eg biopsy, nevus excision, elimination of needlestick pain prior to injection.

The invention will be described in more detail below with reference to a number of examples.

Example 1:

Prilocaine, base 52 g

Lidocaine, base 48 g

100 g

The two locally anesthetically active compounds - in crystalline form - were weighed together and heated to 30 ° C; the two compounds melting and forming a homogeneous oil. The mixture of crystals has a melting point of 22 ° C. The mixture did not crystallize, even when stored for long periods in high temperatures when reheated to 22 ° C.

Example 2:

Prilocaine, base 70 g

Etidocaine, base 30 g

100 g

The two locally anesthetically active compounds - in crystalline form - were weighed together and heated to 35 ° C, the two compounds melting and forming a homogeneous oil. The melting point of the mixture is 29 ° C.

Example 3:

Prilocaine, base 85 g

Mepivacaine, base 15 g

100 g

The two locally anesthetically active compounds - in crystalline form - were weighed together and heated to 40 ° C, the two compounds melted and formed a homoge ness oil. The melting point of the mixture is 33 ° C.

Example 4:

Prilocaine, base 80 g

Bupivacaine, base 20 g

100 g

The two locally anesthetically active compounds, in crystalline form, were weighed together and heated to 40 ° C., the compounds melting and forming a homogeneous oil. The melting point of the mixture is 34 ° C.

Example 5:

Prilocaine, base benzocaine, base g 30 g

100 g

Nr.364451

The two locally anesthetically active compounds - in crystalline form - were weighed together and heated to 35 ° C, the compounds melting and forming a homogeneous oil. The melting point is 29 ° C.

Example 6:

Tetracaine, base 50 g

Lidocaine, base 50 g

100 g

The two locally anesthetically active compounds - in crystalline form - were mixed together and then heated to 25 ° C, the compounds melting and forming a homoge- neous oil. The melting point of the mixture is 17 ° C.

Example 7: A mixture according to Example 1 was applied to a support of paper in an amount of 1.5 mg / cm² applied. The carrier, 1 cm²with the mixture was applied to the gum near the root point of the tooth to be treated, before making a deep hole in a living tooth. After about 5 minutes, the treatment could be carried out without the patient feeling any pain.

Lidocaine and prilocaine alone do not give such anesthetic effect.

Biological effect: The biological effect of the locally aesthetically effective combination preparations obtainable according to the invention was determined in an experimental investigation of the skin analgesia by epidermal application of various local anesthetic formulations.

In the present study, 12 volunteer subjects showed that the response to pinpoint-induced pain was partially blocked by epidermal application of various local anesthetic formulations. Skin analgesia (tested by pin-pricks) was strongest in a formulation made according to the invention which consisted of a eutectic mixture of lidocaine and prilocaine base and was converted to an aqueous emulsion at a total concentration of 10%. The other two formulations tested, containing 10% lidocaine and 10% prilocaine base respectively, were less effective in the analgesia of the skin, although they had some detectable effects, unlike a placebo emulsion.

Material and Methods: Twelve healthy medical students from the University of Uppsala Clinic participated in the study.

Preformed cellulosic swabs, 2 x 2 cm, were made in a standard procedure with either 5% lidocaine and 5% prilocaine base, emulsifier and water, 10% lidocaine base in the same carrier, 10% prilocaine base in the same carrier, or only emulsifier and water containing Sugg estionsmittelemulsion soaked. On one forearm of the volunteer subject, the four different emulsions were applied under occlusive dressings of impermeable tape while on the other arm the four emulsions were applied under a non-occluded dressing using surgical tape (3M). A certain distance has been chosen between the fields of application to make the

To avoid risk of mutual interference.

On the arms of Volunteers 11 and 12, the emulsions were applied directly to the skin without the use of cellulose swabs, but using closed and unclosed bandages as with the other volunteers.

The application time was 60 minutes for the swabs.

Immediately after removal of the swabs, the square areas were under the two

Bandage types marked on the edges. Furthermore, a line was marked within each application area, by which it was divided into two equal triangles. One of these surfaces was then used for the needle stick experiments, the other for the study of other effects.

Skin analgesia testing: The needle stick test was performed with disposable needles. Ten pinpricks were performed on each test area. 10/10 means perfect analgesia, 0/10 no analgesia.

Results: It was found that the lidocaine-prilocaine emulsion was significantly more effective than the lidocaine emulsion, the prilocaine emulsion and the placebo emulsion, resulting in the production of the

Analgesia of the skin is concerned. The t-test of the students showed the following:

Nr.364451

Lidocaine-prilocaine

Lidocaine Frilocain

Lidocaine-prilocaine versus opposite

Placebo:

lidocaine:

prilocaine:

p = 0.001 'p = 0.001>

p = 0.01 under closed dressing

Lidocaine prilocaine versus lidocaine prilocaine versus lidocaine-prilocaine

<td>Placebo:</td><td>p = 0.01</td>

<td>lidocaine:</td><td>p = 0.01</td>

<td>prilocaine:</td><td>p = 0.01</td>

under non-sealed bandage

It was found that lidocaine and prilocaine emulsions were marginally more effective than placebo emulsions under occlusion, and that they differed only insignificantly from a placebo under non-occlusive dressing, as shown in the following Table I, Statistical Data.

Table I

<td rowspan="2"></td><td colspan="4">needlestick locked</td><td colspan="4">non-sealed</td>

<td>LP</td><td>L</td><td>P</td><td>placebo</td><td>LP</td><td>L</td><td>P</td><td>placebo¹</td>

<td>1</td><td>10/10</td><td>2.10</td><td>0/10</td><td>0/10</td><td>10.7</td><td>0/10</td><td>0/10</td><td>0/10</td>

<td>2</td><td>10/10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>10/10</td><td>0/10</td><td>0/10</td><td>0/10</td>

<td>3</td><td>2.10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td>

<td>4</td><td>10/10</td><td>5.10</td><td>10/10</td><td>0/10</td><td>10/10</td><td>0/10</td><td>6.10</td><td>0/10</td>

<td>5</td><td>9.10</td><td>3.10</td><td>1.10</td><td>0/10</td><td>10.7</td><td>1.10</td><td>0/10</td><td>0/10</td>

<td>6</td><td>8.10</td><td>2.10</td><td>0/10</td><td>0/10</td><td>9.10</td><td>o / io</td><td>0/10</td><td>0/10</td>

<td>7</td><td>8.10</td><td>0/10</td><td>-</td><td>0/10</td><td>2.10</td><td>0/10</td><td>1.10</td><td>0/10</td>

<td>8th</td><td>10/10</td><td>0/10</td><td>2.10</td><td>0/10</td><td>8.10</td><td>0/10</td><td>0/10</td><td>0/10</td>

<td>9</td><td>10.7</td><td>2.10</td><td>0/10</td><td>4.10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td>

<td>10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>0/10</td><td>2.10</td>

<td>M 1-10</td><td>7.40</td><td>1.40</td><td>1.44</td><td>0.40</td><td>5.10</td><td>0.10</td><td>0.70</td><td>0.20</td>

<td>11</td><td>10/10</td><td>8.10</td><td>10.7</td><td>0/10</td><td>5.10</td><td>0/10</td><td>2.10</td><td>0/10</td>

<td>12</td><td>10/10</td><td>6.10</td><td>9.10</td><td>0/10</td><td>3.10</td><td>0/10</td><td>0/10</td><td>0/10</td>

<td>M 1-1 2</td><td>7.82</td><td>2.33</td><td>2.64</td><td>0.30</td><td>4.92</td><td>0.08</td><td>0.75</td><td>0.17</td>

Statistical data Patient no.

<td>1-10</td><td>LP / Placebo: t LP / L: t LP / P: t</td><td>= 5.78^xxx= 5.87^xxx= ll, 33^xx</td><td>LP / placebo: t = 3.40^xxLP / L: t = 3.70^xxLP / P: t = 3.50^xx</td>

<td>1-12</td><td>LP / placebo: t</td><td>= 7, ll^xxx</td><td>LP / placebo: t = 3.96^xx</td>

<td></td><td>LP / L: t</td><td>= 6.03^xxx</td><td>LP / L: t = 4.29^xx</td>

<td></td><td>LP / P: t</td><td>= 4.30^xx</td><td>LP / P: t = 3.97^xx</td>

- 8 Table I (continued)

Nr.364451

<td>needlestick</td><td></td>

<td>locked</td><td></td>

<td>Patient No.</td><td></td>

<td>1-10</td><td>L / placebo: t = 1.58 n</td>

<td></td><td>P / placebo: t = 0.80 n</td>

<td>1-12</td><td>L / placebo: t = 2.32^x</td>

<td></td><td>P / placebo: t = 1.71 n</td>

not locked

1-10 L / Flacebo: t = 0.42 ns

P / placebo: t = 0.76 ns

1-12 L / placebo: t - 0.43 ns

P / placebo: t = 1.05 ns

LP - lidocaine-prilocaine compound

L = lidocaine compound

P = prilocaine compound

It has also been found that the combinations of local anesthetic agents produced according to the invention have significant antiperspirant properties. They can thus be used for the preparation of antiperspirant compositions in the form of emulsions for roll-ons or of emulsions or solutions for sprays.

PATENT CLAIMS:

1. A process for the preparation of locally anesthetically effective combination preparations in which the active component is present as an oil, characterized in that a locally anesthetically active compound from the group prilocaine, tetracaine, Butanilicain and Trimecain, in base form, with another locally anesthetically active compound from the Group benzocaine, lidocaine, bupivacaine, dibucaine, mepivacaine, etidocaine, tetracaine, butanilica and trimecain, in base form, is melted together in such proportions that the resulting mixture has a melting point of below 40 ° C.

2. The method according to claim 1, characterized in that prilocaine or tetracaine, in the form of the base, with one of the compounds benzocaine, lidocaine, bupivacaine, mepivacaine, etidocaine or tetracaine, in the form of its base, is melted together.

3. Method according to