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

0001The present invention relates to a mixture of local anesthetically active compounds in base form in order to obtain topical anesthesia through skin, and process for its preparation.

0002The object of the present invention is to obtain a possibility of utilizing local anesthetically active compounds in base form and to obtain a maximal concentration of active substance at the site of application on the skin in order to obtain local anesthesia with as low a dose as possible.

0003It is previously known, e.g. from Swedish Patent No. 352 239, to produce a local anesthetically active film comprising lidocaine in crystalline, microdispersed form in a solid carrier. The film is hereby intended to be used for anesthesia of mucous membranes, especially in the mouth cavity for blocking the nerves around the teeth in order to facilitate smaller incisions. Lidocaine is present in the film in 2 to 40% by weight. The drawback of said solid carrier is that an exactly determined dose can not be administered for penetration as in each case there is no possibility to determine how much of the lidocaine is left in the film carrier. A high concentration of lidocaine in the film carrier cannot be obtained and because penetration is dependent on concentration, more doses than necessary have to be used.

0004It is further known to combine two or more local anesthetics in the form of acid addition salts in aqueous solutions for injection. (Cf British Patent Specification No. 1 360 820). In such case the active agents are present in water soluble form and do not form a homogenous oil.

0005Previously, the problem has also been to utilize local anesthetically active compounds in the form of their bases as these are in crystalline form at room temperature and an acceptable effect is not obtained when the substance is applied in crystalline form.

0006The wish has then been to obtain an oil phase, containing high amount of local anesthetic, which, by means of a simple carrier, can be easily applied on the intended surface.

0007It has now surprisingly been found that it is possible to obtain such a form by means of the present invention, whereby moreover, a deeper penetrative effect as well as an improved local anesthesia is obtained, whereby the invention is characterized in that it comprises a first local anesthetic agent in the form of its base and as such having a melting point of 30 to 50°C and a second, different local anesthetic agent in the form of its base and as such having a melting point of above 30°C, preferably above 40°C, which agents when brought and heated together form a homogenous oil which has a melting point below 40°C, more preferably below 25°C.

0008In accordance with the invention <ul id="ul0001" list-style="none"><li>a) a first local anesthetic agent in the form of its base is mixed with</li><li>b) a second local anesthetic agent in the form of its base, whereby the agent under a) has a melting point of 30 to 50°C and the agent under b) has a melting point of above 30°C preferably above 40°C.</li></ul>

0009According to a preferred embodiment of the invention prilocaine or tetracaine in base form is mixed with one of benzocaine, lidocaine, bupivacaine, mepivacaine, or etidocaine or tetracaine in base form. It is evident that when tetracaine is used as first base it can not be used as second base.

0010According to a preferred embodiment prilocaine and benzocaine are mixed in a weight ratio of 63:37 to 96:4, preferably 65:35 to 80:20, most preferably 70:30.

0011According to a preferred embodiment prilocaine and lidocaine are mixed in a weight ratio of 42:58 to 80:20, preferably 47:53 to 62:38, most preferably 55:45.

0012According to another preferred embodiment prilocaine and etidocaine are mixed in a weight ratio of 55:45 to 95:5, preferably 60:40 to 80:20, most preferably 70:30.

0013According to a further preferred embodiment prilocaine and mepivacaine are mixed in a weight ratio of 80:20 to 97:3, preferably 85:15 to 90:10, most preferably 87:13.

0014According to another, further preferred embodiment prilocaine and bupivacaine are mixed in a weight ratio of 72:28 to 97:3, preferably 78:22 to 88:12, most preferably 85:15.

0015According to another preferred embodiment of the invention tetracaine and lidocaine in their base forms are mixed in a weight ratio of 40:60 to 70:30, preferably 45:55 to 55:45, most preferably 50:50.

0016Compounds under a) are prilocaine, tetracine, butanilicaine and trimecaine.

0017Compounds under b) are benzocaine, lidocaine, bupivacaine, dibucaine, mepivacaine and etidocaine, as well as tetracaine, butanilicaine and trimecaine.

0018When the local anesthetic agents of a) and b) respectively in base, crystalline form are mixed together and heated the mixture shall have a resulting melting temperature of below 40°C and thereby form a homogenous oil. The oil is completely reformed if heated to the melting point even after a storage at low temperature for long time.

0019The above given weight ratios give mixtures which melt at temperatures below 40°C and are present in the form of an oil. The mixtures form eutectic mixtures with eutectic minima.

0020The present invention is intended for providing local anesthesia by means of topical application on skin, whereby a mixture of the invention of preferably prilocaine or tetracaine in the form of its base, and any of the compounds benzocaine, lidocaine, bupivacaine, mepivacaine, etidocaine or tetracaine in a therapeutically effective amount is applied onto the skin surface through which anesthesia is to be obtained.

0021Thereby the mixture is added in a dose of 0.5 to 10 mg/cm² of skin.

0022The expression skin above relates to mucous membrane as well as intact or wounded skin.

0023Further, injectable compositions are obtained, which injectable compositions contain in oil form one local anesthetic agent in base form and as such having a melting point of 30° to 50°C, and one other local anesthetic agent in base form and as such having a melting point of above 30°C, preferably above 40°C.

0024Such a composition will have a potent clinical use in more rapid onset of effect and/or prolonged duration of local anesthetic effect.

0025Above given compounds except for benzocaine, dibucaine, and tetracaine are represented by the general formula <chemistry id="chem0001" num="0001"><img file="EP0002425B1_D0001.tif" /></chemistry>wherein R¹ is <chemistry id="chem0002" num="0002"><img file="EP0002425B1_D0002.tif" /></chemistry><chemistry id="chem0003" num="0003"><img file="EP0002425B1_D0003.tif" /></chemistry>and R² is hydrogen or methyl, whereby R² is hydrogen when R' is <chemistry id="chem0004" num="0004"><img file="EP0002425B1_D0004.tif" /></chemistry>or wherein R¹ is -CH₂NH(CH₂)₃CH₃ and R² is chloro. <ul id="ul0002" list-style="none"><li>or wherein R^I is -CH₂N(C₂H₅)₂ and R² is methyl and a further methyl group is present in para- position to the carbamoyl containing side chain.</li><li>Benzocaine, 4-aminobenzoic acid ethyl ester, has the formula <chemistry id="chem0005" num="0005"><img file="EP0002425B1_D0005.tif" /></chemistry>Tetracaine, 2-(dimethylamino)ethylester of p-butylaminobenzoic acid has the formula <chemistry id="chem0006" num="0006"><img file="EP0002425B1_D0006.tif" /></chemistry>Dibucaine, 2-butoxy-N-(2-diethylaminoethyl)cinchoniamide, has the formula <chemistry id="chem0007" num="0007"><img file="EP0002425B1_D0007.tif" /></chemistry>1-methyl-2-(2,6-xylylcarbamoyl)piperidine is known under the generic name mepivacaine and is sold under the trade mark Carbocaine®. <ul id="ul0003" list-style="none"><li>1-butyl-2-(2,6-xylylcarbamoyl)piperidine is known under the generic name bupivacaine and is sold under the trade mark Marcaine@.</li><li>2-propylamino-N-(2-tolyl)propionamide is known under the generic name prilocaine and is sold under the trade mark Citanest®.</li><li>Diethylaminoacet-2,6-xylidide is known under the generic name lidocaine and is sold under the trade mark Xylocaine@.</li><li>2-(ethylpropylamino)-2',6'-n-butyroxylidide is known under the generic name etidocaine and is sold under the trade mark Duranest®.</li><li>2-(butylamino)-6'-chloro-o-aceto-toluidide is known under the generic name butanilicaine.</li><li>2-diethylamino-2',4',6'-trimethylacetanilide is known under the generic name trimecaine.</li></ul></li><li>Prilocaine has a melting point of 38°C, lidocaine a melting point of 68°C; etidocaine a melting point of 88°C; mepivacaine a melting point of 155°C; bupivacaine a melting point of 110°C; benzocaine a melting point of 89°C, tetracaine a melting point of 41 °C, butanilicaine a melting point of 45-46°C, trimecaine a melting point of 44°C, and dibucaine a melting point of 65°C.</li></ul>

0026The oil formed from the mixture of local anesthetically active compounds in the form of their bases can be administered as such, or be transferred onto a carrier such as paper, or be introduced into a liquid carrier in order to form an emulsion, or as an emulsion in an ointment base. The different forms of preparation, depend on where one wants to obtain anesthesia.

0027After anesthesia through the skin the following incisions can be made.

0028Mucous membrane: the taking of a punch biopsy, smaller incisions in underlying mucous membrane, e.g. curettage, or gingivectomi or tooth tartar removal, elimination of needle prick pain at an injection. Otholaryngological incisions in nose and throat, e.g., biopsy or trepanation.

0029Paracentesis of drum-membrane.

0030Sample excision in the urogenitalic area.

0031Local anesthesia of cervix at delivery.

0032Intact skin: Smaller cutaneous incisions e.g. biopsy, or excision of naevi, elimination of needle prick pain before injection.

0033The present invention will in the following be described more in detail with reference to a number of examples.

Example 1

0034<tables id="tabl0001" num="0001"><img file="EP0002425B1_D0008.tif" /></tables>

0035The two local anesthetically active compounds in crystalline form were mixed together and heated to 30°C, whereby the two compounds melted and formed a homogeneous oil. The mixture of crystals has a melting point of 22°C. The mixture did not crystallize even after a long storage at low temperature, when reheated to 22°C.

Example 2

0036<tables id="tabl0002" num="0002"><img file="EP0002425B1_D0009.tif" /></tables>

0037The two local anesthetically active compounds, in crystalline form, were mixed together and were heated to 35°C, whereby the two compounds melted and formed a homogenous oil. The melting point of the mixture is 29°C.

Example 3

0038<tables id="tabl0003" num="0003"><img file="EP0002425B1_D0010.tif" /></tables>

0039The two local anesthetically active compounds in crystalline form, were mixed together and were heated to 40°C, whereby the two compounds melted and formed a homogenous oil. The melting point of the mixture is 33°C.

Example 4

0040<tables id="tabl0004" num="0004"><img file="EP0002425B1_D0011.tif" /></tables>

0041The two local anesthetically active compounds, in crystalline form, were mixed together and heated to 40°C, whereby the compounds melted and formed a homogenous oil. The melting point of the mixture is 34°C.

Example 5

0042<tables id="tabl0005" num="0005"><img file="EP0002425B1_D0012.tif" /></tables>

0043The two local anesthetically active compounds, in crystalline form, were mixed together and were heated to 35°C, whereby the compounds melted and formed a homogenous oil. The melting point is 29°C.

Example 6

0044<tables id="tabl0006" num="0006"><img file="EP0002425B1_D0013.tif" /></tables>

0045The two local anesthetically active compounds, in crystalline form, were mixed together and were then heated to 25°C, whereby the compounds melted and formed a homogenous oil. The melting point of the mixture is 17°C.

Example 7

0046A mixture according to Example 1 was applied onto a carrier of paper in an amount of 1.5 mg/cm². The carrier, 1 cm², with the mixture was applied on the teeth gums in the vicinity of the root point of the tooth to be treated, prior to a deep cavity preparation in a vital tooth. After about 5 min the treatment could be carried out without giving the patient any pain sense.

0047Lidocaine and prilocaine alone do not give such an anesthetic effect.

Biological effect

0048The biological effect of the local anesthetic mixture of the present invention was determined in an experimental investigation of dermal analgesia by epidermal application of different local anesthetic formulations.

0049In the present investigation it was shown in 12 volunteers that the pain response, induced by pin-pricking, was partly blocked by epidermal application of different local anaesthetic formulations. Dermal analgesia (tested by pin-pricking) was most pronounced with a formulation consisting of a eutectic mixture of lidocaine base and prilocaine base, in a total concentration of 10%, as an aqueous emulsion. The other two tested formulations, containing 10% lidocaine and 10% prilocaine base respectively, were less effective, with regard to dermal analgesia, even if these produced some demonstrable effects, different from a placebo emulsion.

Material and method

005012 healthy medical students from the Uppsala University Hospital took part in the study.

0051Pre-formed pads, consisting of cellulose fibres, 2 times 2 centimetres, were soaked by a standardized procedure in either an emulsion containing 5% lidocaine base + 5% prilocaine base, an emulsifying agent and water, 10% lidocaine base in the same vehicle, 10% prilocaine bases in the same vehicle, or a placebo emulsion containing the emulsifying agent and water only. On one forearm of the volunteer the four different emulsions were applied under occlusive dressings consisting of impervious tape, while on the other arm the four emulsions were applied under a non-occlusive dressing, using surgical tape (3M). A certain distance between the application areas was chosen in order to avoid any risk of interference between them.

0052On the arms of the volunteers 11 and 12 the emulsions were applied directly to the skin, with no cellulose pads, but with occlusive and non-occlusive dressings applied as in the other volunteers.

0053The application time for the pads was 60 minutes.

0054Immediately after removal of the pads, the square areas under the two types of dressing were marked at the edges. A line was also marked within each applied area dividing them into two identical triangles. One of these surfaces were then used for the pin-prick experiments, the other for studying other effects.

Testing of dermal analgesia

0055The pin-pricking procedure was carried out with disposable dental needles. In each of the test areas 10 pin-pricks were made. 10/10 represents full analgesia, 0/10 no analgesia.

Results

0056The lidocaine-prilocaine emulsion was found to be significantly more effective than the lidocaine emulsion, the prilocaine emulsion and the placebo emulsion in producing dermal analgesia. By the XX test it was found that: <tables id="tabl0007" num="0007"><img file="EP0002425B1_D0014.tif" /></tables><tables id="tabl0008" num="0008"><img file="EP0002425B1_D0015.tif" /></tables>

0057The lidocaine and prilocaine emulsions were found to be insignificantly more effective than the placebo emulsion under occlusion as well as insignificantly different in effect to placebo under a non-occlusive bandage, as evident from Table I, statistical data, below. <tables id="tabl0009" num="0009"><img file="EP0002425B1_D0016.tif" /></tables><tables id="tabl0010" num="0010"><img file="EP0002425B1_D0017.tif" /></tables>

0058It has also been shown that the present combinations of local anesthetics possess worthwile properties in inhibiting perspiration. They can thus be used in antiperspirant compositions as emulsions for roll-on, or emulsions or solutions for spraying.