EUTECTIC ANESTHETIC TOPICAL COMPOSITIONS

Abstract

A eutectic anesthetic composition used to deliver pharmaceutical products topically as well as a method for producing the eutectic anesthetic composition, which may contain up to 80% additive ingredients. Preferred embodiments of the invention may include eutectic emulsion compositions which provide high viscosity/no separation due to API, are not temperature-sensitive, have no shear stress from the ointment mill/EMP, have no gumming up/stickiness or hardening, have improved active penetration and skin adhesion, and can use larger amounts of lipophilic active substances without lessening storage stability.

Claims

1. A eutectic anesthetic composition comprising: at least one adjuvant anesthetic; at least one polar oil having a droplet diameter in the range of about 10 microns to about 100 microns and having a Hydrophile-Lipophile Balance (HLB) number above about 11.0; at least one lipophilic emulsifier having a HLB number above 11.0; at least one penetrating agent comprising phosphatidylcholine; and at least one thermogelling agent with long-chain, straight or branched polymers.

2. The eutectic anesthetic composition of claim 1, wherein the adjuvant anesthetic comprises an aromatic ring, an intermediate chain, and an amine group, or a mixture thereof.

3. The eutectic anesthetic composition of claim 1, wherein the adjuvant anesthetic is selected from the group consisting of benzocaine, bupivacaine, dibucaine, diphenhydramine, etidocaine, gabapentin, lidocaine, mepivacaine, nifedipine, pregabalin, prilocaine, procaine, ropivacaine, tetracaine, verapamil, and mixtures thereof.

4. The eutectic anesthetic composition of claim 1, wherein the at least one adjuvant anesthetic is a mixture of two adjuvant anesthetics selected from the group consisting of benzocaine, bupivacaine, dibucaine, diphenhydramine, etidocaine, gabapentin, lidocaine, mepivacaine, nifedipine, pregabalin, prilocaine, procaine, ropivacaine, tetracaine, and verapamil.

5. The eutectic anesthetic composition of claim 1, wherein the adjuvant anesthetic is present in a concentration range from about 0.1 to about 35.0 weight percent.

6. The eutectic anesthetic composition of claim 1, wherein the polar oil has a viscosity ranging from about 5 to about 500 mPa s.

7. The eutectic anesthetic composition of claim 1, wherein the polar oil is present in a concentration range from about 5.0 to about 80.0 weight percent.

8. The eutectic anesthetic composition of claim 1, wherein the polar oil has a HLB number ranging from about 11.0 to about 20.0.

9. The eutectic anesthetic composition of claim 1, wherein the lipophilic emulsifier has a HLB number ranging from about 11.0 to about 20.0.

10. The eutectic anesthetic composition of claim 1, wherein the lipophilic emulsifier is present in a concentration range from about 1.0 to about 20.0 weight percent.

11. The eutectic anesthetic composition of claim 1, wherein the penetrating agent is present in a concentration range from about 0.1 to about 5.0 weight percent.

12. The eutectic anesthetic composition of claim 1, wherein the thermogelling agent is present in a concentration range from about 0.1 to about 4.0 weight percent.

13. The eutectic anesthetic composition of claim 1, further comprising at least one saturated fatty alcohol.

14. The eutectic anesthetic composition of claim 13, wherein the saturated fatty alcohol is present in a concentration range from about 0.1 to about 5.0 weight percent.

15. The eutectic anesthetic composition of claim 1, further comprising at least one moisturizer.

16. The eutectic anesthetic composition of claim 15, wherein the moisturizer is present in a concentration range from about 0.1 to about 5.0 weight percent.

17. The eutectic anesthetic composition of claim 1, further comprising at least one antimicrobial agent.

18. The eutectic anesthetic composition of claim 17, wherein the antimicrobial agent is present in a concentration range from about 1.0 to about 2.0 weight percent.

19. The eutectic anesthetic composition of claim 1, further comprising at least one solvent.

20. The eutectic anesthetic composition of claim 1, further comprising at least one pH adjustment agent.

21. A eutectic anesthetic composition comprising: at least one adjuvant anesthetic; at least one polar oil having a droplet diameter in the range of about 10 microns to about 100 microns and having a Hydrophile-Lipophile Balance (HLB) number above about 11.0; at least one lipophilic emulsifier having a HLB number above 11.0; at least one penetrating agent comprising phosphatidylcholine; at least one thermogelling agent with long-chain, straight or branched polymers; at least one saturated fatty alcohol; at least one antimicrobial agent; at least one solvent; and at least one pH adjustment agent.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0069] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0070] FIG. 1 shows the HPLC chromatogram of Lidocaine (10%)/Tetracaine (4%)/Benzocaine (20%).

[0071] FIG. 2 shows the total percent Benzocaine that penetrated past the Stratum Corneum with an embodiment (“Eutectic Emulsion”) and a standard ointment (“Ointment”).

[0072] FIG. 3 shows the total percent of Lidocaine that penetrated past the Stratum Corneum with an embodiment (“Eutectic Emulsion”) and a standard ointment (“Ointment”).

[0073] FIG. 4 shows the total percent Tetracaine that penetrated past the Stratum Corneum with an embodiment (“Eutectic Emulsion”) and a standard ointment (“Ointment”).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0074] One aspect of the current disclosure pertains to a eutectic emulsion composition which may be used to deliver anesthetics topically. The disclosure further comprises a method for producing the eutectic emulsion composition, which may contain up to 80% additive ingredients. Preferred embodiments may include eutectic emulsion compositions which provide high viscosity/no separation due to API, are not temperature-sensitive, have no shear stress from the ointment mill/EMP, have no gumming up/stickiness or hardening, have improved active penetration and skin adhesion, and can use larger amounts of lipophilic active substances without lessening storage stability.

Composition

[0075] A preferred embodiment of the composition comprises at least one adjuvant anesthetic which preferably acts on voltage-gated channels. The adjuvant anesthetic may preferably include an aromatic ring, an intermediate chain, and an amine group, or a mixture thereof. Additional preferred embodiments may include eutectic mixtures of first and second pharmaceutically acceptable components which are both pharmacologically active. Examples of the adjuvant anesthetics include benzocaine, bupivacaine, dibucaine, diphenhydramine, etidocaine, gabapentin, lidocaine, mepivacaine, nifedipine, pregabalin, prilocaine, procaine, ropivacaine, tetracaine, verapamil, and mixtures thereof. The eutectic mixtures may be present in a concentration range of 0.1% to 35.0%, preferably 2.5% to 25.0%, and most preferably 5.0% to 15.0%.

[0076] A preferred embodiment further comprises polar oils assigned a high HLB number above about 11.0, preferably in the range of about 11.0 to about 20.0. The preferred polar oils may also have a droplet diameter of about 10 to about 100 microns. Preferred polar oils may also have viscosities ranging from about 5 to about 500 mPa s. Examples may include C12-15 alkyl benzoate, castor oil, isopropyl myristate, and isopropyl palmitate. The polar oils may be present in a concentration range of 5.0% to 80.0%, preferably 7.5% to 50.0%, most preferably 10.0% to 20.0%.

[0077] A preferred embodiment further comprises lipophilic emulsifiers assigned a high HLB number above about 11.0, preferably in the range of about 11.0 to about 20.0. Examples may include ceteareth-20, cetearyl glucoside, ceteth-10, ceteth-20, cocamide MEA, glyceryl stearate (and) PEG-100 stearate, isoceteth-20, isosteareth-20, lauramide, laureth-23, oleth-10, oleth-10/polyoxyl 10 oleyl ether NF, oleth-20, PEG-100 Stearate, PEG-20 methyl glucose sesquistearate, PEG-60 almond glycerides, PEG-8 laurate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 60, polysorbate 80, polysorbate 85, stearamide MEA, and steareth-21. The lipophilic emulsifier may be present in a concentration range of 1.0% to 20.0%, preferably 5.0% to 15.0%, most preferably 7.5% to 12.5%. In preferred embodiments, the lipophilic emulsifier may be caprylic/capric triglyceride, trimethylsiloxy-terminated dimethylsiloxane, C-20 Guerbet alcohol, glyceryl stearate, PEG 100 stearate, or mixtures thereof.

[0078] A preferred embodiment further comprises penetrating agents with phosphatidylcholine. Examples may include soy bean lecithin and egg yolk lecithin. The penetrating agent may be present in a concentration range of 0.1% to 5.0%, preferably 1.0% to 4.0%, most preferably 2.0% to 3.0%. In a preferred embodiment, penetrating agent may be lecithin 50% in isopropyl palmitate.

[0079] A preferred embodiment further comprises thermogelling agents with long-chain, straight or branched polymers. Examples may include acrylates/alkyl acrylate copolymer, acrylates/alkyl acrylate crosspolymer, acryloyldimethyltaurate copolymer and acryloyldimethyltaurate crosspolymer. The thermogelling agent may be present in a concentration range of 0.1% to 4.0%, preferably 1.0% to 3.0%, most preferably 1.5% to 2.5%. In a preferred embodiment, the thermogelling agent is a hydroxyethyl acrylate, sodium acryloyldimethyl taurate copolymer.

[0080] If desired, a saturated fatty alcohol such as myristyl alcohol, pentadecanol, cetyl alcohol, cetearyl alcohol, stearyl alcohol, nonadecanol, arachidyl alcohol, heneicosanol, behenyl alcohol, brassidyl alcohol, lignoceryl alcohol, ceryl alcohol and myricyl alcohol may be used in preferred embodiments. The fatty alcohol has the ability to provide a transitory effect on membrane permeability. The saturated fatty alcohol may be present in a concentration range of 0.1% to 5.0%, preferably 1.0% to 4.0%, most preferably 2.0% to 3.0%.

[0081] If desired, a moisturizer such as aloe vera oil, dimethicone, glycerin, phenyl trimethicone, vitamin E oil, and wheat germ oil may be used in preferred embodiments. The moisturizer stabilizes the skin prior to transmigration of the active agent and assists the skin to repair any damage. The moisturizer may be present in a concentration of 0.1% to 5.0%, preferably 1.0% to 4.0%, most preferably 2.0% to 3.0%.

[0082] If desired, an antimicrobial agent such as diazolidinyl urea, ethylhexylglycerin, methylparaben, phenoxyethanol, and propylparaben may be included in preferred embodiments. The antimicrobial agent is equally effective against bacteria, yeasts and mould fungi. The antimicrobial agent may be present in a concentration of 1.0% to 2.0%, preferably 1.2% to 1.8%, most preferably 1.4% to 1.6%. In a preferred embodiment, the antimicrobial agent is phenoxyethanol and ethylhexylglycerin.

[0083] Additional preferred embodiments may include one or more additional components, including but not limited to solvents or pH adjustment agents. In preferred embodiments, a solvent may be propylene glycol, and a pH adjustment agent may be triethanolamine.

Methods

[0084] The Eutectic Anesthetic composition may be prepared by blending the proper amounts and ratios of all the required ingredients together.

[0085] One example of a method to prepare a preferred embodiment of the composition includes preparation as follows: [0086] POLAR OIL PHASE: Charge a stainless steel tank with Lidocaine USP (anesthetic, component L from Table 1 below). Add Prilocaine USP (anesthetic, component M). Add Isopropyl Palmitate (polar oil, component N). Mix for 1 hour or until homogenous. [0087] LIPOPHILIC SURFACTANT PHASE: Charge a stainless steel tank with lipophilic emulsifier component A (see Table 1 below). Add lipophilic emulsifier component B. Add lipophilic emulsifier component C. Add lipophilic emulsifier component D. Add Glyceryl Stearate & PEG 100 Stearate, lipophilic emulsifiers component E. Heat to 75-80° C.; mix for 20 minutes or until homogenous. [0088] WATER PHASE: Charge a stainless steel tank with Purified Water, component F. Add Propylene Glycol, component G. Heat to 75-80° C.; mix for 20 minutes or until homogenous. [0089] OIL PHASE: Charge a stainless steel tank with LIPOPHILIC SURFACTANT PHASE. Add POLAR OIL PHASE. Heat to 75-80° C.; mix for 20 minutes or until homogenous. [0090] EMULSION PHASE: Charge the triple-motion kettle mixer/sweeper/emulsifier with WATER PHASE. Add OIL PHASE. Heat to 75-80° C.; turn on the mixer/sweeper/emulsifier to 60 Hz and mix, sweep and emulsify for 30 minutes or until homogenous. Cool to 25-30° C. Add Lecithin 50% in Isopropyl Palmitate (penetrating agent in polar oil, component H). Add antimicrobial agent component I. Add pH adjustment agent component J. Add thermogelling agent component K. Decrease the mixer/sweeper/emulsifier to 30 Hz and mix, sweep and emulsify for 30 minutes or until homogenous.

EXAMPLE 1

[0091] A preferred embodiment of the present eutectic emulsion composition was prepared to contain the components in the table below, at the weight percentage amounts provided:

TABLE-US-00004 TABLE 1 Ingredient Amount A LIPONATE ® GC (Vantage Specialty 9.00 Ingredients, Warren, NJ), a caprylic/capric triglyceride lipophilic emulsifier B DOW CORNING ® 200 Fluid, 350 Cst. 3.40 (Dow Corning Corporation, Auburn, MI), a trimethylsiloxy-terminated dimethylsiloxane lipophilic emulsifier C EUTANOL ® G (BASF Corporation, 3.40 Florham Park, NJ), a C-20 Guerbet alcohol lipophilic emulsifier D PROCOL CS20D (Protameen, Totowa, NJ), 7.30 a ceteareth-20 lipophilic emulsifier E Glyceryl Stearate & PEG 100 Stearate, 7.30 lipophilic emulsifiers F Purified Water 45.57 G Propylene Glycol, a solvent 4.60 H Lecithin 50% in Isopropyl Palmitate, a 0.63 penetrating agent in a polar oil I EUXYL ® PE9010 (Schulke & Mayr, 1.00 Norderstedt, Germany), a phenoxyethanol and ethylhexylglycerin antimicrobial J TROLAMINE NF (Spectrum Chemicals, 1.50 Gardena, CA), a triethanolamine pH adjustment agent K SIMULGEL NS (Seppic, Puteaux Cedex, 1.10 France), a hydroxyethyl acrylate, sodium acryloyldimethyl taurate copolymer thermogelling agent L Lidocaine USP 2.50 M Prilocaine USP 2.50 N Isopropyl Palmitate, a polar oil 10.20

EXAMPLE 2

[0092] Eutectic emulsion drug uptake capacity experiments were conducted by dissolving 20.0% Benzocaine, 10.0% Lidocaine and 4.0% Tetracaine into the embodiment set forth above (“Eutectic Emulsion”) in Example 1, in place of the 2.5% Lidocaine USP and 2.5% Prilocaine USP. The remaining components shown in Example 1 above were reduced accordingly, such as by 30.5%. Singular drugs are reported to have an uptake capacity of only 10% in Standard Ointment. Standard Ointment includes 95% white petrolatum and 5% white wax. The Eutectic Emulsion sample showed a steady simultaneous permeation of up to 100%, as shown in the table below. Permeation was measuring using Franz type diffusion cells and a normal human 3D model of epidermal tissue.

TABLE-US-00005 Percutaneous Absorption 12 24 36 48 Testing Hours Hours Hours Hours Benzocaine 100% 100% 100% 100% Lidocaine  8%  16%  23%  23% Tetracaine  2%  2%  3%  3%

[0093] The percent of applied dose that penetrated past the stratum corneum with the Eutectic Emulsion was also up to 10.0 times more than a standard ointment containing the same anesthetic, as seen in FIGS. 2-4.

REFERENCES CITED

[0094] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

U.S. Patent Documents

[0095] U.S. Pat. No. 4,529,601 to Broberg, et al., issued Jul. 16, 1985 [0096] U.S. Pat. No. 4,562,060 to Broberg, et al., issued Dec. 31, 1985 [0097] U.S. Pat. No. 5,002,974 to Geria, et al., issued Mar. 26, 1991 [0098] U.S. Pat. No. 5,993,836 to Castillo, et al., issued Nov. 30, 1999 [0099] U.S. Pat. No. 6,841,161 to Passmore, et al., issued Jan. 11, 2005 [0100] U.S. Pat. No. 7,781,429 to Schwarz, et al., issued Aug. 24, 2010 [0101] U.S. Pat. No. 8,609,722 to Fita, et al., issued Dec. 17, 2013 [0102] U.S. Pat. No. 9,254,263 to Sundberg, et al., issued Feb. 9, 2016

REFERENCES

[0103] Nyqvist-Mayer, A., Phase Distribution Studies on an Oil-Water Emulsion Based on a Eutectic Mixture of Lidocaine and Prilocaine as the Dispersed Phase, from “Journal of Pharmaceutical Sciences”, 1985
Welin-Berger, K., Formulations, Release and Skin Penetration of Topical Anesthetics, from “Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy”, 2001
Zasshi, Y., Local Anesthetic Cream Prepared from Lidocaine-Tetracaine Eutectic Mixture, from “Pharmaceutical Society of Japan”, 2008