The present invention concerns a stable diltiazem hydrochloride pharmaceutical composition for cutaneous application, comprising a content of deacethyldiltiazem of less than 0.3 % (w/w), as well as a process for the preparation thereof.

Diltiazem hydrochloride is a calcium channel blocker. An increase in the cytoplasmatic concentration of Ca²⁺ ions causes the rise of the myocardial contraction and of the vascular smooth muscle. The uptake of extracellular Ca²⁺ is more important for the initiation of the contraction of myocardial cells, whereas the release of Ca²⁺ from the intracellular storage sites also participates in the vascular smooth muscle (Goodman and Gilman's, 8^th edition, 1990).

The in vitro degradation of diltiazem hydrochloride is potentiated in acidic medium and at high temperatures. The main degradation product is deacethyldiltiazem (Martindale The Complete Drug Reference, 32^nd edition, The Pharmaceutical Press). This degradation product (deacethyldiltiazem) has about 50% of the potency of diltiazem hydrochloride as a vasodilator (Goodman and Gilman's, 8^th edition, 1990).

European Patent EP 0 275 054, filed on January 9, 1998 , refers as example the composition and preparation process for the formulation of a 1% diltiazem hydrochloride rectal infusion. This rectal infusion comprises in its composition a carboxyvinyl polymer and an amino acid (L-valine). According to EP 0 275 054 this formulation, which contains water in its composition, has a pH value of 6.9.

International Patent application WO 98/36733, filed on February 23, 1998 , describes a pharmaceutical composition for cutaneous application, which comprises at least one cholinergic agent or a calcium channel blocker, for local anal administration, for the treatment of benign anal disorders. This patent application refers as formulation examples, a formulation in the form of a gel which comprises sodium carmelose and polyethylene glycol, and a formulation in the form of an emulgel which comprises carbomer, propylene glycol, dimethyl sulphoxide and oily excipients. Both formulations have water in its composition.

European Patent EP 0 526 561, filed on April 16, 1991 , discloses a composition for transdermic administration of drugs. In this patent, a formulation containing an ethanol aqueous solution and a slight exciding amount of Octanol is described.

The diltiazem hydrochloride is used as a vasodilator for cutaneous application. However, the formulations which are part of the state of the art are unstable with the formation of the degradation product deacethyldiltiazem. As mentioned above, this product has only 50% of the vasodilator capacity of diltiazem hydrochloride, causing thereby a decrease in the vasodilator activity of the formulations for cutaneous application.

It is object of the present invention a stable diltiazem hydrochloride pharmaceutical composition for cutaneous application, comprising a deacethyldiltiazem content of less than 0.3% (w/w) in the final product, as well as a process for the preparation thereof.

The pharmaceutical composition according to the invention consists in a diltiazem hydrochloride paste, comprising in its composition only oily excipients.

The diltiazem hydrochloride paste that has a deacethyldiltiazem content of less than 0.3% (w/w) and which is object of the present invention is obtained by the melting of the oily components, in which the diltiazem hydrochloride is subsequently dispersed. According to the present invention, the diltiazem hydrochloride is dispersed at a specific temperature, which allows to obtain a homogeneous active substance dispersion, but does not promote the formation of deacethyldiltiazem.

The qualitative and quantitative composition and the preparation process according to the present invention allows to obtain a stable formulation during shelf life, with good properties for application to the skin and mucosa, and with excellent vasodilator properties, due to its low deacethyldiltiazem content (< 0.3%).

It is an object of the present invention the obtention of a stable pharmaceutical composition, suitable for cutaneous application and with a deacethyldiltiazem content of less than 0.3% (w/w). This is achieved by the combination of diltiazem hydrochloride to oily excipients, to one or more tensioactive agents, and one or more preservatives, in the absence of water or any other aqueous excipient.

The diltiazem hydrochloride can be included in the formulation according to the invention in concentrations between 0.5% and 10% of the formulation total mass, preferentially between 2% and 6% of the formulation total mass.

The oily excipients may be selected from the oily excipients generally used in the semi-solid pharmaceutical forms, provided that its association allows the obtention of a formulation having suitable characteristics for cutaneous application. For example, as oily excipients, emollients (Cetiol LC®, solid and/or liquid paraffin, vegetal oils), thickeners (ketostearyl alcohol) may be used.

The tensioactive agents may be selected among those that act simultaneously as tensioactives and as cutaneous absorption promoters. Examples of tensioactive agents, acting simultaneously as cutaneous absorption promoters, are polysorbate 40, polysorbate 80.

The elected preservative should be soluble in one of the selected oily excipients. As preservatives, benzoic acid, sorbic acid, phenylethyl alcohol and chorbutanol may be used.

The formulation pH value should range between 2.5 and 5, preferably between 3.5 and 4.5.

The formulation final viscosity should range between 100 mPas and 1500 mPas, preferably 200 mPas and 500 mPas.

According to one way of preparation, the preservative is dissolved in one of the oily components of the formulation. The solid oily excipients are melted at a temperature which is higher than their melting point. The temperature is decreased to 40°C to 65°C, or preferably to 45°C to 55°C, and the active substance is homogenously dispersed. It is cooled down to room temperature, under stirring.

The present invention is illustrated by the following examples and assays.

Composition (%) / lot DILC23- 020161A Diltiazem hydrochloride 2.0 Water 98.0 TOTAL 100.0

The diltiazem hydrochloride was dissolved in water.

The obtained solution was filled into amber glass flasks.

The flasks containing the solution were stored at 25°C/60% RH and at 50°C. The solution was analysed for day 0, 2, 7 and 12. The performed tests consisted in the assessment of the aspect, pH determination, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

The results are shown in tables 4 to 6.

Composition (%) / lot DILC23- 020161B Diltiazem Hydrochloride 2.0 Water 97.8 Sodium Benzoate 0.2 TOTAL 100.0

The sodium benzoate was dissolved in water. The diltiazem hydrochloride was dissolved in the sodium benzoate solution.

The obtained solution was filled into amber glass flasks.

The flasks containing the solution were stored at 25°C/60% RH and at 50°C. The solution was analysed for day 0, 2, 7 and 12. The performed tests consisted in the assessment of the aspect, pH determination, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

The results are shown in tables 4 to 6.

Composition (%) / lot DL6-01006- 1C Diltiazem Hydrochloride 2.0 Water 5.0 Propylene glycol 93.0 TOTAL 100.0

The diltiazem hydrochloride was dissolved in water. The propylene glycol was added to the solution.

The obtained solution was filled into amber glass flasks.

The flasks containing the solution were stored at 25°C/60% RH and at 50°C. The solution was analysed for day 0, 2, 7 and 12. The performed tests consisted in the assessment of the aspect, pH determination, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

The results are shown in tables 4 to 6.

Tables 4 to 6 show the results (aspect, pH, assay and related compounds) of the stability study performed for the solution referred in EXAMPLE 1, EXAMPLE 2 and EXAMPLE 3.

The solutions obtained were clear and colourless. The aspect did not suffer any changes during the storage period. Lot / Storage Conditions pH 0 d 2 d 7 d 12 d 25°C/60% RH 50°C 25°C/60% RH 50°C 25°C/60% RH 50°C DILC23- 020161A 4.61 4.30 4.72 3.94 4.74 3.80 DILC23- 020161B 5.64 5.50 5.40 4.84 5.36 4.76 DL6-01006- 1C 4.27 n.p. n.p. 4.19 n.p. n.p. d - days; n.p. - not performed Lot / Storage Conditions ⁽²⁾ Assay ± V.C. (%) 0 d 2 d 7 d 12 d 25°C/60% RH 50°C 25°C/60% RH 50°C 25°C/60% RH 50°C DILC23-020161A 98.86 ± 0.11 99.32 ± 0.60 98.78 ± 1.59 95.00 ± 0.28 n.p. n.p. DILC23-020161B 102.29 ± 1.19 95.84 ± 1.26 97.32 ± 0.06 96.76 ± 0.07 n.p. n.p. DL6-01006-1C 100.95 ± 0.22 101.00 ± 0.26 n.p 99.86 ± 0.33 97.70 ± 0.048 89.79 ± 0.99 V.C. - Variation Coefficient; d - days; n.p. - not performed;

⁽²⁾-mean of 2 samples Lot / Storage Conditions Related Compounds (%) 0 d 2 d 7 d 12 d 25°C/60 % RH 50°C 25°C/60 % RH 50°C 25°C/60 % RH 50°C DILC23-020161A 0.055⁽¹⁾ 0.527⁽¹⁾ 0.238⁽¹⁾ 1.314⁽¹⁾ n.p. n.p. DILC23-020161B 0-184⁽¹⁾ 1.837⁽¹⁾

0.023 1.032⁽¹⁾ 5.339⁽¹⁾ n.p. n.p. DL6-01006-1C 0.048⁽¹⁾

0.022 0.079⁽¹⁾

0.020 n.p. 0.280⁽¹⁾ 0.106⁽¹⁾ 0.428⁽¹⁾ d - days; n.p. - not performed; ⁽¹⁾ Deacethyldiltiazem

In accordance with the performed studies it was possible to conclude that the diltiazem hydrochloride is unstable in aqueous medium. This active substance is hydrolysed in acidic or alkaline medium, with the production of deacethyldiltiazem, which has about 50% of the vasodilator capacity of diltiazem hydrochloride.

The following example is part of the state of the art (European Patent EP 275054 ) and will be used for comparison with the formulation, object of the present invention.

Composition (%) / lot DILC22-020181E Diltiazem hydrochloride 1.0 4% (w/w) Carbopol solution 12.5 4% (w/w) L-valine aqueous solution 25.0 2% (w/v) Sodium hydroxide aqueous solution 10.0 Purified water 51.5 TOTAL 100.0

Purified water is added to the carboxyvinyl polymer aqueous solution. Subsequently, the diltiazem is gradually added under stirring. The L-valine solution is added very slowly to this mixture and the resulting mixture is uniformly stirred in order to increase the viscosity. Finally, the sodium hydroxide solution is added. The mixture is stirred so that a gel is obtained.

The gel was packed in amber glass flasks.

The flasks containing the formulation were stored at 25°C/60%RH and at 50°C, analyses having been performed for day 0, day 2 and day 8. The formulation was characterized with respect to its aspect, pH, viscosity, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

The results are shown in Tables 12 to 16.

This example corresponds to an example referred in the European Patent application EP 969813 and will be used for comparison with the formulation, object of the present invention.

Composition / lot DILC22-020181F Diltiazem hydrochloride 2.0 g Sodium Carmelose 6.0 g Polyethylene glycol 30.0 ml Methyl p-hydroxybenzoate 150.0 mg Propyl p-hydroxybenzoate 15.0 mg Purified water (to complete) s.q.t. TOTAL 100.0 g s.q.t - sufficient quantity to

The preservatives are dissolved in part of the water (80°C). It is cooled down to room temperature. The diltiazem hydrochloride is added to the obtained solution and stirred until complete dissolution. Following the obtention of a solution, the polyethylene glycol and the sodium carmelose are added. The remaining water is added to the obtained gel.

The gel was packed in amber glass flasks.

The flasks containing the gel were stored at 25°C/60%RH and 50°C. Analyses were performed for day 0, day 2 and day 8. The formulation was characterized with respect to its aspect, pH, viscosity, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

The results are shown in Tables 12 to 16.

This example was referred in the European Patent application EP 969813 and will be used for comparison with the formulation, object of the present invention.

Composition (g) / lot DILC21-020181B Diltiazem hydrochloride 10.0 Dimethyl sulphoxide 250.0 Carbomer 5.0 White solid Paraffin 15.0 Ketomacrogel 115.0 Propylene glycol 23.0 Methyl p-hydroxybenzoate solution s.q.t. TOTAL 500 s.q.t - sufficient quantity to

The propylene glycol is added to the preservative aqueous solution. The carbomer is dispersed in the obtained solution, so that a colloidal suspension is obtained. Then, the dimethyl sulphoxide is added under strong agitation, so that a translucent gel is obtained.

On the other hand, the oily phase components are melted.

The diltiazem hydrochloride is dissolved in the remaining preservative solution. The diltiazem hydrochloride solution is then added to the gel. Finally, the oily phase components are added to the gel.

The emulgel was packed in amber glass flasks.

The flasks containing the emulgel were stored at 25°C/60%RH and 50°C, analyses having been performed for day 0, day 2, day 8 and day 90. The formulation was characterized with respect to its aspect, pH, viscosity, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

The results are shown in Tables 12 to 16.

The following example corresponds to an example referred in the European Patent EP 0 526 561 and will be used for comparison with the formulation, object of the present invention.

Composition / lot DILC22-020181G Diltiazem hydrochloride 902.0 mg 25% (v/v) Ethanol aqueous solution 10.0 ml Octanol 100.0 ml Polyvinyl pirrolidone 1000.0 mg

The diltiazem hydrochloride is dissolved in the ethanol aqueous solution. The octanol is added and afterwards the polyvinyl pirrolidone is dissolved.

The hydrogel was packed in amber glass flasks.

The flasks containing the hydrogel were stored at 25°C/60%RH and at 50°C, analyses having been performed for day 0, day 2 and day 8. The formulation was characterized with respect to its aspect, pH, viscosity, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002 , for diltiazem hydrochloride).

The results are shown in Tables 12 to 16.

Composition (%) / lot DILC23-020181A Diltiazem hydrochloride 6.00 Cetiol LC^® (coco-caprilate/caprate) 52.80 Liquid Paraffin 12.00 Tween 40^® (polysorbate 40) 10.00 Lanette O^® (Ketostearyl alcohol) 19.00 Benzoic acid 0.20

Briefly, in a container of proper dimensions, the Lanette O® (thickener), the liquid paraffin (emollient/oily carrier) and the Tween 40® (tensioactive/cutaneous absorption promoter) are melted at 70°C. After the obtention of a homogeneous phase the temperature is decreased to 50°C. The o Cetiol LC® (emollient) and the benzoic acid (preservative) are then added to oily phase obtained, under stirring. After obtaining a homogenous oily phase, the diltiazem hydrochloride (active substance) is dispersed under strong agitation.

The paste was packed in phenol coated aluminium tubes.

The tubes containing the paste were stored at 25°C/60%RH and at 50°C, analyses having been performed for day 0, day 2, day 8 and day 90. The formulation was characterized with respect to its aspect, pH, viscosity, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

The results are shown in Tables 12 to 16.

Tables 12 to 16 show the results obtained from the stability study performed (aspect, pH, viscosity, assay and related compounds) for the formulations referred in EXAMPLE 4, EXAMPLE 5, EXAMPLE 6, EXAMPLE 7 and EXAMPLE 8. Lot / Storage conditions Aspect 0 d 2 d 8 d 90 d 25°C/60%RH 50°C 25°C/60%RH 50°C 25°C/60%RH 50°C DILC22-020181E White aqueous Gel n.p. DILC22-020181F Aqueous, viscous, translucent Gel n.p. DILC21-020181B White aqueous Emulgel White aqueous Emulgel n.p. DILC22-020181G Whitish hydrogel n.p. DILC23-020181A Bright white Paste Bright white Paste with diltiazem hydrochloride sedimentation Bright white Paste Bright white Paste with diltiazem hydrochloride sedimentation Bright white Paste n.p. d - days; n.p. - not performed Lot / Storage conditions pH 0 d 2 d 8 d 90 d 25°C/60% RH 50°C 25°C/60%RH 50°C 25°C/60%RH 50°C DILC22-020181E 6.77 6.51 6.52 6.07 n.p. DILC22-020181F 6.15 5.87 5.79 5.44 n.p. DILC21-020181B 4.45 4.48 4.86 4.56 3.36 n.p DILC22-020181G 3.55 3.60 3.30 3.65 n.p. DILC23-020181A 3.15 3.12 3.13 3.10 2.99 n.p d - days; n.p. - not performed Lot / Storage conditions Viscosity (mPas) 0 d 2 d 8 d 25°C/60%RH 50°C 25°C/60%RH 50°C DILC22-020181E 54.14 n.p. 84.39 17.39 DILC22-020181F 3255.21 n.p. 3205.60 2211.34 DILC2I-020181B 1777.11 n.p. 1909.08 1717.22 DILC22-020181G 9.34 n.p. 8.57 7.72 DILC23-020181A 228.73 n.p. 256.11 276.72 d - days; n.p. - not performed Lot / Storage conditions ⁽²⁾ Assay ± V.C. (%) 0d 2d 8 d 90 d 25°C/ 60% RH 50°C 25°C/60%RH 50°C 25°C/60%RH 50°C DILC22-020181E 94.05 ± 0.96 79.44 ± 0.04 92.72 ± 1.52 n.p. n.p. n.p. DILC22-020181F 96.49 ± 0.08 67.76 ± 0.04 91.70 ± 1.12 n.p. n.p. n.p. DILC21-020181B 98.03 ± 0.08 98.32 ± 0.05 n.p. 99.61 ± 0.77 96.49 ± 0.07 n.p. DILC22-020181G 97.20 ± 0.58 97.24 ± 0.09 n.p. 97.05 ± 0.69 n.p. n.p. DILC23-020181A 98.55 ± 0.89 n.p. 100.99 ± 0.13 98.87 ± 1.45 97.92 ± 0.87 n.p. V.C. - Variation coefficient; d - days; n.p. - not performed; ⁽²⁾ - mean of 2 samples Lot / Storage conditions Related compounds (%) 0 d 2 d 8 d 90 d 25°C/60% RH 50°C 25°C/60% RH 50°C 25°C/60% RH 50° C DILC22-020181E ⁽¹⁾1.783 ⁽¹⁾15.803 ⁽¹⁾7.651 n.p. n.p. n.p. DILC22-020181F ⁽¹⁾0.882 ⁽¹⁾2.470 ⁽¹⁾2.729 n.p. n.p. n.p. DILC21-020181B ⁽¹⁾0.046 ⁽¹⁾0.194 n.p. ⁽¹⁾1.123 1.018 n.p . DILC22-020181G ⁽¹⁾0.044 ⁽¹⁾0.319 n.p. ⁽¹⁾ 2.202 n.p.. n.p. DILC23-020181A ⁽¹⁾0.052 n.p. ⁽¹⁾ 0.045 ⁽¹⁾ 0.067 ⁽¹⁾0.047

0.246 n.p . d - days; n.p. - not performed; (1) deacethyldiltiazem

Unexpectedly, it was ascertained that the deacethyldiltiazem content greatly increased for the formulations belonging to the state of the art (DILC22-020181E, DILC22-020181F, DILC21-020181B, DILC22-020181G), and consequently the diltiazem hydrochloride content decreased. The deacethyldiltiazem increase was verified even for those formulations stored at 25°C/60%RH, during a period of time of only 48 hours.

Even more unexpected was the fact that the deacethyldiltiazem content of the formulation according to the present invention (DILC23-020181A) was maintained under 0.3%, even after 90 days at a temperature of 25°C.

The composition and preparation are identical to those described for EXAMPLE 8. This formulation corresponds to the lot number DL6-01006-1V.

The tubes containing the paste were stored at 25°C/60% RH and at 75°C. The paste was analysed for day 0, day 3 and day 7. The performed tests consisted in aspect assessment, pH determination, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

Tables 17 to 21 show the results (aspect, pH, assay and related compounds) of the accelerated stability study performed for the diltiazem hydrochloride paste of EXAMPLE 9. Time (days) Storage conditions 25°C/60%RH 75°C 0 Bright white paste -- 3 -- Bright white paste, with diltiazem hydrochloride sedimentation 7 Bright white paste

Table 17 describes the aspect of the paste stored at 25°C/60%RH and at 75°C. As it can be ascertained, the sedimentation of the diltiazem hydrochloride takes place at 75°C, due to the melting of the oily excipients. After homogenization during the cooling period, the paste reacquires a bright white colour. Time (days) Storage conditions 25°C/60%RH 75°C 0 3.16 -- 3 -- 3.01 7 -- 3.17

The pH of the 6% (w/w) diltiazem hydrochloride paste remained unchanged during the accelerated stability study, even after 7 days at 75°C. Time (days) Storage conditions 25°C/60%RH 75°C 0 100.26 ± 0.360 -- 3 -- 95.72 ± 2.327 7 -- 100.78 ± 1.128 Time (days) Storage conditions 25°C/60%RH 75°C 0 96.52 ± 0.416 -- 3 -- 95.72 ± 2.327 7 -- 96.74 ± 0.318 Time (days)) Storage conditions 25°C/60%RH 75°C 0 rrt 0.49 (Ddilc) = n.q.

Total = n.q. -- 7 -- rrt 0.52 (Ddilc) = 0.231

rrt 1.82 = 0.026

Total = 0.257 Ddilc - Deacethyldiltiazem; n.q.- not quantifiable; rrt - relative retention time; Quantification Limit: Q.L. = 0.052%

Surprisingly, the assay of the diltiazem hydrochloride and of the preservative benzoic acid remains stable, even after 7 days at 75°C (Tables 19 and 20). The related compounds (Table 21) suffered a light increase after 7 days at 75°C, but are maintained after this period of time, according to the specification for the final product (≤ 0.3%).

The composition and preparation are identical to those described for EXAMPLE 8. This example corresponds to formulations which have the lot numbers DL6-01006-2A, DL6-01006-2B and DL6-01006-2C.

The tubes containing the paste were stored at 25°C/60%RH, 30°C/60%RH and 40°C/75%RH. The paste was analysed for 0 days, 3 months and 6 months. The tests performed consisted in the aspect assessment, pH determination, assay and related compounds (in accordance with the European Pharmacopoeia monograph, 4th edition, 2002, for diltiazem hydrochloride).

The aspect of the paste remains unchanged during the storage period.

Figures 1 to 12 show the results (pH, assay and related compounds) of the stability study performed for the diltiazem hydrochloride paste referred in EXAMPLE 10.

• FIGURE 1: pH Variation during the stability (6 months, 25°C/60%RH);
• FIGURE 2: Variation of the assay of diltiazem hydrochloride during the stability (6 months, 25°C/60%RH);
• FIGURE 3: Variation of the benzoic acid assay during the stability (6 months, 25°C/60%RH);
• FIGURE 4: Related compounds variation (6 months, 25°C/60%RH);
• FIGURE 5: pH Variation during the stability (6 months, 30°C/60%RH);
• FIGURE 6: Variation of the assay of diltiazem hydrochloride during the stability (6 months, 30°C/60%RH);
• FIGURE 7: Variation of the benzoic acid assay during the stability (6 months, 30°C/60%RH);
• FIGURE 8: Related compounds variation during the stability (6 months, 30°C/60%RH);
• FIGURE 9: pH Variation during the stability (6 months, 40°C/75%RH);
• FIGURE 10: Variation of the assay of diltiazem hydrochloride during the stability (6 months, 40°C/75%RH);
• FIGURE 11: Variation of the benzoic acid assay during the stability (6 months, 40°C/75%RH);
• FIGURE 12: Related compounds variation during the stability (6 months, 40°C/75%RH).

Figures 1 to 12 confirm the high stability of the developed formulation. The product kept its characteristics with respect to the studied parameters, even when the paste was stored at 40°C/75%RH during 6 months. The total content determined for the related compounds was less than 0.3% (w/w).