TOPICAL PHARMACEUTICAL COMPOSITION IN GEL FORM COMPRISING AT LEAST AMITRIPTYLINE FOR USE IN THE TREATMENT OF NEUROPATHIC PHANTOM LIMB PAIN

Abstract

The present invention relates to a method for treating neuropathic phantom limb pain comprising the topical application of a pharmaceutical composition containing amitriptyline or one of the pharmaceutically acceptable salts thereof.

Claims

1. Method for treating neuropathic phantom limb pain comprising the topical application of a pharmaceutical composition in aqueous gel form containing from 10 to 30% by weight, with respect to the total weight of the composition, of amitriptyline and/or one of the pharmaceutically acceptable salts thereof.

2. Method according to claim 1, characterized in that the pharmaceutical composition is applied by the cutaneous route.

3. Method according to claim 1, for the preventive or curative treatment of neuropathic phantom limb pain.

4. Method according to claim 1, characterized in that the total content of amitriptyline and/or of one of the pharmaceutically acceptable salts thereof is between 10 and 25% by weight, with respect to the total weight of the pharmaceutical composition.

5. Method according to claim 1, characterized in that the total content of amitriptyline and/or of one of the pharmaceutically acceptable salts thereof is between 10 and 20% by weight, more preferably between 10 and 15% by weight, with respect to the total weight of the pharmaceutical composition.

6. Method according to claim 1, characterized in that the pharmaceutical composition further comprises at least one cellulose polymer; preferably chosen from cellulose ethers; more preferably from non-ionic cellulose ethers; even more preferably from (a) (C.sub.1-C.sub.4)alkylcelluloses such as methylcelluloses and ethylcelluloses, (b) (poly)hydroxy(C.sub.1-C.sub.4)alkylcelluloses such as hydroxymethylcelluloses, hydroxyethylcelluloses and hydroxypropylcelluloses, (c) mixed (poly)hydroxy(C.sub.1-C.sub.4)alkyl-(C.sub.1-C.sub.4)alkylcellulose celluloses such as hydroxypropyl-methylcelluloses, hydroxyethyl-methylcelluloses, hydroxypropyl-ethylcelluloses, hydroxyethyl-ethylcelluloses and hydroxybutyl-methylcelluloses, and (d) mixtures thereof; more preferably, the composition comprises at least one (poly)hydroxy(C.sub.1-C.sub.4)alkylcellulose such as hydroxymethylcelluloses, hydroxyethylcelluloses and hydroxypropylcelluloses; and even more preferably, the composition comprises at least hydroxyethylcellulose.

7. Method according to claim 1, characterized in that the pharmaceutical composition further comprises at least one C.sub.2-C.sub.8 polyol; preferably chosen from C.sub.3-C.sub.6 polyol, ethylene glycol, and mixtures thereof; more preferably from propylene glycol, 1,3-propanediol, 1,3-butylene glycol, pentane-1,2-diol, dipropylene glycol, hexylene glycol, pentylene glycol, glycerol, ethylene glycol, and a mixture of these compounds; more preferably, the composition comprises at least propylene glycol.

8. Method according to claim 1, characterized in that the viscosity of the pharmaceutical composition, at a temperature of 20° C. and at atmospheric pressure, is between 400 and 2500 mPa.Math.s; preferably between 600 and 2000 mPa.Math.s; and more preferably between 800 and 1500 mPa.Math.s.

9. Method according to claim 1, characterized in that the water content of the pharmaceutical composition is greater than or equal to 65% by weight, preferably between 65 and 90% by weight; more preferably between 70 and 90% by weight, even more preferably between 75 and 85% by weight, with respect to the total weight of the pharmaceutical composition.

10. Method according to claim 1, characterized in that the pharmaceutical composition is free from fatty substances.

11. Method according to claim 1, characterized in that the pH of the pharmaceutical composition is between 3 and 8, preferably between 4 and 7, and more preferably between 5 and 6.

12. Method according to claim 1, characterized in that the pharmaceutical composition comprises: (i) from 10 to 30% by weight of amitriptyline or one of the pharmaceutically acceptable salts thereof, preferably from 10 to 20% by weight, more preferably from 10 to 15% by weight, with respect to the total weight of the composition; (ii) from 0.1 to 10% by weight of at least one cellulose polymer, with respect to the total weight of the composition; (iii) from 0.1 to 15% by weight of at least one C.sub.2-C.sub.8 polyol, with respect to the total weight of the composition; and (iv) water, preferably at a content ranging from 65 to 90% by weight with respect to the total weight of the composition.

Description

EXAMPLES

Example 1

[0150] Comparative ex vivo study of the percutaneous absorption of amitriptyline in a formulation A in aqueous gel form (invention) and in a formulation B in cream form (comparative).

[0151] The following aqueous gel (composition A) was prepared from the ingredients indicated in the table hereinafter, the quantities of which are expressed as a % by weight.

TABLE-US-00001 TABLE 1 COMPOSITION A (Invention) Quantity Amitriptyline hydrochloride 10 Hydroxyethylcellulose 1 Propylene glycol 5 PEG-7 Glyceryl cocoate 2 Disodium ethylene diaminetetraacetic salt 0.1 Propyl gallate 0.05 pH agent Q.s. pH 5.5 ± 0.5 Water Q.s. 100

[0152] Composition B (cream) comprises 10% by weight of amitriptyline hydrochloride and 90% by weight of Excipial Hydrocreme® cream, marketed by Galderma, with respect to the total weight of composition B.

[0153] Each of compositions A and B was applied on separate human skin samples. For each composition, the experiment was repeated 3 times with 3 skin samples from 3 different donors, i.e., 9 samples.

[0154] The skin samples are mounted in a Frantz cell and are heated to a surface temperature of 32° C.±1° C.

[0155] Composition A or B is spread evenly using a spatula on each skin sample at a rate of 10 mg per cell, corresponding to 5 mg/cm.sup.2 of skin.

[0156] The skin samples are rinsed 16 hours after application.

[0157] Each skin sample was placed with a tweezers on a paper towel (dermis facing downward).

[0158] The stratum corneum is removed using adhesive strips.

[0159] After removing the stratum corneum, the sample is perforated. The epidermis is then separated from the dermis. Each of them is placed in separate bottles.

[0160] The different samples were then extracted.

[0161] This penetration profile demonstrated its clinical efficacy in the study described by the article by Rossignol et al (“High concentration of topical amitriptyline for treating chemotherapy-induced neuropathies”. Support Care Cancer 27, 3053-3059 (2019)).

[0162] The results of these extractions are compiled in the table below.

TABLE-US-00002 TABLE 2 Composition A Composition B (Invention) (Comparative) Amitriptyline concentration remaining 2.4 ± 1.5 3.3 ± 1.6 on skin surface - stratum corneum (μg) Amitriptyline concentration in 3.6 ± 2.6 4.1 ± 2.5 epidermis (μg) Amitriptyline concentration in dermis 5.2 ± 2.5 4.4 ± 2.2 (μg) Amitriptyline concentration in recipient 0.15 ± 0.08 0.13 ± 0.13 fluid (bloodstream) Bioavailability (μg/cm.sup.2 of skin) 9.0 ± 4.8 8.7 ± 4.0

[0163] It was also observed that the systemic passage of amitriptyline was less than 0.1% of the administered dose. As a result, the systemic passage of amitriptyline is negligeable.

[0164] It is noted that the aqueous gel A according to the invention has a satisfactory skin penetration profile of amitriptyline, similar to the skin penetration profile of amitriptyline obtained with the comparative cream B.

[0165] It is also noted that the bioavailability obtained from composition A and that obtained from composition B are similar.

[0166] It was also observed that composition A is particularly effective in the treatment of neuropathic phantom limb pain.

Example 2

[0167] Another pharmaceutical composition in aqueous gel form according to the invention (composition A′) was prepared from the ingredients indicated in the table hereinafter, the quantities of which are expressed as a % by weight.

TABLE-US-00003 TABLE 3 COMPOSITION A′ (Invention) Quantity Amitriptyline hydrochloride 15 Hydroxyethylcellulose 1 Propylene glycol 5 Methyl paraben 0.1 pH agent Q.s. pH 5.5 ± 0.5 Water Q.s. 100

[0168] It was observed that the aqueous gel A′ according to the invention has a satisfactory skin penetration profile of amitriptyline and amitriptyline bioavailability.

[0169] It was also observed that composition A′ is particularly effective in the treatment of neuropathic phantom limb pain.

Example 3

[0170] Stability study of a formulation C in aqueous gel form (invention) and of a formulation B in cream form (comparative).

[0171] The following aqueous gel (composition C) was prepared from the ingredients indicated in the table hereinafter, the quantities of which are expressed as a % by weight.

TABLE-US-00004 TABLE 4 COMPOSITION C (Invention) Quantity Amitriptyline hydrochloride 10 Hydroxyethylcellulose 1 Propylene glycol 5 PEG-7 Glyceryl cocoate 2 pH agent (NaOH, 1N solution) Q.s. pH 5.5 ± 0.5 Water Q.s. 100

[0172] Composition B (cream) comprises 10% by weight of amitriptyline hydrochloride and 90% by weight of Excipial Hydrocrème® cream, marketed by Galderma, with respect to the total weight of composition B.

[0173] Each of compositions B and C was placed in an oven at a temperature of 40° C.

[0174] The stability of the compositions was then assessed visually over time (at T.sub.0, when entering the oven; at T.sub.24 h, 24 hours after entering the oven; and at T.sub.3 months, 3 months after entering the oven).

[0175] The results of these extraction are compiled in the table below.

TABLE-US-00005 TABLE 5 Appearance Compositions at T.sub.0 at T.sub.24 h at T.sub.3 months Composition B Opaque white Phase separation ND (Comparative) oil-in-water observed. emulsion The top oily phase is white and opaque. The bottom aqueous phase is transparent Composition C Translucent Translucent Translucent (Invention) colorless gel gel gel

[0176] No syneresis was observed for composition C in aqueous gel form according to the invention after 3 months at 40° C.

[0177] A phase separation of comparative composition B in oil-in-water emulsion form is also observed after merely 24 hours at 40° C.

[0178] Furthermore, a full stability study was performed on composition C according to the invention for 6 months at 40° C.

[0179] The results are compiled in Tables 6 and 7 hereinafter.

TABLE-US-00006 TABLE 6 RESULTS TESTS SPECIFICATIONS T0 T1 month T3 months T6 months Visual Translucent Translucent Translucent Translucent Translucent appearance colorless gel colorless gel colorless gel colorless gel colorless gel pH 4.5 to 6.0 5.5 5.6 5.5 5.3 Viscosity 450 to 1039 mPa .Math. s 883 mPa .Math. s 765 mPa .Math. s 756 mPa .Math. s 1500 mPa .Math. s Amitriptyline 95.0 mg/g to 102.7 mg/g 99.9 mg/g 99.6 mg/g 100.6 mg/g HCl assay 105.0 mg/g

TABLE-US-00007 TABLE 7 Amitriptyline HCl RESULTS degradation products SPECIFICATIONS T0 T1 month T3 months T6 months Cyclobenzaprine ≤0.1% <limit of detection <limit of detection <limit of detection <limit of detection Dibenzosuberone ≤0.1% Not detected Not detected Not detected Not detected Unknown impurities Reported if ≤0.1%, Not detected Not detected Not detected Unknown impurity 1 None < 0.2% RRT 0.38 min < 0.1%; Unknown impurity 2 RRT 0.45 min < 0.1% Total Impurities   ≤1% N/A N/A N/A <0.1%

[0180] No syneresis was observed for composition C in aqueous gel form according to the invention after 6 months at 40° C.

[0181] No major variations were also observed on each of the tests conducted.

[0182] The good physicochemical stability of the compositions in aqueous gel form according to the invention can thus be noted.

[0183] It was also observed that composition C in aqueous gel form according to the invention is particularly effective in the treatment of neuropathic phantom limb pain.