Composition comprising an active agent with low aqueous solubility

Abstract

The present invention relates to a composition comprising at least one active ingredient with low aqueous solubility, said active ingredient being present therein in a form noncovalently associated with nanoparticles formed by at least one POM polymer of formula (I), and in which said active ingredient is present in a proportion of at least 5 mol/g of POM. It is also directed towards the use of such nanoparticles, noncovalently associated with an active ingredient, with a view to increasing the aqueous solubilization of said active ingredient.

Claims

1. Composition comprising at least one active ingredient with aqueous solubility less than 1 g/l in pure water, measured at ambient temperature, said active ingredient being present therein in a form noncovalently associated with nanoparticles formed by at least one POM polymer of formula (II) below, or a pharmaceutically acceptable salt thereof: ##STR00006## in which: R.sup.1 is selected from the group consisting of: a hydrogen atom, a linear C.sub.2 to C.sub.10 acyl group, a branched C.sub.3 to C.sub.10 acyl group, a pyroglutamate group and a hydrophobic group G; R.sup.2 is a NHR.sup.5 group or a terminal amino acid residue linked by the nitrogen; R.sup.5 is selected from the group consisting of: a hydrogen atom, a linear C.sub.1 to C.sub.10 alkyl group, a branched C.sub.3 to C.sub.10 alkyl group and a benzyl group; G is a tocopheryloxy radical; m and n are positive, non-zero integers; (m+n) ranges from 25 to 100; the molar grafting rate of the hydrophobic groups G, (n)/(n+m) ranges from 10 to 21%; in which said active ingredient is present in a proportion of at least 20 mol/g of POM, and wherein the aqueous solubilization of said active ingredient is increased when in said composition.

2. The composition of claim 1, wherein the POM bears at least one graft of polyalkylene glycol type linked to a glutamate unit.

3. The composition of claim 1, wherein the polyalkylene glycol is a polyethylene glycol.

4. The composition of claim 1, wherein the size of the nanoparticles formed by said POM polymer ranges from 1 to 1,000 nm.

5. The composition of claim 1, wherein said active ingredient has a mass of less than 2,000 Da.

6. The composition of claim 1, wherein said active ingredient is a nonpeptide active ingredient.

7. The composition of claim 1, wherein said active ingredient is a molecule of therapeutic, cosmetic, prophylactic or imaging interest.

8. The composition of claim 1, wherein said active ingredient is a therapeutic active ingredient.

9. The composition of claim 1, wherein said composition provides a release profile, for said active ingredient, which is regulated as a function of time.

10. The composition of claim 1, wherein said nanoparticles noncovalently associated with said active ingredient are agglomerated in the form of microparticles.

11. The composition of claim 1, wherein said nanoparticles noncovalently associated with said active ingredient are used in a supported form.

12. The composition of claim 9, wherein said nanoparticles noncovalently associated with said active ingredient are used in the form of microparticles, said microparticles having a core containing said nanoparticles noncovalently associated with said active ingredient and at least one coating layer conditioning a release profile, for said active ingredient, which is also regulated as a function of pH, said coating layer being formed by a composite material comprising at least one polymer A having a solubilization pH value within the pH range of 5 to 7, and at least one hydrophobic compound B.

13. The composition of claim 12, wherein the polymer A is selected from the group consisting of: copolymer(s) of methacrylic acid and methyl methacrylate, copolymer(s) of methacrylic acid and ethyl acrylate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, shellac gum, polyvinyl acetate phthalate, and mixtures thereof.

14. The composition of claim 12, wherein the coating layer contains from 25% to 90% by weight of polymer(s) A relative to its total weight.

15. The composition of claim 12, wherein the hydrophobic compound B is selected from products that are crystalline in the solid state and that have a melting temperature T.sub.mb greater than or equal to 40 C.

16. The composition of claim 15, wherein the compound B is selected from the group consisting of: vegetable waxes; hydrogenated vegetable oils taken alone or as a mixture with one another; monoesters glycerol and of at least one fatty acid, diesters of glycerol and of at least one fatty acid, triesters of glycerol and of at least one fatty acid and mixtures thereof.

17. The composition of claim 12, wherein the compound B is a polymer that is insoluble in the gastrointestinal fluids.

18. The composition of claim 17, wherein said polymer B is chosen from: water-insoluble derivatives of cellulose, and water-insoluble derivatives of (meth)acrylic (co)polymers.

19. The composition of claim 10, wherein the size of the microparticles is less than 2,000 m.

20. The composition of claim 1, wherein said composition comprises at least two types of nanoparticles noncovalently associated with said active ingredient, said nanoparticles differing from one another by virtue of the nature of the active ingredient or of the POM associated with said active ingredient.

21. The composition of claim 12, wherein said composition combines at least two types of microparticles which differ from one another by virtue of the nature of their coating layer or of the active ingredient that they incorporate.

22. The composition of claim 1, wherein said composition is formulated in the form of a powder or a suspension, or in the form of a tablet or a gelatin capsule.

23. The composition of claim 1, wherein said composition is intended for use in the preparation of medicaments.

24. The composition of claim 10, wherein said composition is suitable for releasing, in a first step, the active ingredient associated with the nanoparticles of POM polymer(s) and then dissociating, in a second step, the active ingredient from said nanoparticles.

25. The composition of claim 1, wherein the size of the nanoparticles ranges from 5 to 500 nm.

26. The composition of claim 1, wherein the size of the nanoparticles ranges from 30 to 300 nm.

27. The composition of claim 1, wherein the size of the nanoparticles ranges from 10 to 100 nm.

28. The composition of claim 8, wherein said active ingredient is selected from the group consisting of: paclitaxel, carvedilol base, simvastatin, nifedipine, ketoconazole, and cyclosporin A.

29. The composition of claim 12, wherein the coating layer contains from 30% to 80% by weight of polymer(s) A relative to its total weight.

30. The composition of claim 12, wherein the coating layer contains from 35% to 70% by weight of polymer(s) A relative to its total weight.

31. The composition of claim 12, wherein the coating layer contains from 40% to 60% of polymer(s) A relative to its total weight.

32. The composition of claim 12, wherein the hydrophobic compound B is selected from products that are crystalline in the solid state and that have a melting temperature T.sub.mb greater than or equal to 50 C.

33. The composition of claim 12, wherein the hydrophobic compound B is selected from products that are crystalline in the solid state and that have a melting temperature 40 C.T.sub.mb90 C.

34. The composition of claim 18, wherein said polymer B is a water-insoluble derivatives of cellulose chosen from ethylcellulose, cellulose acetate butyrate and cellulose acetate.

35. The composition of claim 18, wherein said polymer B is a water-insoluble derivatives of (meth)acrylic (co)polymers selected from the group consisting of: ammonio (meth)acrylate copolymers, (co)polymers of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate, type A or type B, and poly(meth)acrylic acid esters.

36. The composition of claim 10, wherein the size of the microparticles is 100 to 1,000 m.

37. The composition of claim 36, wherein the size of the microparticles is 100 to 800 m.

38. The composition of claim 37, wherein the size of the microparticles is 100 to 500 m.

Description

EXAMPLES

Example 1

(1) Preparation of a Solution of Paclitaxel in an Aqueous Buffer (Reference)

(2) 0.49 mg of paclitaxel (Bioxel) is introduced into a 2 liter volumetric flask. The flask is topped up to the fill line with a 0.05 M phosphate buffer at pH 7.0. The preparation is stirred using a magnetic bar, at 37 C. After magnetic stirring for 2.5 h at 37 C., a few grains of undissolved powder remain.

(3) The preparation is then placed in an ultrasonic bath for 60 min at ambient temperature. A few grains of powder are still undissolved after ultrasonic treatment.

(4) The solubility of paclitaxel in an aqueous buffer at pH 7.0 is less than 0.25 g/ml, i.e. less than 0.3 mol/l.

Example 2

(5) Preparation of Aqueous Formulations of Paclitaxel with a Sodium Polyglutamate with a Degree of Polymerization DP=100 and 20%-grafted with Vitamin E, at a Polymer Concentration of 20 mg/ml

(6) Formulation 1

(7) 4.99 mg of paclitaxel (Bioxel) are introduced into a pill-box. 10 ml of aqueous solution of polyglutamate with a DP=100, 20%-grafted with vitamin E, at pH 7.0 and at a concentration of 20 mg/ml, are added. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. After ultrasonic treatment, a completely clear solution is obtained.

(8) Formulation 2

(9) 10.33 mg of paclitaxel (Bioxel) are introduced into a pill-box. 10 ml of aqueous solution of polyglutamate polymer with a DP=100, 20%-grafted with vitamin E, at pH 7.0 and at a concentration of 20 mg/ml, are added. The preparation is placed in an ultrasonic bath at ambient temperature for 2.5 h. After ultrasonic treatment, a few grains of paclitaxel powder have not dissolved.

(10) Formulation 3

(11) 7 mg of paclitaxel (Bioxel) are introduced into a pill-box. 10 ml of aqueous solution of polyglutamate polymer 20%-grafted with vitamin E, at pH=7.0 and at a concentration of 20 mg/ml, are added. The preparation is placed in an ultrasonic bath at ambient temperature for 2.5 h. After ultrasonic treatment, a completely clear solution is obtained.

(12) The solubility of paclitaxel in an aqueous solution containing 20 mg/ml of polyglutamate with a DP=100, 20%-grafted with vitamin E is around 0.8 mg/ml, i.e. 47 mol of paclitaxel per gram of POM polymer.

(13) The solubility of paclitaxel is thus considerably improved by the use of the POM polymer nanoparticles described above.

Example 3

(14) Preparation of Aqueous Formulations of Paclitaxel with a Sodium Polyglutamate with a DP=100 and 20%-grafted with Vitamin E, at a Polymer Concentration of 90 mg/ml

(15) Formulation 1

(16) 21.21 mg of paclitaxel (Bioxel) are introduced into a pill-box. 10 ml of aqueous solution of polyglutamate polymer with a DP=100, 20%-grafted with vitamin E, at pH=7.0 and at a concentration of 90 mg/ml, are added. The preparation is placed in an ultrasonic bath at ambient temperature for 60 min. After ultrasonic treatment, a completely clear solution is obtained. All the paclitaxel powder is solubilized.

(17) Formulation 2

(18) 39.68 mg of paclitaxel (Bioxel) are introduced into a pill-box. 10 ml of aqueous solution of polyglutamate polymer with a DP=100, 20%-grafted with vitamin E, at pH=7.0 and at a concentration of 90 mg/ml, are added. The preparation is placed in an ultrasonic bath at ambient temperature for 5 h. After ultrasonic treatment, a few grains of paclitaxel powder have not dissolved.

(19) Formulation 3

(20) 35.05 mg of paclitaxel (Bioxel) are introduced into a pill-box. 10 ml of aqueous solution of polyglutamate polymer 20%-grafted with vitamin E, at pH=7.0 and at a concentration of 90 mg/ml, are added. The preparation is placed in an ultrasonic bath at ambient temperature for 5 h. After ultrasonic treatment, a few grains of paclitaxel powder have not dissolved.

(21) The solubility of paclitaxel in an aqueous solution containing 90 mg/ml of polyglutamate 20%-grafted with vitamin E is comprised between 3.5 mg/ml and 4 mg/ml, i.e. 49 mol of paclitaxel per gram of POM polymer.

Example 4

(22) Preparation of Aqueous Formulations of Paclitaxel Solubilized by Different POM Polymers (Formulations Containing 20 g/l Polymer)

(23) In this example the POM polymers used are sodium polyglutamates having a DP=100 and variable vitamin E grafting rates.

(24) Preparation of the formulations is based on the protocol described in Example 2. The solubility value is estimated by a successive approach by attempting to dissolve 5 to 10 mg of paclitaxel in 10 ml of aqueous solution of POM polymer at pH 7.0 and with a polymer concentration of 20 mg/ml. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. The preparation is then left under stirring at ambient temperature overnight. The appearance of the solution is then visually checked in order to see if the paclitaxel powder introduced is entirely solubilized or if residual paclitaxel crystals remain.

(25) TABLE-US-00001 TABLE 1 Solubilization of paclitaxel in an aqueous solution containing 20 g/l of sodium polyglutamate with a DP = 100, 5%-20%-grafted with vitamin E (VE), at pH = 7.0 at ambient temperature. Total concentration of active ingredient Solubilized active % VE on solibilized for 20 ingredient in mol polymer g/l of polymer (mol/l) per g of polymer 5 2.3 .Math. 10.sup.4 12 10 5.9 .Math. 10.sup.4 29 15 9.4 .Math. 10.sup.4 47 20 9.4 .Math. 10.sup.4 47

(26) The solubility of the active ingredient measured without polymer in similar conditions in Example 1 is 3.Math.10.sup.7 mol/l. Table 1 thus shows that the presence of POM polymer at 20 g/l allows the solubility of paclitaxel to be increased by a factor of 500 to 3,000 according to the polymer.

(27) Table 1 clearly shows that for a polymer with a DP=100 a maximum solubilizing power is obtained for polymers having between 15% and 20% vitamin E and thus it is for these polymers that the largest quantity of solubilized active ingredient is observed.

Example 5

(28) Preparation of Aqueous Formulations of Paclitaxel Solubilized by Different POM Polymers (Formulations Containing High Polymer Concentrations)

(29) In this example the POM polymers used are sodium polyglutamates with a degree of polymerization DP=100 and variable vitamin E grafting rates. The POM polymer solution is used at a high concentration in order to solubilize as much active ingredient as possible. However, in order that the solution can be easily handled, the viscosity of the solution is maintained at <100 mPa.Math.s (at 20 C.) which thus limits the polymer concentration in a different manner according to the polymers.

(30) Preparation of the formulations is based on the protocol described in

(31) Example 3. The solubility value is estimated by the successive approach by attempting to dissolve 5 to 15 mg of paclitaxel in 2 ml of concentrated aqueous solution of POM polymer at pH 7.0. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. If insoluble matter remains visible to the naked eye, the solution is replaced in the ultrasonic bath for a further 90 minutes. The preparation is then stirred at ambient temperature overnight. The appearance of the solution is then visually checked in order to see if the paclitaxel powder introduced is completely solubilized or if residual paclitaxel crystals remain.

(32) TABLE-US-00002 TABLE 2 Solubilization of paclitaxel by a concentrated aqueous solution of sodium polyglutamate with DP = 100, 5% to 30%-grafted with vitamin E (VE), at pH = 7.0, at ambient temperature % VE on Concentration Total concentration Solubilized active polymer of the polymer of solubilized active ingredient in mol (%) solution (mg/ml)) ingredient (mol/l) per g of polymer 10 52.8 1.5 .Math. 10.sup.3 29 15 84.6 3.5 .Math. 10.sup.3 42 20 156 6.4 .Math. 10.sup.3 41 30 53.5 <1.4 .Math. 10.sup.3 <26

(33) Table 2 shows that the polymers with a DP=100 containing between 15% and 20% vitamin E allow the polymer concentration to be substantially increased while maintaining an acceptable viscosity and thus allowing significant concentrations of solubilized active ingredient (>3.Math.10.sup.3 mol/l) to be obtained. It should be recalled that the solubility of the active ingredient measured without polymer in similar conditions in Example 1 is 3.Math.10.sup.mol/l i.e. more than 10,000 times less.

Example 6

(34) Preparation of Aqueous Formulations of Simvastatin and Nifedipine Solubilized by a Sodium Polyglutamate with a DP=100 and 20%-grafted with Vitamin E (Formulations Containing 20 g/l of Polymer)

(35) Proceeding according to the method disclosed in Examples 1 and 2 above, the aqueous solubility of simvastatin and nifedipine were determined, firstly in the absence of POM polymer, then in the presence of polyglutamate with a degree of polymerization of 100, 20%-grafted with vitamin E, at pH 7.0 and concentrated to 20 g/l. The results are summarized in Table 3 below.

(36) TABLE-US-00003 TABLE 3 Solubilization of simvastatin and nifedipine with an aqueous solution containing 20 g/l of polyglutamate with a DP = 100, 20%-grafted with vitamin E, at pH = 7, at ambient temperature Solubilized Molecular active ingredient Solubilized active Active mass M Solubility for 20 g/l polymer ingredient in mol agent (g/mol) (mol/l) (mol/L) per g of polymer Simvastatin 419 1.19 .Math. 10.sup.4 7.64 .Math. 10.sup.3 382 Nifedipine 346 2.89 .Math. 10.sup.5 8.67 .Math. 10.sup.4 43

(37) It should be noted that the polyglutamate polymer with a DP of 100, 20%-grafted with vitamin E, dramatically solubilizes the relatively insoluble active ingredients. It should also be noted that even higher solubilities can be obtained with higher concentrations of POM polymer.

Example 7

(38) Preparation of Aqueous Formulations of Carvedilol Base Solubilized by Different POM Polymers (Formulations Containing 20 g/l of Polymer)

(39) In this example the POM polymers used are sodium polyglutamates with a degree of polymerization comprised between 25 and 100 and variable vitamin E grafting rates. Polymers the glutamates of which are partly modified with arginine (cationic groups) and ethanolamine (neutral groups) are also tested.

(40) 40 to 50 mg of carvedilol base are introduced into a 15 ml Falcon tube. 5 ml of aqueous solution of concentrated POM polymer at 20 mg/ml and at pH 7.0 are added. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. After this stage, the preparation is centrifuged at 9,000 rpm for 30 minutes in order to eliminate any undissolved crystals. In all cases, the supernatant is perfectly clear. It is diluted 1,000 times with a phosphate buffer at pH 7.0. The concentration of solubilized carvedilol is determined by UV spectrometry (at a wavelength of 240 nm and using a cell with a 1 cm optical path).

(41) TABLE-US-00004 TABLE 4 Solubilization of carvedilol base with an aqueous solution containing 20 g/l of sodium polyglutamate with a DP = 100, 2 to 20%-grafted with vitamin E (VE), at pH = 7.0 at ambient temperature. Total concentration % VE on of the solubilized active Solubilized active polymer ingredient for 20 g/l ingredient in mol (%) of polymer (mol/l) per g of polymer 2 2.95 .Math. 10.sup.3 148 5 6.64 .Math. 10.sup.3 332 10 1.53 .Math. 10.sup.2 763 20 1.53 .Math. 10.sup.2 763

(42) TABLE-US-00005 TABLE 5 Solubilization of carvedilol base with an aqueous solution containing 20 g/l of sodium polyglutamate with a DP ranging from 25 to 100, 10%- grafted with vitamin E, at pH = 7.0 at ambient temperature. Total concentration Degree of of solubilized active Solubilized active polymerization ingredient for 20 g/l ingredient in mol of the polymer of polymer (mol/l) per g of polymer 25 1.48 .Math. 10.sup.2 738 50 1.53 .Math. 10.sup.2 677 100 1.53 .Math. 10.sup.2 763

(43) TABLE-US-00006 TABLE 6 Solubilization of carvedilol base with an aqueous solution containing 20 g/l of sodium polyglutamate with a DP = 50, 10%-grafted with vitamin E, with cationic (arginine) and optionally neutral (ethanolamine) grafts at pH = 7.0 at ambient temperature. Total concentration of solubilized active Solubilized active % % ingredient for 20 g/l ingredient in mol arginine ethanolamine of polymer (mol/l) per g of polymer 40 45 1.72 .Math. 10.sup.3 86 60 0 9.35 .Math. 10.sup.3 467

(44) The same experiment is carried out in the absence of polymer and it is found that the solubility of carvedilol base at pH 7 is 1.2.Math.10.sup.4 mol/l.

(45) In the presence of 20 mg/ml of POM polymer, the solubility of carvedilol base is thus increased by a factor of approximately 10 to 100 depending on the polymers. Table 4 further shows that for sodium polyglutamates with a DP=100 grafted with vitamin E, the maximum solubilization is obtained for polyglutamates 10 to 20%-grafted with vitamin E.

Example 8

(46) Preparation of Aqueous Formulations of Carvedilol Base Solubilized with Different POM Polymers (Formulations Containing High Polymer Concentrations)

(47) In this example the POM polymers used are sodium polyglutamates with a degree of polymerization DP=100 and variable vitamin E grafting rates. The POM polymer solution is used at a high concentration in order to solubilize as much active ingredient as possible. However, in order to ensure that the solution can be handled easily, the solution is maintained at a viscosity <100 mPa.Math.s (at 20 C.), which thus limits the polymer concentration in a different manner according to the polymers.

(48) 50 to 100 mg of carvedilol base is introduced into a pill-box. 2 ml of concentrated aqueous solution of POM polymer at pH 7 is added. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. If insoluble matter remains which is visible to the naked eye, the solution is replaced in the ultrasonic bath for a further 90 minutes. The formulation is then stirred at ambient temperature overnight. As in the previous example, the formulation is then centrifuged and the supernatant is analyzed by HPLC.

(49) TABLE-US-00007 TABLE 7 Solubilization of carvedilol base with a concentrated aqueous solution of sodium polyglutamate with a DP = 100, 10 to 20%-grafted with vitamin E (VE) at pH = 7.0 at ambient temperature. % VE on Concentration Total concentration Solubilized active polymer of the polymer of solubilized active ingredient in mol (%) solution (mg/ml) ingredient (mol/l) per g of polymer 10 52.8 3.37 .Math. 10.sup.2 638 15 84.6 4.01 .Math. 10.sup.2 474 20 156 8.46 .Math. 10.sup.2 543

(50) Table 7 shows that the total concentration of active ingredient solubilized in the presence of POM polymers in concentrated solution is significantly greater that the solubility of carvedilol base in pure water at the same pH (1.2.Math.10.sup.4 mol/l). The solubility is thus increased by a factor comprised between 100 and 1,000.

Example 9

(51) Preparation of Aqueous Formulations of Ketoconazole Solubilized with Different POM Polymers (Formulations Containing 20 g/l of Polymer)

(52) In this example the POM polymers used are sodium polyglutamates with a degree of polymerization of 100 and variable vitamin E grafting rates. A polymer the glutamates of which are partly modified by arginine (cationic groups) is also tested.

(53) 2 to 40 mg of ketoconazole powder is introduced into a 15 ml Falcon tube. 10 ml of aqueous solution of POM polymer at pH 7.0 and concentrated at 20 mg/ml is added. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. The preparation is then stirred at ambient temperature overnight. The appearance of the solution is then checked visually in order to see if the ketoconazole powder introduced is completely solubilized or if residual ketoconazole crystals remain.

(54) TABLE-US-00008 TABLE 8 Solubilization of ketoconazole with an aqueous solution containing 20 g/l of sodium polyglutamate with a DP = 100, 2 to 20%-grafted with vitamin E (VE), at pH = 7.0, at ambient temperature Total concentration % VE on of solubilized active Solubilized active polymer ingredient for 20 g/l ingredient in mol (%) of polymer (mol/l) per g of polymer 2 5.65 .Math. 10.sup.4 28 5 2.54 .Math. 10.sup.3 127 10 7.16 .Math. 10.sup.3 358 15 7.16 .Math. 10.sup.3 358 20 6.97 .Math. 10.sup.3 348

(55) Table 8 shows clearly that maximum solubilization is obtained for the polymers which are 10 to 20%-grafted with vitamin E.

(56) The same tests were carried out with a cationic polymer.

(57) TABLE-US-00009 TABLE 9 Solubilization of carvedilol with an aqueous solution containing 20 g/l of sodium polyglutamate with a DP = 50, 10%-grafted with vitamin E with cationic grafts (arginine) at pH = 7.0, at ambient temperature Total concentration of solubilized active Solubilized active arginine ingredient for 20 g/l ingredient in mol (%) of polymer (mol/l) per g of polymer 60 5.65 .Math. 10.sup.4 28

(58) The same experiment is carried out in the absence of polymer and it is found that the solubility of ketoconazole at pH 7.0 is approximately 2.Math.10.sup.5 mol/l.

(59) In the presence of 20 mg/ml of POM polymer, the solubility of ketoconazole is thus increased by a factor comprised between 25 and 400 depending on the polymers.

Example 10

(60) Preparation of Aqueous Formulations of Ketoconazole Solubilized with Different POM Polymers (Formulations Containing High Polymer Concentrations)

(61) In this example, the POM polymers used are sodium polyglutamates with a degree of polymerization DP=100 and variable vitamin E grafting rates. The solution of POM polymer is used at a high concentration so as to solubilize as much active ingredient as possible. However, in order that the solution can be easily handled, the viscosity of the solution is maintained <100 mPa.Math.s (at 20 C.) which thus limits the polymer concentration in a different manner according to the polymer.

(62) 10 to 60 mg of ketoconazole powder is introduced into a glass pill-box, 2 ml of concentrated aqueous solutions of POM polymer at pH 7.0 is added. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. If insoluble matter visible to the naked eye remains, the solution is replaced in the ultrasonic bath for a further 90 minutes. The preparation is then stirred at ambient temperature overnight. The appearance of the solution is then visually checked in order to see if the ketoconazole powder introduced is completely solubilized or if residual ketoconazole crystals remain.

(63) TABLE-US-00010 TABLE 10 Solubilization of ketoconazole with a concentrated aqueous solution of sodium polyglutamate with a DP = 100, 2 to 30%-grafted with vitamin E (VE) at pH = 7.0 at ambient temperature % VE on Concentration Total concentration Solubilized active polymer of the polymer of solubilized active ingredient in mol (%) solution (mg/ml) ingredient (mol/l) per g of polymer 10 52.8 1.60 .Math. 10.sup.2 303 15 84.6 3.11 .Math. 10.sup.2 367 20 156 5.35 .Math. 10.sup.2 343 30 53.5 1.41 .Math. 10.sup.2 264

(64) Table 10 shows that the polymers with a DP=100 containing between 15% and 20% vitamin E allow the polymer concentration to be substantially increased while maintaining an acceptable viscosity and thus allowing significant concentrations of solubilized active ingredient (>3.Math.10.sup.2 mol/l) to be obtained. It is recalled that the solubility of the active ingredient measured without polymer in similar conditions as in the previous example is 2.Math.10.sup.5 mol/l i.e. more than 1,000 times less.

Example 11

(65) Preparation of Aqueous Formulations of Cyclosporin-A Solubilized with Different POM Polymers (Formulations Containing 20 g/l of Polymer).

(66) In this example the POM polymers used are sodium polyglutamates having a degree of polymerization comprised between 25 and 100 and variable vitamin E grafting rates.

(67) 40 to 50 mg of cyclosporin-A is introduced into a 15 ml Falcon tube. 5 ml aqueous solution of POM polymer at pH 7 and concentrated at 20 mg/ml is added. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. The preparation is then stirred at ambient temperature overnight. The preparation is centrifuged at 9,000 rpm for 30 minutes. The supernatant is measured by HPLC in order to determine the concentration of cyclosporin-A in the aqueous solution.

(68) TABLE-US-00011 TABLE 11 Solubilization of cyclosporin-A with an aqueous solution containing 20 g/l of sodium polyglutamate with a DP = 100, 5 to 30%-grafted with vitamin E (VE) at pH = 7.0, at ambient temperature Total concentration % VE on of solubilized active Solubilized active polymer ingredient for 20 g/l ingredient in mol (%) of polymer (mol/l) per g of polymer 5 4.46 .Math. 10.sup.3 223 10 6.24 .Math. 10.sup.3 312 15 6.49 .Math. 10.sup.3 324 20 5.78 .Math. 10.sup.3 289 30 4.03 .Math. 10.sup.3 202

(69) TABLE-US-00012 TABLE 12 Solubilization of cyclosporin-A with an aqueous solution containing 20 g/l of sodium polyglutamate with a DP between 25 and 100, 10%- grafted with vitamin E at pH = 7.0 at ambient temperature Total concentration Degree of of solubilized active Solubilized active polymerization ingredient for 20 g/l ingredient in mol of the polymer of polymer (mol/l) per g of polymer 25 5.86 .Math. 10.sup.3 293 50 6.16 .Math. 10.sup.3 308 100 6.24 .Math. 10.sup.3 312

(70) The same experiment was carried out in the absence of polymer and it was found that the solubility of cyclosporin-A at pH 7 is approximately 2.5.Math.10.sup.5 mol/l

(71) In the presence of 20 mg/ml of POM polymer, the solubility of ketoconazole is thus increased by a factor of approximately 200. Table 11 further shows that for sodium polyglutamates with a DP=100 grafted with vitamin E, the maximum solubilization is obtained for polyglutamates 10 to 20%-grafted with vitamin E

Example 12

(72) Preparation of Aqueous Formulations of Cyclosporin-A Solubilized with Different POM Polymers (Formulations Containing High Concentrations of Polymer).

(73) In this example the POM polymers used are sodium polyglutamates with a degree of polymerization of 100 or 25 and variable vitamin E grafting rates. The solution of POM polymer is used at a high concentration in order to solubilize as much active ingredient as possible. However, in order that the solution can be easily handled, the viscosity of the solution is maintained at <100 mPa.Math.s (at 20 C.) which thus limits the polymer concentration in a different manner depending on the polymers.

(74) 60 to 100 mg of cyclosporin-A base is introduced into a pill-box. 2 ml of concentrated aqueous solution of POM polymer at pH 7 is added. The preparation is placed in an ultrasonic bath at ambient temperature for 90 minutes. If insoluble matter remains which is visible to the naked eye, the solution is replaced in the ultrasonic bath for a further 90 minutes. The preparation is then stirred at ambient temperature overnight. The preparation is then centrifuged at 9,000 rpm for 30 minutes. The supernatant is measured by HPLC in order to determine the cyclosporin-A concentration in the aqueous solution.

(75) TABLE-US-00013 TABLE 13 Solubilization of cyclosporin-A with a concentrated aqueous solution of sodium polyglutamate with a DP = 100, 10 to 20%-grafted with vitamin E (VE) at pH = 7.0 at ambient temperature. % VE on Concentration Total concentration Solubilized active polymer of the polymer of solubilized active ingredient in mol (%) solution (mg/ml) ingredient (mol/l) per g of polymer 10 52.8 4.80 .Math. 10.sup.2 910 15 84.6 7.85 .Math. 10.sup.2 928 20 90.0 7.89 .Math. 10.sup.2 876

(76) TABLE-US-00014 TABLE 14 Solubilization of cyclosporin-A with a concentrated aqueous solution of sodium polyglutamate with a DP of 25 or 100, 20%- grafted with vitamin E at pH = 7.0 at ambient temperature. Degree of Concentration Total concentration Solubilized active polymer- of the polymer of solubilized active ingredient in mol ization solution (mg/ml) ingredient (mol/l) per g of polymer 100 90 7.89 .Math. 10.sup.2 876 25 145 9.44 .Math. 10.sup.2 651

(77) Table 13 shows that the polymers with a DP=100 containing between 15% and 20% vitamin E allow the polymer concentration to be substantially increased while maintaining an acceptable viscosity and thus allowing significant concentrations of solubilized active ingredient (>2.6.Math.10.sup.2 mol/l) to be obtained. It is recalled that the solubility of the active ingredient measured without polymer in similar conditions in the previous Example is approximately 2.5.Math.10.sup.5 mol/l i.e. more than 1,000 times less.

Example 13

(78) Measurement of the Shear Viscosity (mPa/s) of an Aqueous Solution of POM Polymer at a Concentration of 50 mg/ml with a Velocity Gradient of 10 s.sup.1.

(79) All the samples are prepared at 50 mg/ml, either by dilution in pure water of concentrated solutions if the initial concentration after synthesis is >50 mg/ml, or after concentration in a rotary evaporator if the initial concentration of the solution is <50 mg/ml.

(80) The viscosity of aqueous polymer solutions is measured at 20 C. using a Bohlin Gemini model rheometer equipped with a cone-plane type geometry of 4 cm diameter and 1 angle.

(81) TABLE-US-00015 TABLE 15 Measurements of viscosity (at 20 C. and for a shear gradient of 10 s.sup.1) of solutions at 50 mg/ml of sodium polyglutamates with different DPs 5%-grafted with vitamin E (VE). Viscosity (Mpa .Math. s) Degree of 25 <10 polymerization 50 <10 100 25 220 >1,000

(82) These results show clearly that for vitamin E grafting rates of 5%, a polymer not according to the invention in terms of DP results in a too high viscosity.