MXPA00010447A - Topical anesthetic formulation - Google Patents

Abstract

A topical, transdermal anesthetic formulation comprising a eutectic mixture of, preferably, lidocaine and prilocaine in a ratio of about 3:1 by weight, incorporated within a lipophilic base. In addition to the property of rapid-onset, the formulation of the present invention has high storage stability and is less restricted by dosage limitations of other prilocaine-containing transdermal anesthetics and is, advantageously, not dependent upon occlusive dressing for optimal transdermal absorption.

Description

TOPIC ANESTHESIA FORMULATION Field of the Invention This invention is related to a new formulation of topical anesthesia, and particularly, a topical anesthesia formula, through fast-acting skin, and with better stability.

Background of the Invention Surgical techniques such as cosmetic reconstruction including surgical ablation with an Erbium ™ AG laser, and other laser procedures including vaporization, suppression, incision, and coagulation of soft tissues in medical specialties including dermatology, plastic surgery, Podiatry, neurosurgery, gynecology, otorhinolaryngology (ENT), asthroscopy (knee surgery), invasive and endoscopic general surgery, can only be performed after the highly sensitive findings of the nerves in the skin have been anesthetized. The preferred method of administering anesthesia is through the skin.

The skin, siembargo, is a formidable barrier for the absorption of anesthetics. Because the skin must serve as a barrier to the entry of pathogens and toxic substances, and for the release of physiological liquids, the skin is highly impermeable. This impermeability allows the skin to preserve its own integrity while simultaneously maintaining a dynamic balance of electrolytes in the body. Therefore, the skin functions both as a containment mechanism and as a microbiological, chemical, radiation and thermal barrier. This impermeability can be attributed to the nature of a very thin layer created by normal development and physiological changes in the skin. After the cells are formed in the basic layer, they begin to migrate towards the surface of the skin, until eventually they are detached away. When they experience this migration, the cells progressively dehydrate and keratise. When the cells reach the surface, just before being discarded, they form a thin layer of dense, metabolically inactive cells of approximately ten microns (10-15 cells) thick, the outer layer of the skin. As a result of the high degree of keratization of the cells that includes the outer layer of the skin, a formidable barrier is created. The absorption through the surface of the mucosa is generally efficient, because the outer layer of the skin is absent. Therefore, any formulation to be used as an efficient topical anesthetic, through the skin, has to be able to be readily absorbed through the skin. In addition to the thickness and integrity of the epidermis of the outer layer of the skin, percutaneous absorption or through the skin can significantly alter the kinetics of the drug and depends on a variety of factors including the site of application, size of the molecules active of the drug, the permeability of the membrane of the delivery system of the drug through the skin, the state of skin hydration, the pH of the drug, the metabolism of the drug by the flora of the skin, the solubility of the lipids, and the alteration of the blood flow in the skin by the additives and the temperature of the body. Certainly, the use of topical anesthesia, through the skin, is well known in dental applications such as applying anesthetics to the gums before injecting anesthesia. In mucous membranes, such as those that cover the mouth, topical anesthetics are readily absorbed and work very well. Siembargo, in the skin, the mechanics and physiology of absorption is very different. Anesthetics through the skin are also used to numb the area before piercing the veins, as in drawing blood. Pain relief is especially important in the area of pediatrics, where even the slightest pain can result in an anxious and non-cooperative patient. In addition to the advantages over intravenous delivery, other advantages of skin delivery include, avoiding the risks associated with previous treatments; the elimination of the drawbacks of the above treatments, and the elimination of the gastrointestinal irritations that result from the exposure of the gastrointestinal tract to active pharmaceutical preservatives, tablet agents, and the like. In the past, several types of methodologies for topical anesthetics have been treated, including skin freezing. This is done more easily by applying ice or spraying the skin with a chemical that evaporates quickly. This chemical freezes the surface of the skin. As an example of this we have ethyl chloride (chloroethane). Unfortunately, ethyl chloride has many disadvantages. It is difficult to numb large areas using this method and the effect lasts little, rarely lasting more than several seconds to one minute. Additionally, ethyl chloride is flammable, and when used to produce a local freeze, the area adjacent to the skin should be protected by applying petroleum jelly. Finally, the thawing process can be painful, and freezing can lower local resistance to infections and delay healing. Cocaine solutions are also known, and act by blocking the initiation or conduction of the nervous pulse. For example, CT (a mixture of tetracaine, adrenaline and cocaine) essentially eliminates pain and increases hemostasis during saturation of an open laceration, but is not effective on intact skin. Additionally, levels of the cocaine system have been documented after a simple application of bandages, soaked in TAC, in an open wound, accentuating the need to calculate and limit the dose of cocaine administered. The strict limitations of the total dose of each component according to the weight of the body without fat of the patient are crucial. As with any narcotic, there is the potential for respiratory depression and oxygen desaturation with moderate rapid absorption through any mucosa. Lidocaine is very effective and is commonly used as a local anesthetic in the United States, especially in the form of aqueous solutions of lidocaine hydrochloride (Xylocaine ®), which is administered intravenously or through direct injection or by serum. Lidocaine stabilizes the neuron membrane by inhibiting the flow of ions required for the initiation and conduction of impulses, thus affecting the action of local anesthesia. Lidocaine can be formulated as a gelatin (Xylocaine ® 2%), an ointment, and sprayed for use as an anesthetic. Unfortunately, these formulations are only effective to be absorbed by the mucosal surface and not by the skin. A more recent development of transdermal anesthetics using lidocaine is the EMLA® cream (a Eutectic mixture of local anesthetics), which patients prefer instead of lidocaine serum or ethyl chloride spray. EMLA ® is an oil-in-water emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1: 1 by weight (2.5% and 2.5% respectively), and including 92% purified water. The eutectic mixture is a mixture that has a lower melting point than all its ingredients; therefore these two anesthetics after being heated and mixed exist as a liquid oil at room temperature, instead of as crystals. EMLA ® cream is described in U.S. Pat. No. 4,529,601 (Broberg, et al.) and in U.S. Pat. No. 4,562,060 (Broberg, et al.), which teaches the mixture of specific proportions of certain local anesthetic agents in the form of their bases to form a homogeneous oil having a melting point below 40 ° C, preferably 25 ° C. ° C. Like lidocaine, prilocaine is a local anesthetic agent of a type of amide. The amides, are favorable as anesthetic agents, in comparison with the esters, which are more sensitive and can cause redness, swelling, irritation, itching, and other reactions. Unfortunately, methemoglobinemia (a condition that causes iron in hemoglobin to be unable to carry oxygen) and cyanosis (bluish discoloration, especially of the skin and mucous membranes, due to the reduction of hemoglobin in the blood ) apparently occur more frequently with prilocaine than with other local anesthetics. Methemoglobinemia describes the formation of oxidized iron compounds in the heme protein (the iron component (red color) of hemoglobin, which is not a protein) of red blood cells. This is a state of erythrocyte disease. The voltage of the cellular oxidant causes structural changes in the hemoglobin. If the oxidant voltage is very large, the levels of methemoglobin rise and the function of the erythrocytes is compromised. Symptoms usually occur when doses of prilocaine hydrochloride exceed about 8 mg per kg of body weight but younger ones tend to be more susceptible. For an average 70 kg person, this represents a dose of 560 mg. This severely limits the size of the area that will be anesthetized. The biggest drawback with EMLA ® is that intact local anesthesia of the skin is not achieved until at least 60 minutes after application. For more invasive procedures, such as skin grafts, at least 2 hours are required. This delay in onset is a significant disadvantage, as it is a great inconvenience for patients and medical personnel. This delay is particularly a problem in the area of pediatrics, where any tional waiting time only contributes to making the patient uneasy. Another disadvantage with EMLA ® cream is that, for deep penetration effects, it is necessary that the cream is applied on an occlusive bandage. Specifically, a double layer of laminated and absorbent cellulose is fixed in the area of the skin that is to be anesthetized. This bandage is very inconvenient and dirty. It would be desirable, therefore, to have a topical anesthetic, through the skin that has the benefits of lidocaine and prilocaine, but to be free of all the problems described above associated with these two medicines. Accordingly, it is an object of the present invention to provide topical anesthesia, through the skin using prilocaine, without the dose limitations characteristic of prilocaine-containing anesthetics. Another objective of the present invention is to provide a topical anesthesia, through the skin exhibiting a comparatively rapid onset. It is still another object of the present invention to provide a topical anesthetic, through the skin which does not depend on an occlusive bandage for rapid absorption through the skin.

SUMMARY OF THE INVENTION It has been surprisingly discovered that by incorporating a specific ratio concentration of a eutectic mixture including specific proportions of lidocaine and prilocaine in a lipophilic base, an anesthetic formulation through the skin is produced, which has a significantly faster onset than comparable anesthetics, such as EMLA ® cream. For example, when applied to the face before an ablation surgery, such as cosmetic reconstruction including surgical ablation with an Erbium laser, the anesthesia of the present invention works in as little as 10 to 40 minutes without bandaging. In addition to ablation, the present formulation is particularly useful prior to laser procedures that require vaporization, excision, incision, and coagulation of soft tissues in medical specialties including dermatology, plastic surgery, podiatry, neurosurgery, gynecology, otorhinolaryngology (ENT) , arthroscopy (knee surgery),), general invasive and endoscopic surgery. It has also been surprisingly discovered that by using a lipophilic vehicle instead of an oil-in-water delivery system, the formulation is remarkably improved in stability. In a preferred embodiment, the present invention is directed towards the preparation of topical anesthesia, through the skin including (all per cent are by weight): About 10-20%, preferably about 15% lidocaine; About 1-5%, preferably about 5% prilocaine; About 0.0-1.0%, preferably about 0.75% dibucaine; About 0.0-2.0%, preferably about 0.5-1.0%, effective as a local vasoconstrictor, of a sympathomimetic amine, preferably phenylephrine; and the balance being a lipophilic base; where the lidocaine and prilocaine is in the form of a eutectic mixture in ratio from a weight ratio from about 15: 1 to about 2: 1.

In a preferred embodiment of the invention, the ratio of lidocaine to prilocaine is 8: 1 to 2: 1, preferably about 3: 1. While the named analgesics are preferred, some substitutions are allowed. In the present invention, phenylephrine preferably serves as a vasoconstrictor to facilitate localization of the effect. Other sympathomimetica amines that can be used will be described later. Accordingly, the lipophilic base formulation of the present invention is one that does not contain, or substantially does not contain, aqueous components or the functional equivalent aqueous component. Additionally, for the purpose of the present invention the definition of the lipophilic base is not particularly limited, and anyone who is known in the pharmaceutical or cosmetics industry could be used, and includes modified lipophilic materials such as thickeners, diluents, stabilizers, surfactants, etc. In addition to the preferred embodiment described above, alternative formulations may be used including a eutectic mixture of: at least one pharmaceutically active anesthetic selected from a first group consisting of lidocaine, benzocaine, bupivacaine, dibucaine, mepivacaine, etidocaine, tetracaine, butanilicaine and trimecaine; and at least one pharmaceutically active anesthetic selected from a second group consisting of prilocaine, tetracaine, butanilicaine and trimecaine; where the anesthetic (s) selected in the first group differ from the anesthetic (s) chosen from the second group from about 15: 1 to about 2: 1, in the lipophilic base. Preferably, at least one of those anesthetics is selected by a group containing prilocaine and lidocaine. In addition to the property of a rapid onset, the formulation of the present invention is free from the large dose limitations of other transdermal anesthetics containing prilocaine. Additionally, the formulation is, advantageously, independent of the bandages for optimum skin absorption.

The present formulation can be used in place of anesthesia serums for minor procedures, or in combination with these more invasive anesthetic procedures. Cosmetic applications include, but are not limited to, laser reconstruction, electrolysis, permanent makeup application, body piercing, and tattooing. In addition to being used as a preventive anesthetic, the formulation can also be used in therapies for pain relief after operations, especially in pediatrics and in overly emotional patients. The foregoing has broadly summarized the most relevant and important features of the present invention so that the detailed description of the invention that follows is better understood and the contribution to the art can be fully appreciated. The additional features of the invention that form the objective of what is claimed in the invention will be described below. It should be appreciated by those skilled in the art that the conception and the specific incorporations revealed can be used as a basis to modify or design other anesthetic formulations. It must also be done by those skilled in the art that these equivalent formulations start from the spirit and scope of the invention expressed in the added claims.

Detailed Description of the Invention One advantage, as well as a greater distinguishing characteristic, of the formulation of the present invention is first attributed to the eutectic mixture of the two preferred anesthetic agents, lidocaine and prilocaine, in the respective proportional ratio of approximately 15: 1 to 2: 1 in weight; second, to the amount of the eutectic mixture in the lipophilic vehicle; and thirdly, the use of a lipophilic base instead of an aqueous vehicle or an oil-in-water emulsion (the term "water" when referring to oil-in-water emulsions, includes hydrophilic liquids which serve as substitutes for water). The formulation of the present invention preferably contains from 10% to 20% by weight of lidocaine and 1% to 5% by weight of prilocaine based on the total weight of the formulation. Preferably, the formulation contains about 20% by weight of lidocaine and about 5% by weight of prilocaine. The present formulation of the lipophilic base exhibits superior properties, including the accelerated rate of onset, the lack of pronounced limitations of the normally characteristic doses of other transdermal prilocaine anesthetics, and no reliance on bandages for optimal absorption through the skin. . As a lipophilic base, the present invention is not particularly limited, and anyone who is known in the pharmaceutical and cosmetic industry can be used, and this includes modified lipophilic materials such as thickeners, diluents, stabilizers, surfactants, etc. As lipophilic materials, an oleaginous material such as petrolatum, thick mineral oil or a gel with polyethylene, paraffin waxes with high molecular weight, mono gel and diglycerides of high molecular weight fatic acid or complex polyamides of hydroxyestearate, propylene glycol isostearate or an isostearyl alcohol gel with high molecular weight, factual acids and mixtures of these can be used. The lipophilic base must satisfy the following characteristics: the base must allow the oils, and particularly the eutectic mixture, to be completely miscible in that; the base must be compatible with the skin with the least possible number of adverse reactions; the base of being smooth and flexible without adverse odors; the base must have a color appeals to the consumer; the base must be stable and must provide a stable vehicle for the medication; the base must be hydrophobic, for example, have low water absorption capacity; and the base must be able to promptly release the drug incorporated into the skin.

Preferably, the lipophilic component is a high aliphatic alcohol, preferably 8-18 carbon atoms, or an ester thereof. Examples of oleaginous (lipophilic) ointment bases include USP white ointment, yellow NF ointment, USP oleic acid, USP olive oil, USP paraffin, NF petrolatum, USP white petrolatum, spermaceti USP wax , the synthetic Spermaceti NF, the glycerin starch NF, the white wax USP, and the yellow wax USP.

Lidocaine is chemically designated as an acetamide, 2- (diethylamine) -N (2,6-dimethylphenyl) and has an octanol: the ratio of water partition is 43 to a pH of 7.4. Prilocaine is chemically designated as a propanamide, N- (2-methyl-phenyl) -2- (propylamine) and has an octanol: the ratio of water partition is from 25 to a pH of 7.4. As described above, it is preferable that lidocaine and prilocaine are in the formulation as a eutectic mixture at a ratio of about 3: 1. When applied to intact skin, the formulation of the present invention provides a dermal anesthesia by the release of lidocaine and prilocaine from the formulation in the epidermal and dermal layers of the skin and from the accumulation of lidocaine and prilocaine in the vicinity. of dermal pain receptors and nerve terminals. Lidocaine and prilocaine are local anesthetic agents of a type of amide. Both lidocaine and prilocaine stabilize the neuronal membrane by inhibiting the flow of atoms required for the initiation and conduction of impulses, thus affecting the action of local anesthesia. In eutectic mixture, both anesthetics remain liquid at room temperature and the penetration and subsequent systematic absorption of both prilocaine and lidocaine are increased over what would be seen if each component in crystalline form were applied separately. The dosage of the present formulation, which provides effective anesthesia, depends in part on the duration of the application on the treated area. At least one sympathomimetic amine is preferably added to the formulation for its mimic stimulation ability of the lymphatic nervous system. Specifically, when used with a topical anesthetic, these amines act as vasoconstrictors to limit the locality of the effect of anesthesia. Sympathomimetica amines that can be used in the preparation of the present invention include, but are not limited to, adrenaline, amezinium metilsulfate, cinnamedrine, clonazoline, chlorprenaline, coumazoline, cyclopentamine, dimetofion, dimetofrine, dipivefrin, ephedra, ephedrine, ethilefrine, phenoxazoline , hydraxyamphetamine, hydroxyphedrine, indanazoline, isometheptene, levonordefrin, mephentermine, metaraminol, methoxamine, methyllephedrine, midodrine, naphazoline, noradrenaline acid, norfenefrine, octodrine, octopamine, oxedrine, oxilofrine, oxymetazoline, phenylephrine, phenylpropanolamine, prednazoline, psuedoephedrine, tefazoline, tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline and xylometazoline. It is also preferable that the formulation contains about 0.75% dibucaine. The formulation remains effective with a dibucaine content between 0.0% and 0.1%, however. In addition to the preferred embodiment described above, which contains lidocaine and prilocaine, the alternative incorporation includes all formulations comprising an eutectic mixture of at least one pharmaceutically active primary anesthetic selected from the group consisting of benzocaine, lidocaine, bupivacaine, dibucaine, mepivacaine , etidocaine, tetracaine, butanilicaine and trimecaine and at least one second pharmaceutically active anesthetic chosen from the group consisting of prilocaine, tetracaine, butanilicaine and trimecaine, these first and second pharmaceutically active agents are presented in a weight ratio of about 15: 1 to about 2: 1 on a lipophilic base, and this anesthetic (s) is chosen from the first group differs from the anesthetic (s) chosen from the second group, and at least one of these anesthetics is preferably either prilocaine or lidocaine. In addition, the formulation of the present invention can be applied to a paper carrier, patches, or pads, as disclosed in U.S. Pat. No. 4,529,601 (Broberg, et al.) And 4,562,060 (Broberg, et al.), So that the cellulose fibers of the preformed carrier are soaked with the formulation. Also, the present formulation can be prepared as a bar formulation suitable for the delivery of pharmacologically active compounds, as disclosed in U.S. Pat. No. 5,622,993 (McGinity, et al.) The present invention will be described in more detail in the following examples.

Example 1 The formulation according to the invention was made in the following manner (the total amount: 800g): a) 50g of prilocaine was weighed and dissolved in 200 ml of distilled water. b) when the prilocaine was dissolved, the solution was added to a separatory funnel. c) In a small cuvette, 30 g of sodium hydroxide pellets were added to 50 ml of water. This solution was then added to the prilocaine mixture in the funnel, and allowed to stand for 30 minutes. d) after 30 minutes, the bottom layer was decanted in a bucket. This solution was saved. The top layer was saved in a 250 ml cuvette. Step C was repeated with the bottom layer. Again, the bottom layer was decanted and the top layer was saved. The top layer was added to the same 250 ml cuvette. e) 120g of lidocaine were added to the 250 ml cuvette and mixed thoroughly. f) 8g of dibucaine and 5g of phenylephrine-HCl were weighed. These powders were placed in a glass mortar and crushed. Then, 5 ml of ethanol was added to the powders and mixed until they were dissolved. g) The product from step f) was added to the lidocaine / prilocaine mixture. h) once this solution was clear, the final weight was obtained. i) The weight of the mixture was subtracted from 800 to determine the amount of petrolatum needed. J) The petrolatum and the mixture were placed in a base plate of sufficient size and mixed thoroughly. The mixture had less than 1% in water. k) The mixture was distributed in 1oz tubes. The approximate life of the shelf was found to be about 12 months.

Example 2 The method of application of the formulation to the skin: a) the skin was completely defatted using 70% isopropyl alcohol or acetone. b) a thin layer of the product was applied using a finger or a cotton-tipped applicator. c) the patient rested for 30 to 45 minutes while waiting for the anesthetic to take effect. In thick skin such as arms and legs, the patient waited an hour. The patient experienced insensitivity and the anesthesia was good. The duration of the insensibility was found to vary with the amount of the product applied and the length of the waiting period. The minimum time reported was 90 minutes and the longest reported was six hours. The average reported insensitivity period was 180 minutes. With respect to the description above, it was realized that the optimum relationships for the components of the invention, including variations in size, materials, shape, form, function and manner of operation, assembly and the use, are apparent and obvious to a skilled in the art, and in all ratios equivalent to those illustrated in the drawings and described in the specification of the present invention. Therefore, the foregoing is considered as illustrative only of the principles of the invention. Additionally, numerous modifications and changes may occur to those skilled in the art, it is not desired to limit the invention to the exact formulation and operation shown and described, and, consequently, all modifications and appropriate equivalents may be resorted to, entering the scope of the invention. Now that the invention has been described,

Claims (20)

1. Novelty of the Invention I. A formulation for topical local anesthesia through the skin, comprising an eutectic mixture of lidocaine and prilocaine based on the weight of about 15: 1 to about 2: 1 on a lipophilic base.
2. 2. A formulation as in claim 1, wherein this weight ratio of lidocaine to prilocaine is from about 8: 1 to about 2.5: 1.
3. 3. A formulation as in claim 1, wherein the weight ratio of lidocaine to prilocaine is about 3: 1.
4. 4. A formulation as in claim 1, additionally comprising dibucaine from 0 to 1% by weight of the total formulation.
5. 5. A formulation as in claim 1, further comprising a vasoconstrictor.
6. 6. A formulation as in claim 5, wherein this vasoconstrictor is a sympathomimetic amine.
7. 7. A formulation as in claim 6, wherein this sympathomimetic amine is phenylephrine.
8. 8. A formulation as in claim 7, wherein this phenylephrine is present in an amount of 0 to 2% by weight based on the total weight of the formulation.
9. 9. A formulation as in claim 1, wherein this lipophilic base is a petroleum product in the eutectic mixture is completely miscible.
10. 10. A formulation as in claim 1, wherein this lipophilic base is a high aliphatic alcohol with 8-18 carbon atoms, or an ester thereof.
11. II. A formulation as in claim 1, wherein this lidocaine comprises from 10% to 20% by weight, and this prilocaine comprises 1% to 5% by weight, of the total weight of the formulation.
12. 12. A formulation as in claim 1, wherein this lipophilic base comprises from 70% to 89% by the weight of the formulation.
13. 13. A method of obtaining local anesthesia in mammals by topical application, through the skin, this method comprises administering a formulation comprising an eutectic mixture of lidocaine and prilocaine in weight ratio of about 15: 1 to about 2. : 1 in a lipophilic base.
14. 14. A method as in claim 13, wherein the formulation also comprises dibucaine.
15. 15. A method as in claim 13, wherein the formulation comprises, in addition, a vasoconstrictor.
16. 16. A method as in claim 15, wherein the vasoconstrictor is a sympathomimetic amine.
17. 17. A method as in claim 16, wherein the sympathomimetic amine is phenylephrine.
18. 18. A formulation as in claim 18, wherein lidocaine and prilocaine are present in a weight ratio of about 15: 1 to about 2: 1.
19. A local topical anesthetic formulation through the skin comprising an eutectic mixture of at least one pharmaceutically active first anesthetic and at least one second pharmaceutically active anesthetic in a ratio of about 15: 1 to about 2: 1 in a lipophilic base, wherein at least the first pharmaceutically active anesthetic is selected from the group consisting of benzocaine, lidocaine, bupivacaine, dibucaine, mepivacaine, etidocaine, tetracaine, butanilicaine and trimecaine; at least the second pharmaceutically active anesthetic is selected from the group consisting of of prilocaine, tetracaine, butanilicaine and trimecaine, and at least one pharmaceutically active first anesthetic is different from at least one second pharmaceutically active anesthetic.
20. 20. A local topical anesthetic formulation through the skin as in claim 19, comprising at least one of lidocaine and prilocaine.