Frigostable composition for iontophoretic transdermal delivery of a triptan compound

Abstract

The present invention relates to frigostable compositions suitable for iontophoretic transdermal delivery of a triptan compound. The inventive compositions include a salt of a triptan compound, preferably sumatriptan succinate, a polyamine, a dicarboxylic acid, and water or an aqueous solvent mixture, with the composition being free of monocarboxylic acids. The invention further relates to the use of the composition as an integral component of an iontophoretic patch, preferably as an anodic reservoir of the patch.

Claims

1. A composition for iontophoretic transdermal delivery of a salt of a triptan compound, comprising: a salt of a triptan compound, a polyamine, in an amount ranging from 18 to 70%, a dicarboxylic acid, and water or an aqueous solvent mixture, and wherein this composition is free of monocarboxylic acids and the water or aqueous solvent mixture is present in an amount ranging from 30 to 75 wt %.

2. The composition according to claim 1, wherein the triptan compound is a compound that contains a 2-(1H-indol-3-yl)-N,N-dimethylethanamine moiety.

3. The composition according to claim 2, wherein the triptan compound is almotriptan, frovatriptan, eletriptan, zolmitriptan, rizatriptan, sumatriptan or naratriptan.

4. The composition according to claim 1, wherein the salt is a succinate.

5. The composition according to claim 1, wherein the dicarboxylic acid is selected from C.sub.4 to C.sub.10 dicarboxylic acids.

6. The composition according to claim 5 wherein the dicarboxylic acid is selected from the group consisting of succinic acid, glutaric acid, adipic acid and pimelic acid.

7. The composition according to claim 1, wherein the polyamine consists of three different methacrylate-monomers: dimethylaminoethyl-methacrylate, butylmethacrylate and methylmethacrylate.

8. The composition according to claim 7 wherein the polyamine is partially replaced by a replacement polyamine which has the following chemical structure: ##STR00002## with m=5-8 and n=2-4.

9. The composition according to claim 8 wherein the replacement polyamine is N,N-diethylamino-ethylmethacrylate methylmethacrylate copolymer.

10. The composition according to claim 1, further comprising one or more additives.

11. An iontophoretic patch comprising the composition of claim 1.

12. A method of iontophoretic transdermal administration of a triptan compound comprising a step of applying a composition according to claim 1 to a subject's skin, and allowing the triptan compound contained in the composition to be released therefrom and to permeate through the skin facilitated by iontophoresis and to enter the blood circulation of said subject.

13. The composition according to claim 3, wherein the triptan compound is sumatriptan.

14. The composition according to claim 6, wherein the dicarboxylic acid is selected from the group consisting of succinic acid and adipic acid.

15. The composition according to claim 8, wherein m=is 6 or 7, and n=3 or 4.

16. An iontophoretic patch according to claim 11, wherein an anodic reservoir of the patch comprises the composition of claim 1.

17. The composition according to claim 7, wherein the polyamine is present in an amount ranging from 18 to 30%.

18. A composition for iontophoretic transdermal delivery of a salt of a triptan compound, comprising: a salt of a triptan compound, a polyamine, a dicarboxylic acid, and water or an aqueous solvent mixture, wherein this composition is free of monocarboxylic acids and the polyamine is N,N-diethylamino-ethylmethacrylate methylmethacrylate copolymer, present in an amount ranging from 30 to 70%.

19. The composition according to claim 18, wherein the composition ranges in conductivity from 5.05 to 6.14 mS/cm for compositions containing from 48.65 to 50.70% polyamide.

20. The composition according to claim 1, wherein the composition ranges in viscosity from 504 to 2180 mPas.

21. The composition according to claim 1, wherein the acid is adipic acid, present in an amount ranging from 3.21 to 10%.

22. The composition according to claim 1, wherein the methacrylate is butylmethacrylate.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 is a graphical illustration of the viscosity degradation over time of the composition according to U.S. Pat. No. 8,366,600 at 4° C. and 15° C., respectively;

(2) FIG. 2 is a graphical illustration of the viscosity of exemplary compositions;

(3) FIG. 3 is a graphical illustration of the viscosity of the composition of Example 3 (diluted 5);

(4) FIG. 4 is a graphical illustration of the time dependent plasma concentration of the Comparative Example and Example 3 (diluted 5); and

(5) FIG. 5 is a time dependent plasma concentration of the Comparative Example and Example 2a.

DETAILED DESCRIPTION

(6) The compositions according to the present invention comprise water or an aqueous solvent mixture. Preferably, the proportion of water or solvent mixture is at least 30 wt.-%, more preferably 40 wt.-%, relative to the total weight of the composition. According to a further embodiment, the water content or the proportion of said solvent mixture is in the range of 40 to 75 wt.-%.

(7) The term “aqueous solvent mixture” generally includes liquid mixtures containing water and at least one further solvent which is generally selected from polar, water-miscible solvents such as, for instance, alcohols (e. g. ethanol, isopropanol, glycerol).

(8) According to one embodiment of the invention, the polyamine is EUDRAGIT® E 100, which is made from three different methacrylate-monomers: dimethylaminoethyl-methacrylate, butylmethacrylate and methylmethacrylate in a ratio of about 2:1:1.

(9) According to another embodiment of the invention the EUDRAGIT® E 100 is at least partially replaced by a polyamine which is preferably made from methylmethacrylate and at least one C1-C4-alkylated methacrylate monomer which contains a di-C1-C3-alkylamino group. The dialkylamino group is preferably a dimethylamino group or a diethylamino group.

(10) A preferred replacement polyamine is a copolymer made from 5-8 monomer units of methylmethacrylate and 2-4 monomer units of N,N-diethylaminoethylmethacrylate. More preferred from 6 or 7 monomer units of methylmethacrylate and 3 or 4 monomer units of N,N-diethylaminoethylmethacrylate. Thus, a preferred replacement polyamine has the following chemical structure:

(11) ##STR00001##
with
m=5-8, preferably 6 or 7, and
n=2-4, preferably 3 or 4.

(12) A specifically preferred monomeric amine is N,N-diethylamino-ethylmethacrylate. The average molecular weight of the replacement polyamine is between 100,000 and 300,000, preferably between 150,000 and 250,000, more preferred around 200,000 (measured by SEC).

(13) Such a polyamine is commercially available as “KOLLICOAT® SMARTSEAL” from BASF (Ludwigshafen, Germany).

(14) In a further embodiment, the composition of the present invention may comprise a combination of EUDRAGIT® E 100 and the replacement Polyamine as defined above. The weight ratio of EUDRAGIT® E 100 to the replacement Polyamine is not critical. In a preferred embodiment, however, either EUDRAGIT® E 100 or the replacement polyamine alone is used.

(15) Preferably, the proportion of all polyamine(s) is between 10.0 and 60.0 wt.-% (based on the total weight of the composition). If EUDRAGIT® E 100 is used alone its proportion is between 10.0 and 30.0 wt.-%, preferably between 18.0 and 26.0 wt.-% (based on the total weight of the composition). If KOLLICOAT® SMARTSEAL is used alone its proportion is between 30.0 and 70.0 wt.-%, preferably between 45.0 and 55.0 wt.-% (based on the total weight of the composition). This proportion of KOLLICOAT® SMARTSEAL is based on a dispersion which comprises 30.0 wt.-% polyamine (rest: water and small amounts of additives).

(16) In further embodiments of the present invention, the composition further comprises at least one dicarboxylic acid. Monocarboxylic acids, specifically fatty acids such as lauric acid have been found to be less advantageous for triptan compositions for iontophoretic devices since they may impair the frigostability of the composition due to precipitation.

(17) By combining the above-discussed polyamine(s) with one or more dicarboxylic acids, corresponding polyamine salts are obtained. These polyamine salts are generally water-soluble and, upon dissolution in water, form a polymeric electrolyte. The present compositions comprising said polyamine salts are particularly suitable as a carrier or reservoir for triptans, preferably sumatriptan in iontophoretic devices.

(18) The term “dicarboxylic acid” generally includes organic compounds that are substituted with two carboxylic acid functional groups, which compounds include linear, branched and cyclic compounds, which compounds may be saturated or unsaturated. For instance, the dicarboxylic acid may be selected from C.sub.4 to C.sub.10 dicarboxylic acids. Examples of dicarboxylic acids include succinic acid, glutaric acid, adipic acid and pimelic acid; succinic acid and adipic acid being preferred.

(19) In further embodiments, the composition may contain a combination comprising at least two dicarboxylic acids.

(20) Generally, the amount of dicarboxylic acid(s) is adjusted so as to be at least sufficient to solubilize the polyamine(s), and/or other components present in said composition, in order to obtain a hydrogel composition having the desired properties, particularly semisolid consistency as well as skin-adhesive properties.

(21) Preferably, the total amount of dicarboxylic acid(s) in the composition is between 0.5 and 10.0 wt.-%, preferably between 2.0 and 8.0 wt.-% (based on the total weight of the composition).

(22) The term “triptan compound” includes triptan compounds, derivatives and salts. The term also includes compounds that contain a 2-(1H-indol-3-yl)-N,N-dimethylethanamine moiety. Examples of triptan compounds include, but are not limited to, almotriptan, frovatriptan, eletriptan, zolmitriptan, rizatriptan, sumatriptan, naratriptan, and pharmaceutically acceptable salts thereof. The preferred triptan is sumatriptan and the preferred salt is a succinate.

(23) As described above, the compositions of the present invention are formulated as aqueous compositions, particularly as hydrogel compositions. In a further embodiment, the said aqueous compositions have a pH of 3 to 8, preferably 4.0 to 6.0, or most preferably 4.5 to 5.5.

(24) Generally, it is preferred to adjust and maintain the pH in said water-containing compositions so that they do not substantially affect the pH of the skin, when the compositions are applied to the skin (e. g. during transdermal or iontophoretic administration).

(25) The composition according to the present invention may optionally contain one or more further additives. Said additives include, but are not limited to, additives selected from the group comprising solubility enhancers, skin permeation enhancers, preservatives and antimicrobial agents.

(26) In this connection, the term “solubility enhancer” generally relates to compounds capable of increasing the solubility of the cationic active agent within the composition. This can be achieved either by modulating the possible interactions between said cationic active agent and the other components present in the composition, or by additionally incorporating suitable excipients.

(27) Alternatively, the solubility of the active agent can be achieved by changing its crystal modification. Examples of solubility enhancers include, without limitation, water; diols such as propylene glycol and glycerol; monoalcohols such as ethanol, propanol and higher alcohols; dimethylsulfoxide (DMSO), dimethylformamide, N,N-dimethylacetamide, N-substituted alkyl-azacycloalkyl-2-ones. As already described above, compounds selected from the group of dicarboxylic acids are particularly effective for enhancing the solubility of the polyamine(s).

(28) Further, the term “skin permeation enhancer” particularly includes compounds capable of increasing the permeability of the skin for an active agent contained in the composition, particularly for a cationic active agent. Due to this increase in skin permeability, the rate at which the active agent(s) permeate(s) through the skin and enter(s) the blood circulation is also increased. The enhanced permeation effected by the use of said skin permeation enhancers can be assayed and confirmed by measuring the rate of active agent diffusion through animal or human skin using a diffusion cell apparatus generally known in the art.

(29) Examples of permeation enhancers include, but are not limited to, dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10 MSO), polyethylene glycol monolaurate (PEGML), propylene glycol (PG), propylene glycol monolaurate (PGML), glycerol monolaurate (GML), lecithin, the 1-substituted alkyl-azacycloalkyl-2-ones, particularly 1-n-dodecylazacycloheptan-2-one, alcohols, and the like. The permeation enhancer may also be selected from vegetable oils, e. g. safflower oil, cotton seed oil, or corn oil. Combinations comprising two or more different permeation enhancers may also be used.

(30) Further, the term “antimicrobial agent” generally includes agents which are capable of preventing the growth of microbes in a pharmaceutical preparation, particularly in a composition according to the present invention. Examples of suitable antimicrobials include, but are not limited to, salts of chlorhexidine, such as iodopropynyl butylcarbamate, diazolidinyl urea, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine isethionate, chlorhexidine hydrochloride. Other cationic antimicrobial agents may also be used, such as benzalkonium chloride, benzethonium chloride, triclocarbon, polyhexamethylene biguanide, cetylpyridinium chloride, methylbenzethonium chloride.

(31) Other antimicrobial agents include, but are not limited to, halogenated phenolic compounds, such as 2,4,4′-trichloro-2-hydroxy diphenyl ether (Triclosan), parachlorometa xylenol (PCMX); methyl para-hydroxybenzoate; and short-chain alcohols such as ethanol, propanol, and the like. Preferably, the total concentration of said antimicrobial agent(s) is in the range of 0.01 to 2 wt.-%, relative to the total weight of the composition in which it is included.

(32) In further embodiments, the composition may comprise between 0.01 and 1.0 wt.-%, or between 0.05 and 0.5 wt.-%, or between 0.07 and 0.4 wt.-%, or between 0.08 and 0.3 wt.-%, or between 0.09 and 0.2 wt.-%, or about 0.10 of methyl parahydroxybenzoate (NIPAGIN™).

(33) According to a further embodiment, the composition of the present invention has adhesive properties, to ensure that the composition is maintained in direct and complete contact with the skin at the site of application during the whole time period of transdermal drug administration. Adhesiveness can be obtained by incorporating one or more adhesive polymers into said compositions. Adhesive polymers suitable for this purpose are generally known to the skilled person. Preferably, a polyamine or polyamine salt having adhesive properties is used as said adhesive polymer(s).

(34) Preferably, the compositions of the present invention are self-adhesive. To render the compositions self-adhesive, they may further contain one or more additives selected from the group of tackifiers which group includes, but is not limited to, hydrocarbon resins, rosin derivatives, glycols (such as glycerol, 1,3-butanediol, propylene glycol, polyethylene glycol).

(35) The present invention further pertains to any embodiments of the present invention that may result from combining two or more of the above-described embodiments, or from combining one or more individual features that are mentioned throughout the above description with any one of the above-described embodiments of the present invention.

(36) Generally, the compositions of the present invention can be manufactured by conventional methods. Broadly, the compositions of the present invention are obtainable by dissolving or dispersing the various ingredients (i. e. triptan, polyamine, additives) in water or an aqueous solvent mixture. The resulting mixture may then be spread on a flat surface or poured into molds or extruded, and then allowed to solidify to obtain hydrogel compositions having the desired shape.

(37) The present invention further encompasses the use of the above-described composition(s) as an integral component of an iontophoretic patch, preferably as an anodic reservoir of the patch. Preferably, such composition is incorporated into said iontophoretic patch during manufacture, to form the anodic reservoir of the patch. The above-mentioned administration forms are obtainable by manufacturing methods generally known in the art. EP-A 2 285 362, whose United States equivalent is US 2011/0111029 A1 which is hereby incorporated herein, shows how the above composition(s) may be included in an iontophoretic device.

(38) The methods further include iontophoretic methods for transdermal administration. Generally, the above-mentioned methods comprise a step of applying a composition according to the present invention to the skin of said subject, and allowing the active agent e.g. sumatriptan contained in the composition to be released therefrom and to permeate through the skin and to enter the blood circulation of said subject. This process is enhanced by iontophoresis.

Examples

(39) In the following, the invention and its effectiveness are illustrated by means of examples, together with the attached drawing.

(40) FIG. 1 shows the viscosity degradation over time of the composition according to U.S. Pat. No. 8,366,600 at 4° C. and 15° C.

(41) Methods

(42) Conductivity measurements were performed by a VWR EC 300 conductometer. The pH was measured by a Seven Compact pH/ion meter S220.

(43) Viscosity measurements were performed by a Thermo Scientific HAAKE™ RHEOSTRESS™ 6000 rheometer.

(44) Experimental Procedure

(45) The compositions were prepared with a standard laboratory equipment (stirrer, water bath, glassware). The compositions comprising Eudragit E 100 were prepared as follows: 1. Reactor vessel was filled with water 2. methyl para-hydroxy benzoate (NIPAGIN™) was added under continuous stirring 3. Premix of EUDRAGIT® E100, lauric acid and adipic acid added into the vessel 4. The solution was heated to 80° C. for 2 h while continuous stirring 5. Solution was cooled down to 25° C.

(46) The compositions with KOLLICOAT® SMARTSEAL were prepared first by suspension of succinic acid in water (not completely dissolved). Afterwards, the required amounts of KOLLICOAT® SMARTSEAL 30D and water were added alternately until a visually acceptable viscosity was reached. For the composition with adipic acid, the composition was heated to 45° C. due to the increased solubility of adipic acid at higher temperatures. In order to make verum compositions, 57.6 g of each composition was added to 2.4 g sumatriptan succinate, resulting in a concentration of 4% sumatriptan succinate.

(47) The final composition and the measured key parameters are summarized in Tables 1 (composition according to U.S. Pat. No. 8,366,600), 2 (composition with replacement polyamine) and 3 (composition with EUDRAGIT® E 100).

(48) TABLE-US-00002 TABLE 1 Composition and parameters of the composition according to US-A 8,366,600 Comparative Example (US-A 8,366,600 paragraph [0063]) Raw material Amount Sumatriptan succinate 4.00% Lauric acid 3.40% Adipic acid 0.27% EUDRAGIT ® E 100 5.86% NIPAGIN ™ 0.10% Aqua purificata 86.37% Conductivity 4.03 mS/cm pH 5.2 Viscosity 221 mPas

(49) TABLE-US-00003 TABLE 2 Compositions with KOLLICOAT ® SMARTSEAL; lauric acid replaced by adipic or succinic acid Example 1 Example 2 Raw material Succinic acid Adipic acid Sumatriptan succinate 4.00% 4.00% Succinic acid 2.91% — Adipic acid — 3.45% KOLLICOAT ® 50.70% 48.65% SMARTSEAL 30D Aqua purificata 42.39% 43.89% Conductivity [mS/cm] 6.14 5.05 pH 4.52 4.62 Viscosity [mPas] 2180 mPas 1606 mPas

(50) The conductivity of the compositions of Examples 1 and 2 is higher than in the formulation according to U.S. Pat. No. 8,366,600 (Comparative Example). Generally, a higher conductivity is less critical than a lower conductivity, since the required voltage for the needed current is lower, according to Ohm's law.

(51) The pH of the examples 1 and 2 is lower than that of the composition according to U.S. Pat. No. 8,366,600.

(52) The viscosity of both compositions (Examples 1 and 2) was significantly higher than for the composition according to U.S. Pat. No. 8,366,600 (Comparative Example); see FIG. 2 (Example 2). This can be considered as an advantage, since a higher viscosity may prevent the patch from leaking during application.

(53) Both compositions (Examples 1 and 2) were stored at 4° C. and showed no frigoinstability over at least 2 months.

(54) Frigostable composition with EUDRAGIT® E 100 (Example 3)

(55) Based on the results with KOLLICOAT® SMARTSEAL (Examples 1 and 2), the frigostable composition with EUDRAGIT® E 100 (Example 3) was modified in such way, that adipic acid was used and the solids content was accordingly increased. The resulting formulation and its key parameters is shown in Table 3.

(56) TABLE-US-00004 TABLE 3 Frigostable compositions with EUDRAGIT ® E 100 and adipic acid (Example 3) Ex. 3 Ex. 3 (dil 1) Ex. 3 (dil 2) Ex. 3 (dil 3) Ex. 3 (dil 4) Ex. 3 (dil 5) EUDRAGIT ® EUDRAGIT ® EUDRAGIT ® EUDRAGIT ® EUDRAGIT ® EUDRAGIT ® Raw E Adipic E Adipic acid E Adipic acid E Adipic acid E Adipic acid E Adipic acid material acid (diluted 1) (diluted 2) (diluted 3) (diluted 4) (diluted 5) Sumatriptan 4.00% 4.00% 4.00% 4.00% 4.00% 4.00% succinate Adipic acid 7.03% 6.03% 5.93% 5.83% 5.73% 5.63% EUDRAGIT ® 24.12% 20.67% 20.33% 19.98% 19.64% 19.29% 100 Aqua 64.75% 69.20% 69.65% 70.09% 70.54% 70.98% purificata NIPAGIN ™ 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Solids 35.25 30.80 30.36 29.91 29.47 29.02 content [%] Conductivity 5.52 5.67 5.81 5.70 5.74 5.70 [mS/cm] pH 4.90 5.01 4.98 4.99 5.01 4.95 Viscosity 23990 1134 937 751 589 504 [mPas]

(57) Since the viscosity of the initial composition (23990 mPas) appeared too high for an iontophoretic application, the composition was diluted with water (Ex. 3 diluted 1-5) in order to reach a similar viscosity as the compositions with KOLLICOAT® SMARTSEAL. As shown in Table 3, the dilution had only a minor impact on the conductivity and pH of the diluted composition.

(58) The composition of Example 3 (diluted 5) was physically stable at 4° C. over at least 2 months. This is shown in FIG. 3.

(59) Preclinical Study

(60) A preclinical study has been performed in 3 female Gottingen SPF minipigs per formulation. The three compositions according to Table 4 were used in the preclinical study. Two iontophoretic transdermal patches containing the same formulation (one activated and one inactivated) were placed dermally on each animal for a period of 4 hours. All drug pads in the patches contained 104 mg sumatriptane succinate. The exposure period has been 4 hours. Blood sampling was performed at the following time points: pre-treatment, and 15 min, 30 min, 60 min, 90 min, 2, 3, 4, 4.5, 5, 6, 8, 10, 12 and 16 hours post-treatment. Concentrations of sumatriptane in plasma samples were determined using solid phase extraction for sample preparation, followed by LC-MS/MS. The results of the study are shown in FIGS. 4 and 5. FIG. 4 shows the time dependent plasma concentration of sumatriptane using the compositions according to the Comparative Example and according to Example 3 (diluted 5). FIG. 5 shows the time dependent plasma concentration of sumatriptane using the compositions according to the Comparative Example and according to Example 2a.

(61) TABLE-US-00005 TABLE 4 Compositions used in the preclinical study Compositions Comparative with Example KOLLICOAT ® (US-A Example 3 SMARTSEAL Raw material 8,366,600) (diluted 5) (Example 2a) Sumatriptan succinate 4.00% 4.00% 4.00% Adipic acid 0.27% 5.63% 3.21% Lauric acid 3.40% — — EUDRAGIT ® E 100 5.86% 19.29% — KOLLICOAT ® — 45.20% SMARTSEAL 30D Aqua purificata 86.37% 70.98% 47.49% NIPAGIN ™ 0.10% 0.10% 0.10%

FIGURES

(62) FIG. 4: Time dependent plasma concentration of the Comparative Example and Example 3 (diluted 5)

(63) FIG. 5: Time dependent plasma concentration of the Comparative Example and Example 2a