PHARMACEUTICAL COMPOSITION FOR TOPICAL USE COMPRISING AT LEAST ONE LOCAL ANAESTHETIC SUBSTANCE

Abstract

A pharmaceutical composition for topical use which is in the form of a water-in-oil emulsion including, for 100% of the weight thereof: —from 0.3% to 5% by weight of at least one local anaesthetic substance; —from 60% to 90% by weight of gelled aqueous phase; —from 9.7% to 35% by weight of a fatty phase including at least one oil and an emulsifying system including a combination of at least one emulsifying surfactant selected from the elements of the group consisting of alkylpolyglycoside compositions and alkylpolyglycoside and fatty alcohol compositions, and of at least one emulsifying surfactant selected from the elements of the group consisting of polyglycerol esters, alkoxylated polyglycerol esters, polyglycol polyhydroxystearates, polyglycerol polyhydroxystearates and alkoxylated polyglycerol polyhydroxystearates.

Claims

1. A pharmaceutical composition suitable for topical use which is in the form of an emulsion of water-in-oil type comprising, per 100% of the composition's weight: from 0.3% to 5% by weight of at least one local anesthetic substance from the family of the amino amides and/or amino esters, from 60% to 90% by weight of a gelled aqueous phase (A1) from 9.7% to 35% by weight of a fatty phase (A2) comprising at least one oil and an emulsifying system comprising a combination of at least one emulsifying surfactant (S1) selected from the elements of the group consisting of compositions of alkyl polyglycosides, and compositions of alkyl polyglycosides and of fatty alcohols, and of at least one emulsifying surfactant (S2) selected from the elements of the group consisting of polyglycerol esters, alkoxylated polyglycerol esters, polyglycol polyhydroxystearates, polyglycerol polyhydroxystearates, and alkoxylated polyglycerol polyhydroxystearates.

2. The pharmaceutical composition as claimed in claim 1, wherein the gelled aqueous phase comprises, per 100% of its weight: from 0.5% to 10% by weight of a crosslinked anionic polyelectrolyte, from 90% to 99.5% by weight of water.

3. The pharmaceutical composition as claimed in claim 2, wherein the crosslinked anionic polyelectrolyte comprises a proportion of greater than or equal to 25 mol % of monomer units derived from 2-methyl-2-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid in free acid or partially or totally salified form.

4. The pharmaceutical composition as claimed in claim 1, wherein the local anesthetic substance is chosen from the elements, being in neutral or salt form, of the group consisting of ethyl 4-aminobenzoate (CAS number=94-09-7) or benzocaine of formula (Ia) ##STR00017## 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (CAS number=137-58-6) or lidocaine of formula (Ib) ##STR00018## (RS)—N-(2-methylphenyl)-N2-propylalaninamide (CAS number=721-50-6) or prilocaine in the R enantiomer form of formula (Ic.sub.1) and in the S enantiomer form of formula (Ic2) ##STR00019## 2-(dimethylamino)ethyl 4-(butylamino)benzoate (CAS number=94-24-6) or tetracaine of formula (I.sub.d) ##STR00020## (RS)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (CAS number=38396-39-3) or bupivacaine of formula (I.sub.e) ##STR00021## N-(2,6-dimethylphenyl)-2-(ethyl(propyl)amino)butanamide (CAS number=36637-18-0) or etidocaine of formula (I.sub.f) ##STR00022## 2-butoxy-N-[2-(diethylamino)ethyl]quinoline-4-carboxamide (CAS number=85-79-0) or cinchocaine of formula (I.sub.g) ##STR00023## 2-diethylaminoethyl 4-amino-3-butoxybenzoate (CAS number=99-43-4) or oxybuprocaine of formula (I.sub.h) ##STR00024## 4-[3-(4-butoxyphenoxy)propyl]morpholine (CAS number=140-65-8) or pramocaine of formula (I.sub.i) ##STR00025## butyl 4-aminobenzoate (CAS number=94-25-7) or butamben of formula (I.sub.j) ##STR00026## 2-(diethylamino)ethyl 3-amino-4-propoxybenzoate (CAS number=499-67-2) or proxymetacaine of formula (I.sub.k) ##STR00027##

5. The pharmaceutical composition as claimed in claim 1, wherein the local anesthetic substance is chosen from the elements of the group consisting of the hydrochloride, phosphate, nitrate, propionate and citrate salts of the compounds of formula (Ia), (Ib), (Ic1), (Ic2), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik).

6. The pharmaceutical composition as claimed in claim 1, wherein the emulsifying surfactant (S1) consists of at least one alkyl polyglycoside composition (C1) represented by formula (VIII):
R1-O-(G)x-H  (VIII) in which x represents a decimal number between 1.05 and 2.5, G represents the glucosyl or β-D-glucopyranosyl radical, obtained from the removal of the hemiacetal hydroxyl group from β-D-glucopyranose, and R1 represents a radical chosen from the elements of the group consisting of the radicals n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl and n-behenyl, said composition (C1) consisting of a mixture of compounds represented by formulae (VIII1), (VIII2), (VIII3), (VIII4) and (VIII5):
R1-O-(G)1-H  (VIII1)
R1-O-(G)2-H  (VIII2)
R1-O-(G)3-H  (VIII3)
R1-O-(G)4-H  (VIII4)
R1-O-(G)5-H  (VIII5) in the respective molar proportions a1, a2, a3, a4 and a5, such that: the sum a1+a2+a3+a4+a5 is equal to 1, and that the sum a1+2a2+3a3+4a4+5a5 is equal to x.

7. The pharmaceutical composition as claimed in claim 1, wherein the emulsifying surfactant (S1) consists of at least one composition (C2) comprising, per 100% of weight: from 10% to 50% by weight of at least one alkyl polyglycoside composition (C1) represented by formula (VIII):
R1-O-(G)x-H  (VIII) in which x represents a decimal number between 1.05 and 2.5, G represents a glucose residue, and R1 represents a radical chosen from the elements of the group consisting of the radicals n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl and n-behenyl, said composition consisting of a mixture of compounds represented by formulae (VIII1), (VIII2), (VIII3), (VIII4) and (VIII5):
R1-O-(G)1-H  (VIII1)
R1-O-(G)2-H  (VIII2)
R1-O-(G)3-H  (VIII3)
R1-O-(G)4-H  (VIII4)
R1-O-(G)5-H  (VIII5) in the respective molar proportions a1, a2, a3, a4 and a5, such that: the sum a1+a2+a3+a4+a5 is equal to 1, and that the sum a1+2a2+3a3+4a4+5a5 is equal to x; and from 90% to 50% by weight of at least one fatty alcohol of formula (IX):
R′1-OH  (IX), in which R′1 represents a radical chosen from the elements of the group consisting of the radicals n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl and n-behenyl, where R′l may be identical to or different from R1.

8. The pharmaceutical composition as claimed in claim 1, wherein the emulsifying surfactant (S.sub.2) consists of at least one polyglycol polyhydroxystearate represented by formula (XII): ##STR00028## in which y.sub.2 represents an integer greater than or equal to 2 and less than or equal to 50, R.sub.4 represents a hydrogen atom, a methyl radical or an ethyl radical, and Z.sub.2 represents a radical of formula (XIII): ##STR00029## in which y′.sub.2 represents an integer greater than or equal to 0 and less than or equal to 10, and Z′.sub.2 represents a radical of formula (XIII) as defined above, where Z.sub.2′ may be identical to or different from Z.sub.2, or a hydrogen atom.

9. The pharmaceutical composition as claimed in claim 1, wherein the weight ratio between the emulsifying surfactant (S1) and the emulsifying surfactant (S2) is greater than or equal to ¼ and less than or equal to 1.

10. The pharmaceutical composition as claimed in claim 1, wherein that said composition is intended to be used for therapy in a human being or animal.

11. A method for treating pain, pruritus and/or anorectal disorders in a human being or animal, comprising applying an effective amount of the pharmaceutical composition of claim 1 to the human being or animal in need thereof.

12. The pharmaceutical composition as claimed in claim 1, wherein said composition being suitable for use in a surgical method in a human being or animal.

13. A method for anesthetizing an area of the skin, of the scalp or of the mucous membranes of human beings or of animals, comprising applying an effective amount of the pharmaceutical composition of claim 1 to the skin, the scalp, or the mucous membranes of the human being or the animal in need thereof.

14. The pharmaceutical composition as claimed in claim 1, further comprising at least one or more auxiliary compounds chosen from foaming and/or detergent surfactants, thickening and/or gelling surfactants, thickening and/or gelling agents, stabilizers, film-forming compounds, solvents and cosolvents, hydrotropic agents, plasticizing agents, opacifying agents, pearlescent agents, superfatting agents, sequestering agents, chelating agents, antioxidants, fragrances, essential oils, preservatives, conditioning agents, deodorants, mineral fillers or pigments.

15. A device which is in a form chosen from a pot, a pump-bottle, a wipe, a mask, a transdermal device, a patch, a poultice, a compress, a tube, or a spray, said device comprising a composition (E1) as defined in claim 1.

16. The pharmaceutical composition as claimed in claim 2, wherein the local anesthetic substance is chosen from the elements, being in neutral or salt form, of the group consisting of ethyl 4-aminobenzoate (CAS number=94-09-7) or benzocaine of formula (Ia) ##STR00030## 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (CAS number=137-58-6) or lidocaine of formula (Ib) ##STR00031## (RS)—N-(2-methylphenyl)-N2-propylalaninamide (CAS number=721-50-6) or prilocaine in the R enantiomer form of formula (Ic.sub.1) and in the S enantiomer form of formula (Ic.sub.2) ##STR00032## 2-(dimethylamino)ethyl 4-(butylamino)benzoate (CAS number=94-24-6) or tetracaine of formula (I.sub.d) ##STR00033## (RS)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (CAS number=38396-39-3) or bupivacaine of formula (I.sub.e) ##STR00034## N-(2,6-dimethylphenyl)-2-(ethyl(propyl)amino)butanamide (CAS number=36637-18-0) or etidocaine of formula (I.sub.f) ##STR00035## 2-butoxy-N-[2-(diethylamino)ethyl]quinoline-4-carboxamide (CAS number=85-79-0) or cinchocaine of formula (I.sub.g) ##STR00036## 2-diethylaminoethyl 4-amino-3-butoxybenzoate (CAS number=99-43-4) or oxybuprocaine of formula (I.sub.h) ##STR00037## 4-[3-(4-butoxyphenoxy)propyl]morpholine (CAS number=140-65-8) or pramocaine of formula (I.sub.i) ##STR00038## butyl 4-aminobenzoate (CAS number=94-25-7) or butamben of formula (I.sub.j) ##STR00039## 2-(diethylamino)ethyl 3-amino-4-propoxybenzoate (CAS number=499-67-2) or proxymetacaine of formula (I.sub.k) ##STR00040##

17. The pharmaceutical composition as claimed in claim 3, wherein the local anesthetic substance is chosen from the elements, being in neutral or salt form, of the group consisting of ethyl 4-aminobenzoate (CAS number=94-09-7) or benzocaine of formula (Ia) ##STR00041## 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (CAS number=137-58-6) or lidocaine of formula (Ib) ##STR00042## (RS)—N-(2-methylphenyl)-N2-propylalaninamide (CAS number=721-50-6) or prilocaine in the R enantiomer form of formula (Ic.sub.1) and in the S enantiomer form of formula (Ic.sub.2) ##STR00043## 2-(dimethylamino)ethyl 4-(butylamino)benzoate (CAS number=94-24-6) or tetracaine of formula (I.sub.d) ##STR00044## (RS)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (CAS number=38396-39-3) or bupivacaine of formula (I.sub.e) ##STR00045## N-(2,6-dimethylphenyl)-2-(ethyl(propyl)amino)butanamide (CAS number=36637-18-0) or etidocaine of formula (I.sub.f) ##STR00046## 2-butoxy-N-[2-(diethylamino)ethyl]quinoline-4-carboxamide (CAS number=85-79-0) or cinchocaine of formula (I.sub.g) ##STR00047## 2-diethylaminoethyl 4-amino-3-butoxybenzoate (CAS number=99-43-4) or oxybuprocaine of formula (I.sub.h) ##STR00048## 4-[3-(4-butoxyphenoxy)propyl]morpholine (CAS number=140-65-8) or pramocaine of formula (I.sub.i) ##STR00049## butyl 4-aminobenzoate (CAS number=94-25-7) or butamben of formula (I.sub.j) ##STR00050## 2-(diethylamino)ethyl 3-amino-4-propoxybenzoate (CAS number=499-67-2) or proxymetacaine of formula (I.sub.k) ##STR00051##

18. The pharmaceutical composition as claimed in claim 2, wherein the local anesthetic substance is chosen from the elements of the group consisting of the hydrochloride, phosphate, nitrate, propionate and citrate salts of the compounds of formula (Ia), (Ib), (Ic1), (Ic2), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik).

19. The pharmaceutical composition as claimed in claim 3, wherein the local anesthetic substance is chosen from the elements of the group consisting of the hydrochloride, phosphate, nitrate, propionate and citrate salts of the compounds of formula (Ia), (Ib), (Ic1), (Ic2), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik).

20. The pharmaceutical composition as claimed in claim 4, wherein the local anesthetic substance is chosen from the elements of the group consisting of the hydrochloride, phosphate, nitrate, propionate and citrate salts of the compounds of formula (Ia), (Ib), (Ic1), (Ic2), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (Ik).

Description

[0118] The examples that follow illustrate the invention without, however, limiting it.

Preparation and Evaluation of Water-in-Oil Emulsions According to the Invention and of Comparative Water-in-Oil Emulsions.

1) Preparation of the Water-in-Oil Emulsions

[0119] Three water-in-oil emulsions according to the invention, denoted (F.sub.1) to (F.sub.2), and three water-in-oil emulsions according to the prior art, denoted (F′.sub.1) to (F′.sub.3), the proportions by weight of the constituents of which are recorded in table 1 below, the contents by weight of the polyelectrolytes being indicated as a percentage of polymeric solids, are prepared by performing the following process.

[0120] The constituents of the fatty phase are introduced successively into a beaker, mixed and brought to a temperature of 20° C. after an 80° C. heating step; the mixing is performed using a mechanical stirrer equipped with a propeller-type stirring spindle at a speed of 100 rpm. The glycerol and water are mixed at ambient temperature in a beaker using a mechanical stirrer at a speed of 2000 rpm and the thickening agent is then added gradually. The stirring is maintained for a duration which makes it possible to obtain an aqueous phase which is in the form of a homogeneous gel. The fatty phase is added in one go to the aqueous gel at ambient temperature and at a moderate stirring speed (75 to 300 rpm) using a stirrer equipped with an anchor-type spindle. This stirring is then maintained for 10 minutes and no cooling step is necessary.

TABLE-US-00001 TABLE 1 (F.sub.1) (F.sub.2) (F'.sub.1) (F'.sub.2) (F'.sub.3) Fatty phase Lidocaine  2%  2%  0%  2%   2% Lanol ™ 2681.sup.(1) 10% 15% 10%  8%  10% Sepineo ™ SE 68.sup.(2)  1%  1%  1%  1%   0% Sepicide ™ HB .sup.(3)  1%  1%  1%  1%   1% Simaline ™WO.sup.(4)  3%  3%  3%  3% 0.3% Montane ™80.sup.(6)  0%  0%  0%  0% 1.2% Aqueous phase Sepineo ™P600.sup.(5)  5%  5%  4%  5%   5% Water q.s. q.s. q.s. q.s. q.s. 100% 100% 100% 100% 100% .sup.(1)Lanal ™ 2681, or Coco-Caprylate/Caprate. .sup.(2)Sepineo ™ SE 68 is a mixture comprising, per 100% of its weight, from 78% to 85% by weight of a mixture of n-hexadecanol and n-octadecanol, and from 15% to 22% by weight of a mixture of n-hexadecyl glucoside with a mean degree of polymerization of 1.20 and n-octadecyl glucoside with a mean degree of polymerization of 1.20, used as emulsifying agent. .sup.(3) Sepicide ™ HB is a mixture of phenoxyethanol, methylparaben, ethylparaben, butylparaben and n-propylparaben, used as a preservative. .sup.(4)Simaline ™WO, or PEG 30 Dipolyhydroxystearate, is an emulsifying surfactant. .sup.(5)Sepineo ™P600 is a self-invertible inverse latex comprising, per 100% of its weight, between 30% and 40% by weight of a crosslinked copolymer of acrylamide and of sodium acryloyldinnethyltaurate, used as a thickening agent. .sup.(6)Montane ™80 is a composition comprising sorbitan monooleate, used as water-in-oil type emulsifying agent.
2 Demonstration of the Properties of the Water-in-Oil Emulsions (F.sub.1) to (F.sub.2) According to the Invention and of the Water-in-Oil Emulsions (F′.sub.1) to (F′.sub.3) According to the Prior Art.
2.1 Characterization of the Appearance and the Viscosity of the Water-in-Oil Emulsions (F.sub.1) to (F.sub.2) According to the Invention and of the Water-in-Oil Emulsions (F′.sub.1) to (F′.sub.3) According to the Prior Art.

[0121] The emulsions (F.sub.1) to (F.sub.2) and (F′.sub.1) to (F′.sub.3) obtained according to the process described above are then stored in an insulated climatic chamber regulated at a temperature of 25° C. for 3 months. After the conclusion of this period of three months, the appearance (APP) of each emulsion prepared is observed and the dynamic viscosity (μ) of each emulsion is measured (in mPas) by means of a viscometer at 25° C. (Brookfield LVT, speed 6).

[0122] An aliquot of these same emulsions (F.sub.1) to (F.sub.2) and (F′.sub.1) to (F′.sub.3) obtained according to the process described above are also stored in an insulated climatic chamber regulated at a temperature of 45° C. for three months. After the conclusion of this period of three months, the appearance (APP) of each emulsion prepared is observed and the dynamic viscosity (μ) of each emulsion is measured (in mPas) by means of a viscometer at 25° C. (Brookfield LVT, speed 6).

2.2 Characterization of the Direction of the Emulsions (F.sub.1) to (F.sub.2) According to the Invention and of the Emulsions (F′.sub.1) to (F′.sub.3) According to the Prior Art.

[0123] The conductivity (σ) of the emulsions (F.sub.1) to (F.sub.2) according to the invention and of the emulsions (F′.sub.1) to (F′.sub.3) is measured at 25° C., after a period of storage of said emulsions of one day in an insulated climatic chamber regulated at a temperature of 25° C., by means of an LF 196™ brand conductivity meter from the company WTW equipped with a TetraCon™ 96 electrode.

[0124] If, for a given emulsion, (σ)≤0.5 μS.Math.cm.sup.−1, the emulsion is considered to be non-conductive and consequently the external phase is considered not to be the aqueous phase but the oily phase.

[0125] If, for a given emulsion, (σ)>0.5 pS.Math.cm.sup.−1, the emulsion is considered to be conductive and consequently the external phase is considered not to be the oily phase but the aqueous phase.

[0126] This same measurement of the conductivity of the emulsions (F.sub.1) to (F.sub.2) according to the invention and of the emulsions (F′.sub.1) to (F′.sub.3) is measured at 25° C. after three months at 25° C., and after three months at 45° C.

2.3 Results Obtained for the Water-in-Oil Emulsions (F.sub.1) to (F.sub.2) According to the Invention and for the Water-in-Oil Emulsions (F′.sub.1) to (F′.sub.3) According to the Prior Art.

[0127] The evaluation methods described in paragraphs 2.1 and 2.2 were applied to the water-in-oil emulsions (F.sub.1) to (F.sub.2) according to the invention and to the water-in-oil emulsions (F′.sub.1) to (F′.sub.3) according to the prior art. The results obtained are recorded in table 2 below.

TABLE-US-00002 TABLE 2 (F.sub.1) (F.sub.2) (F′.sub.1) (F′.sub.2) ( F′.sub.3) (APP) at 1 Homoge- Homogeneous Homoge- Homoge- Homoge- day (visual) neous liquid liquid neous liquid neous liquid neous liquid O/W O/W (σ) at 1 day ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 >0.5 μS .Math. cm >0.5 μS .Math. cm at 25° C. (APP) at 7 Homoge- Homoge- Homoge- Homoge- Homoge- days at 25° C. neous liquid neous liquid neous liquid neous liquid neous liquid O/W O/W (σ) at 3 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 >0.5 μS .Math. cm >0.5 μS .Math. cm.sup.−1 months at 25° C. (μ) at 3 61 000 mPas 24 000 mPas 120 000 mPas Test not Test not months at measured stored 25° C. since stably since emulsion emulsion was O/W was O/W (APP) at 3 Homoge- Homoge- Homoge- Homoge- / months at neous liquid neous liquid neous liquid neous liquid 45° C. (σ) at 3 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 ≤0.5 μS .Math. cm.sup.−1 >0.5 μS .Math. cm.sup.−1 / months at 45° C. (μ) at 3 52 000 mPas 20 000 mPas 21 000 mPas Test not / months at measured 45° C. since emulsion was O/W

2.4 Analysis of the Results

[0128] The water-in-oil emulsions (F.sub.1) and (F.sub.2) according to the invention are therefore characterized by: [0129] a stability of their water-in-oil form after 3 months of storage at a temperature of 25° C.; the observed appearance after this period of storage is still homogeneous; [0130] a stability of their water-in-oil form after 3 months of storage at a temperature of 45° C.; the observed appearance after this period of storage is still homogeneous; [0131] dynamic viscosity values measured after 3 months of storage at 25° C. by means of a Brookfield LV viscometer at 25° C. and at a speed of 6 rpm of between 24 000 mPa.Math.s (for (F.sub.2)) and 61 000 mPa.Math.s (for (F.sub.1)).

[0132] The formulation (F′.sub.1) differs from (F′.sub.2) by the absence of lidocaine within it; (F′.sub.1) is in the form of an emulsion of water-in-oil type whereas the formulation (F′.sub.2) does not make it possible to obtain an emulsion of water-in-oil type but instead of water-in-oil type.

[0133] When the content by weight of oil (Lanol™ 2681) in the formulation is brought to 10% in the formulation (F.sub.1), the emulsion obtained is of water-in-oil type.

[0134] The formulation (F′.sub.3), which only differs from the formulation (F.sub.1) in the nature of the surfactant, that is to say sorbitan oleate (Montane™80) for the formulation (F′.sub.3) instead of cetearyl polyglucoside/cetearyl alcohol for the formulation (F′.sub.3), does not make it possible to obtain an emulsion of water-in-oil type after storage at 25° C. and at 45° C. for three months.