Freeze-dried composition

Abstract

The invention relates to freeze-dried compositions comprising a) at least one polymer based on polyacrylic acids and salts thereof, b) at least one natural polymer, c) optionally at least one further polymer which differs from a) and b) and d) optionally one or more active compounds and/or auxiliary substances. The invention furthermore relates to a process for the preparation of such freeze-dried compositions, the combination of such freeze-dried compositions in kit-of-parts arrangements together with aqueous solutions and the use of the freeze-dried compositions and of the kit-of-parts combinations for cosmetic and pharmaceutical use, in particular for use as a cosmetic mask or as a wound covering and for the preparation of pharmaceutical agents for treatment of dermal wounds, such as, in particular, chronic wounds, ulcus cruris or decubitus.

Claims

1. A pad for topical application consisting of a mechanically stable, cohesive, freeze-dried composition comprising a) ≧10 wt % of at least one hydrocolloid polymer, wherein the hydrocolloid polymer is a polyacrylate, a synthetic acrylic polymer or a salt thereof, b) ≧40 wt % of one natural polymer, wherein the natural polymer is an anionic natural hydrocolloid, c) at least two further natural polymers which differ from a) and b); and wherein the at least one of the at least two further natural polymers is carrageenan, a carrageenan derivative, hyaluronic acid, a hyaluronic acid derivative, collagen or a collagen derivative, and d) one or more active compounds and/or auxiliary substances, wherein at least one auxiliary substance is caprylic/caproic acid, jojoba oil or squalane; wherein a 1 percent by weight solution or suspension of the freeze-dried composition comprising components (a), (b) and (c) in water at 20° C. has a pH of from 3.0 to 6.5.

2. The pad according to claim 1, which has an optical density of ≧0.02 per 1 mm layer thickness of the freeze-dried composition.

3. The pad according to claim 1, which is neither ionically nor chemically crosslinked and which contains no textile fibre constituents and no additional carrier layers.

4. The pad according to claim 1, wherein at least one hydrocolloid polymer a) is chosen from the group of carbomers.

5. The pad according to claim 1, wherein the anionic natural hydrocolloid polymer b) is chosen from the group of polysaccharides, polyaminosaccharides and glucosaminoglycans.

6. The pad according to claim 5, wherein the anionic natural hydrocolloid polymer b) is chosen from the group of hyaluronic acid and its derivatives.

7. The pad according to claim 1, wherein it comprises at least one auxiliary substance selected from cosmetic oils.

8. A kit-of-parts combination comprising at least one pad according to claim 1 and at least one aqueous solution which contains one or more active compounds and/or optionally one or more auxiliary substances, with the pad and the aqueous solution being arranged in a combined spatial arrangement.

9. The pad according to claim 5, wherein the polysaccharide is chosen from the group of alginates, carrageen, pectins, pullulan, tragacanth, guar gum, carob bean flour, agar-agar, gum arabic, xanthan, natural and modified starches, dextrans, dextrin, maltodextrins, chitosan, glucans, mucopolysaccharides.

10. The pad according to claim 1, which has a thickness of 0.5 to 20 mm.

11. A pad for topical application consisting of a mechanically stable, cohesive, freeze-dried composition consisting of a) one hydrocolloid polymer, wherein the hydrocolloid polymer is a polyacrylate, synthetic acrylic polymer or thereof, in the amount of at least 5 percent by weight of the total composition, b) at least one natural polymer, wherein the natural polymer is an anionic natural hydrocolloid, in the amount of at least 25 percent by weight of the total composition, c) one or more active compounds and/or auxiliary substances, wherein at least one auxiliary substance is caprylic/caproic acid, jojoba oil or squalane, and d) at least two further natural polymers which differ from a) and b); wherein the at least one of the at least two further natural polymers is carrageenan, a carrageenan derivative, hyaluronic acid, a hyaluronic acid derivative, collagen, or a collagen derivative, and wherein a solution or suspension of the freeze-dried composition comprising components (a), (b), (c) and (d) in the amount of 1 percent by weight of the total weight of the solution or suspension in water at 20° C. has a pH of from 3.0 to 6.5.

12. The pad according to claim 11, wherein the anionic natural hydrocolloid b) is selected from the group of glucosaminoglycans, hyaluronic acid and its derivatives.

13. The pad according to claim 1, wherein the pad does not comprise cellulose.

14. The pad according to claim 11, wherein the pad does not comprise cellulose.

Description

EXAMPLES

Example 1

(1) TABLE-US-00001 10.5 g sodium carboxymethylcellulose (CMC) 10.5 g sodium alginate 7.5 g carbomer 1,500 ml RO water

(2) a) Preparation of the Carbomer Premix

(3) 7.5 g of carbomer are dissolved in 750 ml of RO water according to the manufacturer's instructions.

(4) b) Preparation of the Alginate/CMC Premix

(5) 10.5 g of carboxymethylcellulose and 10.5 g of sodium alginate are dissolved homogeneously in 750 ml of RO water while stirring, until no further undissolved alginate/CMC particles are visible.

(6) c) Preparation of the Entire Batch

(7) The carbomer premix from step a) is combined with the alginate/CMC premix from step b) by stirring until a homogeneous mixture is formed. The pH of the combined mixture is adjusted to a pH of 5.0-5.5 with dilute potassium hydroxide solution.

(8) d) Freezing

(9) The alginate/CMC/carbomer batch prepared in c) is frozen either by blowing cold air on to it or by application to a cold plate at temperatures of <−20° C.

(10) e) Freeze Drying

(11) The freeze drying of the frozen shaped body produced under d) is carried out in accordance with the prior art by generally known freeze drying processes.

(12) f) Dividing and Assembling

(13) The freeze-dried composition is cut into thin layers with a layer thickness of 0.5 mm. The layers are optically dense and the material can be wetted completely in less than 10 seconds.

Example 2

(14) TABLE-US-00002 7.5 g sodium carboxymethylcellulose (CMC) 4.5 g carrageenan 4.5 g carbomer 4.5 g fish collagen hydrolysate 4.5 g hyaluronic acid 3.0 g sodium alginate 7.5 g calcium alginate 15.0 g mannitol 1,500 ml RO water

(15) a) Preparation of the Carbomer Premix

(16) 4.5 g of carbomer are dissolved in 500 ml of RO water according to the manufacturer's instructions.

(17) b) Preparation of the Alginate/CMC/Hyaluronic Acid/Mannitol/Fish Collagen Hydrolysate Premix

(18) The remaining substances are dissolved hot in 1,000 ml of RO water, until undissolved substances are no longer detectable. The solution is then allowed to cool to room temperature.

(19) c) Preparation of the Entire Batch

(20) The carbomer premix from step a) is combined with the premix from step b) by stirring until a homogeneous mixture is formed. The pH of the combined mixture is adjusted to a pH of 5.0-5.5 with dilute potassium hydroxide solution.

(21) d) Freezing

(22) The batch prepared in c) is frozen either by blowing cold air on to it or by application to a cold plate at temperatures of <−20° C.

(23) e) Freeze Drying

(24) The freeze drying of the frozen shaped body produced under d) is carried out in accordance with the prior art by generally known freeze drying processes.

(25) f) Dividing and Assembling

(26) The freeze-dried composition is cut into thin layers with a layer thickness of 1.5 mm. The layers are optically dense and the material can be wetted completely in less than 10 seconds.

Example 3

(27) TABLE-US-00003 7.5 g sodium alginate 4.5 g carrageenan 11.25 g carbomer 1,500 ml RO water

(28) a) Preparation of the Carbomer Premix

(29) 11.25 g of carbomer are dissolved in 750 ml of RO water according to the manufacturer's instructions.

(30) b) Preparation of the Alginate/Carrageenan Premix

(31) 7.5 g of Na alginate and 4.5 g of carrageenan are dissolved homogeneously in 750 ml of hot RO water while stirring, until no further undissolved particles are visible.

(32) c) Preparation of the Entire Batch

(33) The carbomer premix from step a) is combined with the alginate/carrageenan premix from step b) by stirring until a homogeneous mixture is formed. The pH of the combined mixture is adjusted to a pH of 5.0 with dilute potassium hydroxide solution.

(34) d) Freezing

(35) The alginate/carrageenan/carbomer batch prepared in c) is frozen either by blowing cold air on to it or by application to a cold plate at temperatures of <−20° C.

(36) e) Freeze Drying

(37) The freeze drying of the frozen shaped body produced under d) is carried out in accordance with the prior art by generally known freeze drying processes.

(38) f) Dividing and Assembling

(39) The freeze-dried composition is out into thin layers with a layer thickness of 2.0 mm. The layers are optically dense and the material can be wetted completely in >30 seconds.

Example 4

(40) TABLE-US-00004 10.5 g sodium carboxymethylcellulose (CMC) 10.5 g sodium alginate 7.5 g carbomer 1.5 g hyaluronic acid 1,500 ml RO water

(41) a) Preparation of the Carbomer Premix

(42) 7.5 g of carbomer are dissolved in 750 ml of RO water according to the manufacturer's instructions.

(43) b) Preparation of the Alginate/Hyaluronic Acid/CMC Premix

(44) 10.5 g of carboxymethylcellulose, 1.5 g of hyaluronic acid and 10.5 g of sodium alginate are dissolved homogeneously in 750 ml of RO water while stirring, until no further undissolved alginate/hyaluronic acid/CMC particles are visible.

(45) c) Preparation of the Entire Batch

(46) The carbomer premix from step a) is combined with the alginate/hyaluronic acid/CMC premix from step b) by stirring until a homogeneous mixture is formed. The pH of the combined mixture is adjusted to a pH of 5.0-5.5 with dilute potassium hydroxide solution.

(47) d) Freezing

(48) The alginate/hyaluronic acid/CMC/carbomer batch prepared in c) is frozen either by blowing cold air on to it or by application to a cold plate at temperatures of <−20° C.

(49) e) Freeze Drying

(50) The freeze drying of the frozen shaped body produced under d) is carried out in accordance with the prior art by generally known freeze drying processes.

(51) f) Dividing and Assembling

(52) The freeze-dried composition is out into thin layers with a layer thickness of 0.5 mm. The layers are optically dense and the material can be wetted completely in less than 5 seconds.

Example 5

(53) TABLE-US-00005 3.0 g sodium carboxymethylcellulose (CMC) 4.5 g carrageenan 4.5 g carbomer 4.5 g fish collagen hydrolysate 1.5 g hyaluronic acid 7.5 g sodium alginate 1,500 ml RO water

(54) a) Preparation of the Carbomer Premix

(55) 4.5 g of carbomer are dissolved in 500 ml of RO water according to the manufacturer's instructions.

(56) b) Preparation of the Alginate/CMC/Carrageen/Hyaluronic Acid/Fish Collagen Hydrolysate Premix

(57) The remaining substances are dissolved hot in 1,000 ml of RO water, until undissolved substances are no longer detectable. The solution is then allowed to cool to room temperature.

(58) c) Preparation of the Entire Batch

(59) The carbomer premix from step a) is combined with the premix from step b) by stirring until a homogeneous mixture is formed. The pH of the combined mixture is adjusted to a pH of 5.0-5.5 with dilute potassium hydroxide solution.

(60) d) Freezing

(61) The batch prepared in c) is frozen either by blowing cold air on to it or by application to a cold plate at temperatures of <−20° C.

(62) e) Freeze Drying

(63) The freeze drying of the frozen shaped body produced under d) is carried out in accordance with the prior an by generally known freeze drying processes.

(64) f) Dividing and Assembling

(65) The freeze-dried composition is cut into thin layers with a layer thickness of 1.5 mm. The layers are optically dense and the material can be wetted completely in less than 1 second.

Example 6

(66) TABLE-US-00006 11.25 g sodium alginate 4.5 g carrageenan 11.25 g carbomer 1.5 g hyaluronic acid 7.5 g sodium carboxymethylcellulose (CMC) 7.5 g mannitol 1,500 ml RO water

(67) a) Preparation of the Carbomer Premix

(68) 11.25 g of carbomer are dissolved in 750 ml of RO water according to the manufacturer's instructions.

(69) b) Preparation of the Alginate/Hyaluronic Acid/Carrageenan/CMC/Mannitol Premix

(70) The remaining substances are dissolved in 750 ml of hot RO water, until no further undissolved particles are visible. The solution is then allowed to cool to room temperature.

(71) c) Preparation of the Entire Batch

(72) The carbomer premix from step a) is combined with the alginate/hyaluronic acid/carrageenan/CMC mannitol premix from step b) by stirring until a homogeneous mixture is formed. The pH of the combined mixture is adjusted to a pH of 5.0 with dilute potassium hydroxide solution.

(73) d) Freezing

(74) The batch prepared in c) is frozen either by blowing cold air on to it or by application to a cold plate at temperatures of <−20° C.

(75) e) Freeze Drying

(76) The freeze drying of the frozen shaped body produced under d) is carried out in accordance with the prior art by generally known freeze drying processes.

(77) f) Dividing and Assembling

(78) The freeze-dried composition is cut into thin layers with a layer thickness of 2.0 mm. The layers are optically dense and the material can be wetted completely in less than 1 second.

Example 7

(79) TABLE-US-00007 7.5 g sodium carboxymethylcellulose (CMC) 4.5 g carrageenan 11.25 g carbomer 1.5 g hyaluronic acid 11.25 g sodium alginate 7.5 g mannitol 1.5 g jojoba oil 0.75 g magnesium ascorbyl phosphate 1,500 ml RO water

(80) a) Preparation of the Carbomer Premix

(81) 11.25 g of carbomer are dissolved in 700 ml of RO water according to the manufacturer's instructions.

(82) b) Preparation of the Alginate/Hyaluronic Acid/Carrageenan/CMC/Mannitol/Jojoba Oil Premix

(83) The remaining substances, apart from the jojoba oil and the magnesium ascorbyl phosphate, are dissolved in 750 ml of hot RO water, until no further undissolved particles are visible. The solution is then allowed to cool to room temperature. The jojoba oil is then mixed in.

(84) c) Preparation of the Magnesium Ascorbyl Phosphate Premix

(85) The 0.75 g of magnesium ascorbyl phosphate are dissolved in 50 ml of RO water until no further undissolved particles are visible.

(86) d) Preparation of the Entire Batch

(87) The carbomer premix from step a) is combined with the alginate/hyaluronic acid/carrageenan/CMC mannitol/jojoba oil premix from step b) by stirring until a homogeneous mixture is formed. The active compound solution from step c) is likewise mixed in homogeneously by stirring. The pH of the combined mixture is then adjusted to a pH of 5.0 with dilute potassium hydroxide solution.

(88) e) Freezing

(89) The batch prepared in d) is frozen either by blowing cold air on to it or by application to a cold plate at temperatures of <−20° C.

(90) f) Freeze Drying

(91) The freeze drying of the frozen shaped body produced under e) is carried out in accordance with the prior art by generally known freeze drying processes.

(92) g) Dividing and Assembling

(93) The freeze-dried composition is cut into thin layers with a layer thickness of 2.0 mm. The layers are optically dense and the material can be wetted completely in less than 1 second.

Example 8

(94) The influence of the structure-forming polymers and various possible combinations thereof in freeze-dried sheet-like compositions in the context of the present invention was investigated with the aid of the speed of wetting and the liquid retention capacity.

(95) In this context, the investigations were conducted on compositions which comprise only one of the structure-forming polymers carbomer, alginate, hyaluronic acid or carrageen, compositions with a combination of two of these structure-forming polymers, such as e.g. are also known from the prior art, and the compositions which are preferred according to the invention, which comprise a combination of the three structure-forming polymers carbomer, alginate and hyaluronic acid. A further preferred composition which furthermore comprises carrageen in addition to these three polymers was moreover investigated.

(96) For this, if possible according to the preparation, the speed of wetting and the liquid retention capacity was determined with the mass swelling index Q.sub.M and the volume of liquid held per gram of composition. The experiments were carried out by the methods described above under the experimental conditions stated there.

(97) All the experiments were carried out both with water and with a physiological saline solution (0.9% strength NaCl solution).

(98) The results are summarized in the following tables, with the following meanings for the notes: at a high DM (dry matter) too viscous or gelling at <40° C. not pumpable, at a low DM unstable in the frozen state mechanically not stable to cutting; this can mean either that the structure of the matrix is too open-pored and crumbles during cutting, or that from the beginning no cohesive cuttable matrix exists, but only fibres laid loosely on one another which are squashed by the blade during cutting and are not cut. expensive
Speed of Wetting:
Compositions with One Structure-Forming Polymer

(99) TABLE-US-00008 Speed of wetting Speed of wetting Example Polymer Processability in water in 0.9% strength NaCl soln. carbomer cannot be cannot be measured cannot be measured prepared (*/**) alginate cannot be cannot be measured cannot be measured prepared (**) hyaluronic acid cannot be cannot be measured cannot be measured prepared (**/***) carrageenan cannot be cannot be measured cannot be measured prepared (*/**)
Compositions with Two Structure-Forming Polymers

(100) TABLE-US-00009 Speed of wetting Speed of wetting Example Polymers Processability in water in 0.9% strength NaCl soln. prior art carbomer + poor disintegrates into small disintegrates into small alginate (**) pieces pieces prior art carbomer + cannot be cannot be measured cannot be measured hyaluronic acid prepared (*/**/***) carbomer + cannot be cannot be measured cannot be measured carrageenan prepared (*) alginate + cannot be cannot be measured cannot be measured hyaluronic acid prepared (**) alginate + cannot be cannot be measured cannot be measured carrageenan prepared (**) hyaluronic acid + cannot be cannot be measured cannot be measured carrageenan prepared (*/***)
Compositions with at Least Three Structure-Forming Polymers

(101) TABLE-US-00010 Speed of wetting Speed of wetting Example Polymers Processability in water in 0.9% strength NaCl soln. 4 carbomer + good  <5 seconds  <5 seconds alginate + hyaluronic acid 3 carbomer + good >30 seconds >30 seconds alginate + carrageenan carbomer + good >10 seconds >10 seconds hyaluronic acid + carrageenan alginate + good >60 seconds >60 seconds hyaluronic acid + carrageenan 5, 6, 7 carbomer + good ≦1 second.sup.  ≦1 second.sup.  alginate + hyaluronic acid + carrageenan
Liquid Uptake/Retention Capacity:

(102) Experiments on the liquid uptake or retention capacity were carried out with compositions which comprise at least three structure-forming polymers, the results of which are as shown below:

(103) TABLE-US-00011 Ø Ø Q.sub.M 0.9% in 0.9% Ø strength Ø strength water NaCl Q.sub.M in NaCl Ø Example Polymers ml/g soln. ml/g water soln. ΔQ.sub.M 4 carbomer + 35 33 36 34 2 alginate + hyaluronic acid 3 carbomer + 48 30 49 31 18 alginate + carrageenan carbomer + 61 28 62 29 33 hyaluronic acid + carrageenan alginate + 23 19 24 20 4 hyaluronic acid + carrageenan 5, 6, 7 carbomer + 35 28 36 29 7 alginate + hyaluronic acid + carrageenan

(104) It was found during the preparation of the various matrices that compositions which comprised only one polymer either could not be processed in the liquid/viscous state, or were not able to show a sufficient mechanical stability in the freeze-dried state for preparation of cut sheets or pads.

(105) Similar problems during preparation were found from the group of compositions with a combination of two polymers. It was indeed possible to obtain sheet-like compositions here with a carbomer/alginate combination, but these likewise showed a decidedly poor mechanical stability in the application or in contact with liquid, in that they disintegrated into small pieces.

(106) Mechanically stable, sheet-like materials were to be obtained only from compositions with a combination of at least three of the structure-forming polymers.

(107) Clear differences were found with respect to the wetting and liquid retention properties of these materials.

(108) Exclusively compositions which comprise a combination of carbomer, alginate and hyaluronic acid have sufficiently high speeds of wetting. For the other possible combinations, it was indeed possible now to obtain mechanically stable compositions, but these showed clearly disadvantageous speeds of wetting of from >10 to >60 seconds and therefore extremely poor liquid uptake properties.

(109) It was furthermore found that the decidedly good wetting and the liquid uptake properties of compositions with carbomer, alginate and hyaluronic acid can be improved still further by the addition of carrageen.

(110) In this context, however, the experiments also show that the nature of the alginate used has an influence on the wetting properties. A comparison of Example 2, in which carbomer and hyaluronic acid were combined with sodium alginate and calcium alginate, with Example 5, in which a comparable composition exclusively with sodium alginate is shown, illustrates this influence. Ca ions are known to have alginate-crosslinking properties, which is reflected in a disadvantageous manner in the wetting or dissolving of the compositions. Thus, compositions according to Example 2 have higher speeds of wetting, with <10 seconds, than those according to Example 5, which contain no Ca alginate and have a speed of wetting of <1 second.

(111) It thus emerges from this that only compositions which comprise a combination of carbomer, alginate, particularly preferably sodium alginate, and hyaluronic acid achieve the speeds of wetting which are preferred according to the invention, of <10, more preferably of <5, still more preferably <1 second.

(112) The results furthermore show that compositions which comprise a combination of carbomer, alginate and hyaluronic acid have a better capacity for storage of physiological fluids. In particular, it was found in this context that the liquid retention capacity of compositions with carbomer, alginate and hyaluronic acid was consistently good and could be kept stable in the comparison of the storage of pure water to the storage of physiological fluids, which is clear in particular from the significantly lower decrease in the mass swelling index (ΔQ.sub.M) in the comparison of these values. A similarly stable liquid retention capacity was shown only by compositions of alginate, hyaluronic acid and carrageen (without carbomer), such compositions also showing the poorest absolute liquid retention capacity, in addition to an extremely poor speed of wetting.

(113) Summarizing, it can be said that among the polymer combinations investigated, only the compositions which comprise a combination of carbomer, alginate and hyaluronic acid have the combination desired according to the invention of very good liquid uptake and speed of wetting of <10 seconds and a high liquid retention capacity which is also stable in electrolyte-containing liquids.