HK1090940B - Method for producing porous moulded bodies containing alginate - Google Patents

Description

Method for producing porous molded bodies containing alginate

Background

The invention relates to a method for producing porous and/or sponge-like molded bodies containing alginate, and to the molded bodies obtained thereby and to the use thereof.

It is known that alkali metal alginates, such as sodium alginate, are water soluble, whereas alkaline earth metal alginates, such as calcium alginate, are in contrast water insoluble. Thus, the water-insoluble layer may be formed, for example, by using CaCl₂Spraying sodium alginate film to obtain the final product. But conversely if thicker layers are to be produced, difficulties arise for the following reasons: free calcium ions are difficult to incorporate uniformly into the sodium alginate solution due to the large increase in solution viscosity, which results in discrete calcium alginate agglomerates rather than a uniform product.

To overcome this problem, for example US5,718,916 proposes adding a water soluble complexing agent such as sodium citrate to an aqueous solution of a water soluble alginate composition. If, for example, a readily soluble calcium salt such as calcium chloride is subsequently added, immediate precipitation of the calcium alginate is prevented by the presence of the complexing agent, whereby the formation of insoluble calcium alginate globules in the product should be avoided. But the examples of the US patent specification are based on the order of a few millilitres. The gelling time of the alginate solution after the addition of calcium chloride only lasts 30 to 60 seconds. If one tries to convert the process to a larger scale, it is clear that the delay effect expected by adding the complexing agent to the sodium alginate solution is not sufficient and that a relatively large-sized product with a high degree of homogeneity cannot be obtained. In addition, surfactants must be used in the above process to achieve sufficient dispersion of the components. The use of these surfactants, however, can lead to intolerance when applied to the skin. The fact that the process of US5,718,916 does not achieve a sufficient precipitation retarding effect by the prior addition of complexing agents was additionally confirmed by the same inventors in GB2357765, wherein the process of US5,718,916 was therefore described as disadvantageous. GB2357765 discloses a method for producing water-insoluble alginate sponges or foam products for the production of wound plasters or surgical products, wherein water-soluble alginates are additionally crosslinked by addition of polyvalent metal ions in the presence of a foam-generating agent. The complexing agent is intentionally absent. In a preferred variant, ammonium hydroxide is present to reduce the viscosity of the calcium alginate. In the examples, calcium sulfate is added, for example, followed by the addition of the acid. The process also has the following disadvantages: the formation of alginate crosslinked with calcium ions proceeds relatively quickly after the acid has been added, so that a uniformly thick layer cannot be obtained. In addition, the process requires the presence of a foaming agent, a surfactant, a borate buffer, and the above-mentioned ammonium compounds. This makes the process difficult to control and the resulting product contains a variety of components that must be considered for their physiological effects.

In DE20219666U1, a pad for dermatological applications is described, which comprises a carrier material based on polymers, in particular on alginic acid. Specific examples relating to the manufacture of these mats cannot be obtained from this utility model.

Furthermore, DE4328329 discloses freeze-dried biomatrix for moisturizing the skin and for topical transdermal administration of cosmeceutical active substances comprising natural polysaccharides and modified polysaccharides. This document also already mentions the stabilization of biological matrices by the addition of calcium ions to form a calcium alginate backbone. From this printed publication it is not known how to make a uniform thicker alginate layer.

A method for manufacturing small size alginate sponges for oral use by adding a soluble calcium salt (calcium gluconate) to a sodium alginate solution is described in WO 01/17377. However, for the reasons already mentioned above (without uniform introduction of calcium ions), this process is not yet suitable for the manufacture of large-size alginate sponges. Furthermore, the use of the active substances proposed therein is also difficult to carry out due to the occurrence of inhomogeneities.

A process for forming polysaccharide foams, in particular based on alginate, is known from WO 94/00512. In one embodiment, the patent specification also discloses a variant in which insoluble polyvalent metal cation carbonates or bicarbonates are dispersed in the foamed polysaccharide and the foam is subsequently treated with a strong acid to release carbon dioxide and the polysaccharide is crosslinked by the formed cations under conditions to form a dimensionally stable foam structure. According to this printed publication, foams having a thickness of up to 5mm can be stabilized in this manner. However, these thicknesses are not sufficient, in particular when it is desired to subsequently cut the foam moldings into thinner layers. In addition, the gas formed during the manufacturing process causes difficulty in controlling the size of the cells and causes great unevenness of the foam.

Another method for manufacturing alginate sponges is known from US3,653,383. Here, calcium alginate is first made from alginic acid and calcium carbonate, the calcium alginate formed is subsequently comminuted, and the gel obtained is freeze-dried. Relatively large sized sponge-like materials can be made in this manner, but the resulting product disintegrates relatively rapidly in water. Therefore, alginate sponges have insufficient wet strength, especially wet breaking strength, for cosmetic or medical pads, especially when cut into thin layers.

The object of the present invention was therefore to provide relatively large-sized, highly homogeneous mouldings based on alginate and on compounds of polyvalent metal ions, which have a high degree of wet strength, in particular wet break strength, and which can be cut into thin layers using customary cutting equipment, which have an attractive appearance, i.e. in particular a high degree of whiteness, and which can therefore be used in cosmetic or medical applications, for example as cosmetic skin pads or medical plasters and the like. In addition, it should be possible to provide a uniform thick layer of the salt of alginic acid, from which suitable cosmetic or medical application forms, which can also be administered orally, such as implant mouldings, satiated compacts (S) can be produced in a simple manner by compression and/or stampingttiggung-kompirimate), devices for the controlled, in particular delayed, release of active substances or the like.

The inventors of the present patent application have surprisingly succeeded in providing homogeneous, thick, large-sized moldings based on alginates of polyvalent metal salts, which are obtainable by a special process which is also the subject of the present invention, solve the above-mentioned problems of the moldings of the prior art and are therefore very suitable for the production of cosmetic or medical products.

Detailed description of the invention

The present patent application thus provides a process for the production of alginate-containing porous molded bodies, comprising the steps of:

a) an aqueous solution of a water-soluble alginate is prepared,

b1) adding one or more salts of a polyvalent metal ion and a multidentate coordinating anion to an aqueous solution of a water-soluble alginate and moving the complex of the polyvalent metal ion and the multidentate coordinating anion into equilibrium while increasing the available concentration of the polyvalent metal ion in the alginate solution, and thereby forming a salt of the alginate with the above-mentioned polyvalent metal ion,

or

b2) Adding a polydentate complexing agent for polyvalent metal ions to an aqueous solution of a water-soluble alginate and mixing one or more sparingly water-soluble salts of the polyvalent metal ions,

c) pouring the (still) flowable aqueous alginate composition into a mould,

d) drying the aqueous alginate composition while forming porous molded bodies comprising alginate.

Step a)

The water soluble alginates used in step a) are preferably alkali metal alginates such as sodium alginate, potassium alginate and the like.

The basic alginic acid is a natural acidic polysaccharide extracted mainly from so-called brown seaweeds (Phaecophyceae) having a high molecular weight fluctuating between about 30000 and 200000 daltons, the polysaccharide comprising a chain formed by D-mannuronic acid and L-guluronic acid. The degree of polymerization varies depending on the kind of seaweed used for extraction, the season in which the seaweed is collected, the geographical origin of the seaweed, and the age of the plant. The main classes of brown seaweeds used to obtain alginic acid are, for example, kelp, cleustoni, hyperborea, kelp flexicaulis, kelp palmata, ascophyllunosum and fucus serrata. However, alginic acid or alkali metal alginates can also be produced, for example, by mutagenesis with Pseudomonas aeruginosa (Pseudomonas aeruginosa) or Pseudomonas putida (Pseudomonas putida), Pseudomonas fluorescens (Pseudomonas fluorescens) or Pseudomonas mendocina (Pseudomonas mendocica)Are obtained microbially (see, for example, EP-A-251905 and Rmpp Chemie Lexikon "Naturstoffe" Thieme Verlag, 1997 and the documents cited therein).

According to the invention, the alginates preferably have an average particle size of up to about 0.2mm and a viscosity in aqueous solution (1% solution, pH7, 20 ℃, 300 to 800 mPas).

According to the invention, sodium alginate is particularly preferred.

The aqueous solution of water-soluble alginate used in step a) preferably has a concentration such that in the aqueous suspension formed according to step b) an alginate concentration of from 0.2 to 3% by weight, more preferably from 0.3 to 2.5% by weight, and even more preferably from 0.4 to 1.2% by weight, based on the amount of water used, is formed. The solution may be made by suspending the required amount of alginate in, for example, distilled water. The concentration of alginate in the aqueous suspension influences the hardness of the porous moulded bodies formed. Concentrations of more than 2% by weight lead to relatively hard and brittle mouldings, which are less preferred. Concentrations of less than 2% by weight lead to less brittle mouldings, which are more preferred.

Step b1)

In step b1), one or more salts of polyvalent metal ions with multidentate coordinating anions are added to the aqueous solution of the water-soluble alginate obtained in step a).

Suitable polyvalent metal ions are those which form poorly soluble compounds with the alginates used, i.e. metal ions which act as crosslinking metal ions.

These polyvalent metal ions include, for example, alkaline earth metal ions and transition metal ions, which form sparingly soluble compounds with alginates. Alkaline earth metal ions, such as beryllium, magnesium or calcium, are preferred. Calcium is particularly preferred. Beryllium and magnesium are less preferred because above all from a cosmetic point of view they are not acceptable and magnesium has a low crosslinking effect. Calcium salts are therefore particularly preferred according to the invention since they are physiologically, especially cosmetically, acceptable and have a strong crosslinking and/or gelling action on alginates. In addition, barium, strontium, zinc, manganese, iron, aluminum, and the like may also be used.

According to the present invention, the multidentate coordinating anion in the complex salt of a polyvalent metal ion is preferably a carboxylate salt of a polycarboxylic acid. Carboxylates of aliphatic dicarboxylic to tetracarboxylic acids, such as, for example, citric acid (2-hydroxy-1, 2, 3-propanetricarboxylic acid), malic acid, oxalic acid, 1, 3-propanedicarboxylic acid, agaricic acid, ethylenediaminetetraacetic acid (EDTA), 1, 2, 3-propanetricarboxylic acid, and the like, are preferred.

Physiologically tolerable, in particular dermally tolerable, polycarboxylic acids are particularly preferred. Mention may in particular be made here of the carboxylic acid salts of alpha-hydroxypolycarboxylic acids, such as citric acid.

Citrate, malate and EDTA anions are particularly preferred multidentate coordinating anions. Citrate ions are most preferred.

According to the invention, calcium citrate { stoichiometry: ca₃Citrate 2) is a particularly preferred complex salt of a polyvalent metal ion with a multidentate coordinating anion to be added in step 1 b).

The addition of the complex salt of a polyvalent metal ion with a multidentate coordinating anion in step b1) can be carried out by mixing in solid or dissolved form.

The complex salt is suitably added to the alginate solution at a temperature of from 5 to 80 ℃, but preferably at room temperature (20 ℃).

The amount of complex salt added in step b1) is suitably chosen such that the concentration of complex salt in the resulting solution reaches about 0.1 to 500 mmol/l.

The amount of complex salt added in solution (based on the amount of alginate) is preferably chosen such that the molar ratio of complex salt to alginate is between about 0.001 and 0.1.

After addition of the complex salt, the complex formation equilibrium of the polyvalent metal ion and the multidentate coordinating anion in the aqueous solution of the alginate shifts:

[ Metal ion (in water)]x + + [ coordinating anion]x-[ Complex Compounds ]]Of course, given the appropriate stoichiometry, the metal ion and coordinating anion can have unequal charges, such as in a calcium citrate system.

This equilibrium is usually described by the so-called complex formation constant:

wherein [ Me⁺]、[A^-]And [ complexes]Respectively the concentration (activity) of the polyvalent metal ion, the coordinating multidentate anion and the complex in the solution. The complex formation constant is the inverse of the dissociation constant.

The complex formation constant gives information about the stability of the complex in the corresponding chemical environment and is therefore also referred to as the stability constant of the complex. The larger the value of this constant, the more stable the complex.

The shift of the above-mentioned equilibrium in step b1) is carried out according to the invention, for example, by reducing the concentration of the coordinating anion in the solution. The concentration of uncomplexed polyvalent metal ions in the solution is therefore increased according to the equilibrium constant. Since the equilibrium constant depends in particular on the temperature, an even shift can also be effected, for example, by changing, in particular increasing, the temperature. In addition, it is possible to add another metal salt, which affects the complex anion/free anion equilibrium reaction, but does not form insoluble alginates.

However, the equilibrium shift is preferably effected by reducing the concentration of the free coordinating anion in solution, particularly preferably by adding at least one acid:

preferably, the acid added is a stronger acid than the conjugate acid of the coordinating anion, and is therefore capable of protonating it. However, it is also possible to add the conjugate acid itself, such as citric acid (in the case of citrate as the anion). Because of polyvalent cations such as Ca²⁺The citrate salt resulting from salt dissociation is formed in the form of citrate 3-, which is protonated in aqueous solution by the addition of citric acid, while forming the hydrogen citrate salt, and thus leaves the complex forming equilibrium.

For example:

preferred acids are, for example, inorganic mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid or aliphatic carboxylic acids, such as acetic acid, etc.

The amount of acid added depends on the complex salt used and its complex formation constant in aqueous solution. For example, it may be up to 0.1 to 20 times the concentration of the complex salt (mol/mol). In particular, the molar ratio of calcium citrate to acid, such as citric acid, is preferably from 0.1 to 20, more preferably from 0.5 to 10.

Typically, the pH adjusted to below about 6.0 is sufficient to shift the complex formation constant such that the concentration of the multivalent metal salt is increased sufficiently to exceed the solubility product of the alginate, i.e., the insoluble alginate of the multivalent metal salt precipitates or the solution gels.

It has surprisingly been found that the pH value adjusted in this step influences the breaking strength of the resulting porous molded body. In order to obtain a higher breaking strength, a pH value below 6 is preferred, more preferably below 5. These low pH values are particularly preferably combined with a low alginate concentration of less than 2% by weight in the total suspension, which is adjusted in step b).

The rate at which insoluble alginate is formed, and hence the ability of the alginate solution or suspension to flow or pour, can be very precisely and easily controlled by the amount and rate of addition of the acid, and optionally by temperature control, especially due to the high diffusion rate of protons in aqueous solution. This gives homogeneous mouldings having a relatively large thickness of at least about 1cm after drying, a sufficiently high wet strength, in particular wet break strength, so that they can be used as cosmetic or medical sponge-like wet strength material, if desired after subsequent cutting into relatively thin layers or compression and/or perforation, as described below.

Step b2)

In a further embodiment of the process according to the invention (step b2)), the further delay in the formation of insoluble alginate salts in the alginate solution compared to the prior art contributes to a more uniform incorporation of the polyvalent metal salts in the alginate solution and thus to the uniform quality of the porous molded body, not by adding to the alginate solution of step a) soluble salts of polyvalent metal ions which form sparingly soluble salts with alginate (such as calcium chloride), as in the prior art, but by adding sparingly soluble salts of these polyvalent metal salts, such as CaSO₄And then the process is carried out.

First, the multidentate complexing agent for polyvalent metal ions is added to the aqueous solution of water-soluble alginate in step b 2). Of course, the multidentate complexing agent is added in the form of an ionic compound or as a covalent compound, e.g., in the form of a conjugate acid. The polydentate complexing agent may be added to the solution of alginate in solid or dissolved form. In principle, the complexing agent can be either a salt of a polyvalent metal ion which forms a sparingly soluble alginate or a salt of a monovalent or polyvalent metal ion which does not form a sparingly soluble compound with alginate. Mixtures of these metal salts may also be used. Salts of monovalent or polyvalent metal ions that do not form sparingly soluble compounds with alginates (e.g., sodium citrate, or the conjugate acids thereof such as citric acid) are preferred because the retarding effect of the multidentate anion on the formation of free polyvalent metal ions that are available for the formation of sparingly soluble alginates is more pronounced. In principle, however, it is also possible to add salts of polyvalent metal ions with multidentate coordinating anions, such as calcium citrate, as are used in step b 1).

In this and other variations, an acid is also added after or during the mixing of the sparingly soluble metal salt of a polyvalent metal ion, such as calcium sulfate, as needed to increase the concentration of free metal ions that form sparingly soluble compounds with the alginate and to accelerate uniform crosslinking of the alginate. Preferred acids are, for example, inorganic mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid or aliphatic carboxylic acids, such as acetic acid and the like. Hydrochloric acid is particularly preferred.

It can also be seen in the variant of step b2) that the pH value set influences the breaking strength of the porous molded bodies obtained. Therefore, in order to obtain a higher breaking strength, a pH value of less than 6 is likewise preferred in step b2), more preferably less than 5. Likewise, these low pH values are particularly preferably combined with a low alginate concentration of less than 2% by weight in the total suspension, which is adjusted in step b 2). The pH value can in principle also be adjusted by adding an acid, such as HCl, to the alginate solution or to the alginate solution crosslinked with a complexing agent, such as citric acid or sodium citrate, and subsequently adding a sparingly soluble metal salt, such as CaSO₄And then the process is carried out.

The polydentate complexing agent for polyvalent metal ions is added in a concentration of about 0.0001 to 1 mol/liter, preferably 0.001 to 0.5 mol/liter. The molar ratio of the amount of the water-soluble alginate to the added molar amount of the polydentate complexing agent for polyvalent metal ions is preferably 0.0001 to 1, more preferably 0.001 to 0.5.

The polyvalent metal ions added in the form of their sparingly soluble salts in the second addition step of step b2) are those metal ions which crosslink the alginate with or form a sparingly soluble salt, in this connection reference is made to the salts in "step b 1)". In principle, the corresponding anions can be chosen arbitrarily, but they must form sparingly soluble salts with polyvalent metal ions or cations in water. Here again, calcium salts, in particular calcium sulfate, are preferred. CaCO₃E.g. other carbonates are alsoIs less preferred because of CO₂Can be formed under the preferably acidic conditions of the preparation of sparingly soluble alginates, which makes it more difficult to control the reaction or quality of the alginate-containing porous mouldings.

The solubility in water of the less water-soluble salt of a polyvalent metal ion added in step b2) at 20 ℃ is preferably less than 10 g/l, more preferably 5 g/l, further preferably 0.1 to 3 g/l. If the solubility is higher, sparingly soluble alginates can be formed more rapidly, leading to a reduction in possible processing times and thus to inhomogeneous products. If the solubility is below the above range, the formation of poorly soluble or cross-linked alginates may be too slow, which is also disadvantageous.

By mixing other salts, especially those that do not form sparingly soluble alginates, such as sodium sulfate, sodium chloride, etc., the solubility of the sparingly soluble salts of polyvalent metal ions in water can be further reduced, thus further improving processability or homogeneity.

The amount of the sparingly soluble salt of the polyvalent metal ion is suitably selected so that the concentration of the salt in the resulting solution amounts to about 0.1 to 500 mmol/l, where in this case the total amount of salt is referred to relative to the entire solution volume, even if the salt is not completely dissolved.

The amount of the sparingly soluble salt of the polyvalent metal ion to be added is preferably selected so that the molar ratio of alginate to sparingly soluble salt of the polyvalent metal ion is from 0.001 to 1, based on the amount of soluble alginate in the solution.

The amount of the sparingly soluble salt of a polyvalent metal ion to be added is preferably selected so that the molar ratio of the sparingly soluble salt of a polyvalent metal ion to the multidentate complexing agent is 0.1 to 10, based on the amount of the multidentate complexing agent.

According to the two process variants b1) and b2), the formation of sparingly soluble alginates is suitably controlled so that the increase in concentration of uncomplexed divalent metal ions is small, so that the flowability of the alginate solution expressed as the viscosity at room temperature (20 ℃) of less than about 1000mPas is maintained for at least about 1 minute, preferably about 2 minutes, more preferably about 3 minutes.

The formation or mixing of the alginate gel according to steps b1) and b2), respectively, is preferably carried out in a mixer with a stator/rotor system, such as a colloid mill.

Step c)

The (still) flowable alginate composition may be poured in a known manner into the desired mould for subsequent drying. The layer thickness of the flowable alginate composition can be up to about 50 cm. The preferred shape is a box shape with a rectangular arrangement. The pouring may be performed at any suitable stage of the process. For example, the solution of water-soluble alginate from step a) may have been poured into a mould for subsequent drying, provided that sufficient thorough mixing can be ensured in the mould. However, pouring is preferably carried out after the sparingly soluble alginate in step b1) or b2) has begun to crosslink or precipitate.

Step d)

The drying in step d) is carried out in a known manner. Freeze-drying is particularly preferred. This can also be carried out in a known manner, for example with reference to DE4328329C2 or DE4028622C2, which should be mentioned expressly in connection with step d) of the process according to the invention and thus form part of the process according to the invention.

In a preferred embodiment of the process according to the invention, at least one further component is added before step d), in particular before step c), said component being selected from: cosmetic or medical active substances, other natural or synthetic hydrocolloids forming polymers and cosmetic or medical auxiliaries or additives.

Other natural or synthetic hydrocolloid-forming polymers include (partially) water-soluble natural or synthetic polymers which form gels or viscous solutions in aqueous systems. They are suitably selected from other natural polysaccharides, synthetically modified derivatives thereof or synthetic polymers. Other polysaccharides include, for example, homo-or heteroglycans such as, for example, carrageenan, pectin, tragacanth, guar gum, carob gum, agar, acacia gum, xanthan gum, natural and modified starches, dextran, dextrin, maltodextrin, chitosan, glucans, such as beta-1, 3-glucan, beta-1, 4-glucan, such as cellulose, mucopolysaccharides, such as, in particular, hyaluronic acid, and the like. Synthetic polymers include, for example, cellulose ethers, polyvinyl alcohols, polyvinyl pyrrolidones, synthetic cellulose derivatives, such as methylcellulose, carboxymethylcellulose, especially sodium carboxymethylcellulose, cellulose esters, cellulose ethers such as hydroxypropylcellulose, polyacrylic acid, polymethacrylic acid, poly (methyl methacrylate) (PMMA), Polymethacrylates (PMA), polyethylene glycols and the like. Mixtures of these polymers may also be used. However, those polymers in hydrocolloid-forming proteins, such as collagen, are not preferred, as some consumers increasingly prefer to use products of pure vegetable origin, especially in cosmetics.

According to the invention, it is particularly preferred to additionally add hyaluronic acid and/or salts and/or derivatives thereof. Hyaluronic acid is of alternating beta_1-3Glucuronic acid and beta_1-4A highly viscous natural aminodextran of the glucosamine moiety; its molecular weight is between 50000 and several million. Hyaluronic acid is commonly used as the sodium salt, as in therapy, mainly in ophthalmology, surgery and cosmetics. Salts of hyaluronic acid with alkali metal ions, alkaline earth ions, magnesium ions, aluminum ions, ammonium ions or substituted ammonium ions can be used as carriers for increasing absorption of pharmaceutical compositions (see, e.g., Rmpp Chemie Lexikon "Naturstoffe" Thieme Verlag, 1997 and the documents cited therein). Sodium hyaluronate with a molecular weight of about 1000000 to 2500000 daltons is particularly preferred according to the present invention. The hyaluronic acid added according to the method of the invention completely unexpectedly leads to an increase in the whiteness of the resulting alginate-containing porous moulded bodies, in particular in process variant b1) and in process variant b 2). This is particularly preferred in cosmetic applications for aesthetic reasons. In addition, hyaluronic acid also exhibits its therapeutic action, especially in topical or external applicationsFor example, to moisturize the skin or to promote wound healing.

Hyaluronic acid or a salt thereof is added to the alginate-containing porous molded body according to the present invention in an amount of about 0.1 to 90% by weight, preferably 1 to about 70% by weight, based on the dry molded body.

In a further preferred embodiment, the porous molded bodies according to the invention comprise carboxymethylcellulose, in particular sodium carboxymethylcellulose. The addition of sodium carboxymethylcellulose surprisingly leads to an improvement in the optical density of the porous molded bodies according to the invention without increasing the hardness or brittleness of the molded bodies. In contrast, the addition of sodium carboxymethylcellulose results in an improvement in the flexibility of the resulting porous molded bodies. In addition, the addition of carboxymethylcellulose, especially sodium carboxymethylcellulose, leads to a stabilization of the mouldings. In the production of molded bodies containing carboxymethylcellulose, the carboxymethylcellulose, in particular sodium carboxymethylcellulose, surprisingly prevents the formation of sparingly soluble salts, in particular CaSO₄And (4) settling. Carboxymethylcellulose, in particular sodium carboxymethylcellulose, may be present in the mouldings according to the invention in amounts of up to 90% by weight, based on the dry content of the moulding. This corresponds to a preferred range of up to about 3% by weight, preferably 0.2 to 3% by weight, set in the aqueous suspension.

A preferred embodiment of the molded body according to the invention comprises carboxymethylcellulose, in particular sodium carboxymethylcellulose, and hyaluronic acid and/or salts or derivatives thereof.

The active substances to be added according to the invention include, in particular, cosmetic or therapeutic or pharmaceutical active substances, in particular active substances suitable for external use. Preferably, the molded bodies produced according to the invention comprise at least cosmetic and/or pharmaceutical active substances. The preferred mouldings according to the invention are therefore preferably cosmetic or therapeutic compositions. Cosmetic molded bodies in the sense of the present invention or molded bodies produced using cosmetically active substances are essentially substances in the sense of lebensmitel-undbecardgegensenstates (lmbg) (═ german food and daily use regulations), i.e. substances which are applied externally to humans for cleaning, care, or for influencing the appearance or body taste, or for transmitting odor impressions, or formulations made from such substances, unless they are used primarily for slowing down or eliminating diseases, illnesses, physical injuries or pathological disorders. In this sense, the cosmetic molded bodies produced according to the invention are, for example, cosmetic applications such as masks and the like, which are used, for example, as skin washing and skin cleansing agents, skin care products, in particular for facial skin care products, eye cosmetics, lip care products, nail care products, foot care products, and hair care or dental care products.

Cosmetically effective compounds or, if desired, dermatologically effective compounds include: anti-acne agents, antimicrobial agents, anti-perspirant agents, astringents, deodorants, depilatories, skin conditioning agents, skin smoothing agents, agents for increasing skin hydration, such as glycerol or urea, sunscreens, keratolytic proteins, radical scavengers for free radicals, antibacterial substances, agents for treating the symptoms of skin ageing and/or agents for modulating the differentiation and/or proliferation and/or pigmentation of the skin, vitamins such as vitamin C, agents with irritating side effects, such as alpha-hydroxy acids, beta-hydroxy acids, alpha-keto acids, beta-keto acids, retinoids (retinol, retinal, retinoic acid), dithranol (dioxachrysophanol), aloin (anthracanoid), peroxides (especially benzoyl peroxide), minoxidil, lithium salts, antimetabolites, vitamin D and derivatives thereof; catechins, flavonoids, ceramides, fatty substances, such as mineral oils, for example paraffin oil or vaseline oil, silicone oils, vegetable oils, for example coconut oil, sweet almond oil, corn oil, jojoba oil, olive oil, alligator oil, sesame oil, palm oil, eucalyptus oil, rosemary oil, lavender oil, pine oil, thyme oil, peppermint oil, cardamom oil, orange flower oil, soybean oil, bran oil, rice bran oil, rapeseed oil and castor oil, wheat germ oil and vitamin E isolated therefrom, evening primrose oil, vegetable lecithins (for example soybean lecithin), sphingomyelins/ceramides isolated from plants, animal oils or fats, for example beef tallow, lanolin, cream, fatty acid esters, esters of fatty alcohols, and waxes having a melting point corresponding to the skin temperature (animal waxes such as beeswax, carnauba wax and candelilla wax, mineral waxes, for example microcrystalline wax, and synthetic waxes such as polyethylene waxes or silicone waxes), and all oils suitable for use in Cosmetic applications, such as, for example, those mentioned in The CFTA monograph entitled Cosmetic ingredient Handbook, first edition, 1988, cosmetics, toiletries and fragrance association (Cosmetic ingredient Handbook, 1.auflag., 1988, The Cosmetic, Toiletry and france association, inc., Washington), polyunsaturated fatty acids, basic fatty acids (such as gamma-linolenic acid), enzymes, coenzymes, enzyme inhibitors, hydrating agents, skin soothing agents, detergents or foaming agents, and inorganic or delustering synthetic fillers, abrasives.

In addition, mention may be made of plant active substance extracts or essential oils or individual substances obtained therefrom which can be added to the porous shaped bodies produced according to the invention. In general, the plant active substance extract is in principle selected from solid plant extracts, liquid plant extracts, hydrophilic plant extracts, lipophilic plant extracts, various plant inclusions; and mixtures thereof, such as flavonoids and their aglycones: rutin, quercetin, diosmin, hyperoside, (neo) hesperidin, ginkgo biloba (e.g., ginkgo flavone glycoside), hawthorn extract (e.g., low-molecular-weight tannin), buckwheat (e.g., rutin), locust tree (e.g., rutin), birch leaves (e.g., quercitrin, hyperoside and rutin), elderberry flower (e.g., rutin), linden flower (e.g., essential oil with quercetin and farnesol), hypericum oil (e.g., olive oil), calendula, arnica oil (e.g., essential oil with oil of oily flower, polar essential oil with flavonoids), melissa (e.g., flavone, essential oil); immunostimulant: rehmannia glutinosa (e.g. alcohol, fresh plant juice, pressed juice) of Echinacea, Eleutherokokkus senticosus; alkaloid: rootworm (e.g., pulimarin), myrtle (e.g., vincamine); other botanical drugs: aloe vera, horse chestnut (e.g. escin), garlic (e.g. garlic oil), pineapple (e.g. bromelain), ginseng (e.g. ginsenosides), sow fruit (e.g. extract standardized for silymarin), canary root (e.g. spirogenin), valerian (e.g. valerian ether ester, tct. valerian extract), kava root (e.g. kavo lactone), hops (e.g. Hopfenbitter-stoffe), passion flower extract, gentian (e.g. ethanol extract), anthraquinone-containing tinctures, e.g. aloin-containing aloe skin juice, pollen extract, algae extract, licorice root extract, palm extract, Galphimia (e.g. mother tincture), mistletoe (e.g. aqueous ethanol extract), phytosterols (e.g. beta-sitosterol), mullein (e.g. aqueous ethanol extract), felt moss juice (e.g. liqueur extract), prunus salicina (e (e.g. obtained therefrom or sea rat oil), hollyhock root, primrose root extract, mallow, daisy, ivy, horsetail, yarrow, plantago lanceolata extract (e.g., juice), small nettle, celandine, parsley; from Noroloena paphiopediales, Togetes lucida, Teeoma siems, Momordica charantia and Aloe vera skin extracts.

Preferred cosmetic active substances are natural and synthetic moisturizing factors such as, for example, glycerol, urea and ceramides, skin protectants, skin lightening agents, vitamins, antioxidants, so-called anti-ageing agents, anti-irritants, sunscreens and the like.

Further preferred cosmetic active substances are natural fats and oils, i.e. triglycerides of natural fatty acids, e.g. due to their oil-removing and protective action on the skin.

A particularly preferred cosmetic active is urea, which is believed to have a local aesthetic effect.

In contrast to the abovementioned mouldings which are used essentially for cosmetics, in the case of mouldings for therapeutic (pharmaceutical) use (pharmaceutical compositions/medical products), preference is given to those which comprise at least one pharmaceutically active substance or therapeutically, in particular dermatologically, active substance and which are specified within the scope of the pharmaceutical regulations, in particular for the treatment, alleviation or prevention of diseases, ailments, physical damage or pathological disorders. Alginates are also considered as pharmaceutically/therapeutically active ingredients per se. These agents or actives are used for external applications, in which case they may be skin actives and transdermal actives. They include, for example: agents for the treatment of skin diseases, analgesics which may be used externally, such as dexpropoxyphene, pentazocine, meperidine, buprenorphine; antirheumatic/anti-inflammatory agents (NSAR) such as indomethacin, diclofenac (naproxen, ketoprofen, ibuprofen, flurbiprofen, salicylic acid and salicylic acid derivatives such as acyl salicylic acid, Oxicame, steroidal hormones such as betamethasone, dexamethasone, methylprednisolone, ethinyl estradiol, dimethyl ergotamine, dihydroergotoxine, gout drugs such as benzbromarone, allopurinol, external skin disease agents including antibacterial agents, antimycotic agents, antiviral actives, anti-inflammatory actives, antipruritic actives, anesthetic actives such as benzocaine, corticoids, anti-acne agents, antiparasitic actives, externally applicable hormones, intravenous therapies, immunosuppressive agents, and the like, are used topically.

Preferred therapeutic agents are analgesics such as immunosuppressants, hormones, agents for treating skin diseases such as neurodermatitis, atopic dermatitis and the like, and anti-herpes agents.

In addition, the porous moulded bodies produced according to the invention can contain one or more auxiliary substances. The auxiliary substances include: fillers, pH-adjusting agents, such as buffer substances, stabilizers, cosolvents, customary or other dyes and pigments for pharmaceutical and cosmetic purposes, preservatives, plasticizers, lubricants and slip agents, etc. Squalane is a particularly preferred auxiliary substance. Squalane has soothing and smoothing effects on the skin.

In addition, the invention relates to the use of salts of polyvalent metal ions with multidentate coordinating anions for producing porous molded bodies containing alginate. This means that the salt is added as such during the formation of the mouldings, i.e.is not formed partially or completely at any stage of the manufacture of the mouldings.

With the present invention, porous molded bodies comprising alginate of multivalent metal ions can be made, having a thickness of at least 1cm, preferably at least 2cm, and obtained by crosslinking (or precipitating) an aqueous solution comprising alginate with a salt of multivalent metal ions and subsequently drying the resulting aqueous suspension of crosslinked alginate. The thickness of a molded body here means the shortest distance between two points of such a molded body. The prior art to date has not been able to produce these thick, large-size mouldings having the required wet strength, in particular the required wet break strength, which can be cut or the like. These porous molded bodies are preferably obtained by the process according to the invention. The process of freeze-drying, which involves grinding insoluble alginate, results in a porous or spongy material that is brittle and not suitable for the presently contemplated use.

The porous molded bodies according to the invention have a pH of the aqueous phase of less than 7, preferably less than 6, if 1g of the molded body is suspended in 100g of water at 20 degrees celsius. This acid pH is particularly preferred in cosmetic applications of the skin.

The porous moulded body according to the invention preferably has a density of 0.005 to 1g/cm³Preferably 0.01 to 0.5g/cm³(determined according to DIN 53420).

The porous moulded bodies according to the invention preferably have a wet strength of at least about 10mN/mm layer thickness (determined according to DIN 53328).

The porous molded bodies according to the invention comprise no or substantially no spun alginate fibers, such as calcium alginate fibers.

The above-described porous molded bodies according to the invention may additionally comprise at least one further component selected from cosmetic or medical actives, other natural or synthetic hydrocolloid-forming polymers and cosmetic or medical auxiliaries or additives, as described above. The content of these components in the porous molded body according to the invention may be up to 0.75g/g, preferably less than 0.5g/g, of the porous molded body.

The porous molded body according to the present invention described above is very suitable for producing a layered molded body by cutting the porous molded body according to the present invention in a known manner. This is for example not possible with sponge-like materials obtained by freeze-drying of milled insoluble alginate. By cutting the porous molded body according to the invention, a layer thickness of, for example, 0.5 to 20mm is obtained. The invention also relates to the layered porous molded body thus obtained. These layered porous mouldings are particularly suitable for use in external applications, such as cosmetic or medical pads, for example materials for wound bandages, wound dressings, implant materials, cell culture substrates.

Furthermore, the porous molded bodies according to the invention are very suitable for the production of compressed, expandable, sponge-like molded bodies on the basis of collagen, as described, for example, in EP0901792 of the applicant. They can be easily produced on an industrial scale by perforating and/or compressing large-size porous mouldings, in particular after freeze-drying, which has hitherto not been possible according to the prior art.

These compacts are particularly suitable for oral, buccal or nasal applications, for example as satiation compacts, which may optionally additionally contain active substances, nutritional supplements or vitamins (for example DE 19942417).

In addition, owing to the sparingly soluble nature of the porous mouldings according to the invention, they are suitable for producing active substance-loaded forms in which the active substance is released in a controlled, in particular delayed, manner. These include both sponges which contain the active substance, such as implants, pessaries, and orally administrable forms, the latter being expanded, in particular in the wet state, to several times their compressed volume, and compressed substances which release the contained active substance from a spongy matrix (e.g. WO 98/09617).

In addition, the present invention relates to a porous molded body comprising alginate of polyvalent metal ions and hyaluronic acid and/or a salt thereof and/or a derivative thereof. As mentioned above, these mouldings have, entirely surprisingly, an increased whiteness which is particularly highly preferred not only in cosmetics but also in medical applications. As for the composition of these hyaluronic acid-containing porous molded bodies, we can exemplarily mention the above embodiments. The porous molded body containing hyaluronic acid is preferably produced according to the method of the present invention.

In addition, the present invention relates to the use of the porous molded body according to the invention or the molded body obtained by the process according to the invention as a cosmetic composition. Preferably, the porous molded bodies comprise, in the cosmetic context, an alginate of a polyvalent metal ion and a hydroxycarboxylic acid, in particular a hydroxypolycarboxylic acid such as, in particular, citric acid, which has been added in the form of the abovementioned multidentate complexing agent during the production of the porous molded bodies according to the invention.

The use of the porous molded bodies according to the invention in cosmetics is preferably carried out in the form of cosmetic skin pads, which are applied to the skin in a moistened form and are removed after a certain exposure time, for example after having absorbed the active substances contained therein. Alginates themselves have also had cosmetic effects such as hydration and smoothing of the skin.

In addition, the invention relates to the use of the porous molded body according to the invention or of the molded body obtained by the method according to the invention for producing medical products. These medical products include, for example, wound dressings, transdermal dressings, wound plasters, implants, substrates for the culture of cells, devices for the controlled, in particular delayed, administration of active substances in the form of said implants, also as orally administrable delay preparations, or as so-called satiating compacts which have a satiating effect as a result of the expansion of the compressed porous moulded body in the stomach, which can also be loaded with nutritional supplements, vitamins, minerals or other active substances.

The porous molded body according to the invention or the molded body obtained by the method according to the invention is preferably used for external applications such as, in particular, cosmetic or medical pads. In addition, oral, buccal, vaginal, nasal applications, etc. may also be used, as already mentioned. As mentioned, the uniformly thick porous alginate mouldings produced according to the invention can be produced on an industrial scale by any of these application forms using known methods, such as cutting, pressing, or compressing and/or perforating.

Particularly preferred mouldings comprise, on a dry basis, that is to say have no residual moisture:

about 6 to 100% by weight of alginate

From 0 to about 90% by weight of carboxymethylcellulose, especially its sodium salt,

0 to about 70 wt.% hyaluronic acid and/or salts and/or derivatives thereof,

0 to about 90 wt% of a natural or synthetic oil,

0 to about 70 weight percent citric acid or salt thereof,

this corresponds to the preferred range in aqueous suspension to be freeze-dried in step c):

about 0.2 to 3 weight percent alginate,

from 0 to about 3% by weight of carboxymethylcellulose, especially its sodium salt,

0 to about 1% by weight of hyaluronic acid and/or salts and/or derivatives thereof,

0 to about 3 wt% of a natural or synthetic oil,

0 to about 1 wt% citric acid or salt thereof.

The molded body according to the invention preferably has the form of a layer, i.e. the length and width of the molded body is at least 10 times, preferably 20 times, the thickness of the molded body. The layers may also be cut into shapes, such as in the form of a face mold. These layers preferably have a thickness of at least about 25cm²More preferably at least about 50cm²And even more preferably at least about 100cm²The area of (a).

The invention also relates to a laminate comprising at least one of the above-mentioned layers, which is laminated on at least one side with at least one further carrier layer. Preferably, the layer according to the invention is laminated on only one side, preferably with only one carrier layer. The carrier layer is preferably composed of rayon (viscose). These laminates are preferably used as wound dressings or wound plasters, and are particularly preferably cosmetic face masks.

The invention also relates to a combination of at least one porous moulded body according to the invention and at least one aqueous solution containing one or more active substances and/or auxiliaries, with a matching spatial arrangement (application packaging, kit of parts, component arrangement, etc.). The solution of the active substance can be, for example, a solution of a volatile active substance or auxiliary which, as a result of being produced by the freeze-drying process, should not or cannot be incorporated into the moulded body, such as certain fractions of essential oils, fragrances, etc., in addition, the solution can also contain a pharmaceutical or cosmetic active substance which is sensitive to temperature.

The invention is described in more detail with reference to the following examples.

Example (b):

example 1

(production method 1: calcium, complexed with a polydentate ligand, and then equilibrium is shifted by adding citric acid)

Step 1:

2500g RO-water (desalted water, reverse osmosis)

32.5g sodium alginate

10.0g calcium citrate

Alginate powder was added to RO-water using a mixer until a homogeneous mixture was obtained. Then, calcium citrate is added (at this stage, cosmetic and/or medical actives and/or oils or other substances are suitably added to the solution as required)

Step 2:

100g of RO-water

12.5g citric acid

Citric acid was added to 100ml RO-water with stirring.

And step 3:

the solutions of steps 1 and 2 were mixed thoroughly for about 30 seconds.

And 4, step 4:

the mixture of step 3 was poured into a mold and left to react for about 2 h.

And 5:

the gelled molded bodies were flash-frozen and freeze-dried,

step 6:

freeze-dried, large-sized, porous or sponge-like molded bodies, optionally loaded with other substances, are mass-produced in the manner described above.

Example 2

(production method 2: adding the multidentate complexing agent first and then the sparingly soluble calcium salt)

Step 1:

2500g RO-water (desalted water, reverse osmosis)

32.5g sodium alginate

12.5g citric acid

Alginate powder was added to RO-water using a mixer until a homogeneous mixture was obtained. Then, the citric acid is added (at this stage, the cosmetic and/or medical active and/or the oil or other substance is suitably added to the solution as required).

Step 2:

50g RO-water

10.0g calcium sulfate

Calcium sulfate was added to 50ml RO-water with stirring.

And step 3:

the solutions of steps 1 and 2 were mixed thoroughly for about 30 seconds.

And 4, step 4:

the mixture of step 3 was poured into a mold and left to react for about 1 h.

And 5:

the gelled molded bodies were flash frozen and freeze dried.

Step 6:

freeze-dried, large-sized, porous or sponge-like molded bodies, optionally loaded with other substances, can be mass-produced in the manner described above.

Claims (40)

1.A process for the manufacture of freeze-dried alginate-containing porous molded bodies, comprising the steps of:

a) preparing an aqueous solution of a water soluble alginate, the aqueous solution being free of surfactant,

b1) adding one or more salts of a polyvalent metal ion and a multidentate coordinating anion to an aqueous solution of a water-soluble alginate and moving the complex of the polyvalent metal ion and the multidentate coordinating anion into equilibrium while increasing the available concentration of the polyvalent metal ion in the alginate solution, and thereby forming a salt of alginate and the above-mentioned polyvalent metal ion,

or

b2) Adding a polydentate complexing agent for polyvalent metal ions to an aqueous solution of a water-soluble alginate and adding one or more sparingly water-soluble salts of the polyvalent metal ions,

c) pouring a flowable aqueous alginate composition into a mould,

d) the aqueous alginate composition is freeze-dried to form an alginate-containing porous moulded body.

2. The process of claim 1 wherein the water soluble alginate of step a) is an alkali metal alginate.

3. The method of claim 1, wherein the polyvalent metal ion is selected from alkaline earth metal ions.

4. The method of claim 3, wherein the polyvalent metal ion is a calcium ion.

5. The process of any one of claims 1 to 4, wherein the multidentate coordinating anion or coordinator is a carboxylate salt of a polycarboxylic acid.

6. The process of claim 5 wherein the multidentate coordinating anion or coordinator is a carboxylate salt of an α -hydroxypolycarboxylic acid.

7. The method of claim 6, wherein the multidentate coordinating anion or coordinator is selected from the group consisting of citrates and malates.

8. The method of claim 7, wherein the multidentate coordinating anion or coordinator is a citrate salt.

9. The process of claim 1, wherein the shifting of the complex formation equilibrium of the polyvalent metal ion and the multidentate coordinating anion in step b1) is achieved by the addition of at least one acid.

10. The process of claim 1 wherein the sparingly soluble metal salt of a polyvalent metal ion admixed in step b2) has a solubility in water of less than 10 g/liter at 20 ℃.

11. The process of claim 10 wherein the sparingly soluble metal salt of a polyvalent metal ion added is calcium sulfate.

12. The process of claim 1, further comprising, prior to step d), the step of adding at least one additional component selected from the group consisting of: cosmetic or medical substances, other natural or synthetic hydrocolloid-forming polymers and cosmetic or medical auxiliaries or additives.

13. The method of claim 12, wherein the other component is at least one natural or modified polysaccharide.

14. The method of claim 12 or 13, wherein the other component is hyaluronic acid or a salt thereof.

15. The method of claim 12 or 13, wherein carboxymethyl cellulose or a salt thereof is added as an additional component.

16. The process of claim 12 wherein urea is added as an additional component.

17. The process of claim 12, wherein squalane is added as a further component.

18. A porous molded body comprising an alginate salt of a polyvalent metal ion having a thickness of at least 1cm obtainable by the process of any one of claims 1 to 17.

19. The porous molded body of claim 18, which is such that a suspension of 1g of the molded body in 100g of water gives a pH of the aqueous phase at 20 ℃ of less than 7.

20. The cellular molding as claimed in claim 18 or 19, which has a density of from 0.005 to 1g/cm according to DIN53420³。

21. The porous molded body according to claim 18 or 19, which has a wet breaking strength according to DIN53328 of at least 10mN/mm layer thickness.

22. The porous molded body of claim 18, additionally containing at least one additional component selected from the group consisting of: cosmetic or medical substances, other natural or synthetic hydrocolloid-forming polymers and cosmetic or medical auxiliaries or additives.

23. The porous molded body of claim 18 comprising hyaluronic acid or a salt thereof.

24. The porous molded body of claim 18 comprising carboxymethylcellulose or a salt thereof.

25. The porous molded body of claim 18 comprising urea.

26. The porous molded body of claim 18 comprising squalane.

27. A process for producing a layered molded body by cutting a molded body according to any one of claims 18 to 26 or a molded body obtained according to any one of claims 1 to 17.

28. A process for producing a compression-molded body by compressing a molded body according to any one of claims 18 to 26 or a molded body obtained according to any one of claims 1 to 17.

29. The method of claim 28 for the manufacture of an orally administrable formulation.

30. A method according to claim 28 or 29 for the manufacture of an orally administrable satiation compact.

31. The method according to claim 30 for producing an orally administrable formulation for controlled release of an active substance.

32. Use of the porous molded body according to any one of claims 18 to 26 or the porous molded body obtained according to any one of claims 1 to 17 as a cosmetic composition.

33. Use of the porous molded body according to any of claims 18 to 26 or of the porous molded body obtained according to any of claims 1 to 17 for the production of medical products.

34. Use of a porous molded body according to any one of claims 18 to 26 or of a porous molded body obtained according to any one of claims 1 to 17 for the production of a medicament for external, oral, buccal, vaginal or nasal use, or for the production of an implant or as a dressing for wounds or a wound plaster or for the production of a plaster containing an active substance.

35. The porous molded body according to any one of claims 18 to 26 or the porous molded body obtained according to any one of claims 1 to 17, which is in the form of a layer.

36. A laminate comprising at least one layer according to claim 35 laminated on at least one side with at least one further carrier layer.

37. Use of a laminate according to claim 36 for the manufacture of a wound dressing or a wound plaster.

38. Use of the laminate of claim 36 for the preparation of a cosmetic mask.

39. Kit comprising at least one porous molded body according to claims 18 to 26 or a porous molded body obtained according to any of claims 1 to 17 having a matching spatial arrangement and at least one aqueous solution comprising one or more active substances and/or auxiliaries.

40. Use of the kit of claim 39 for the manufacture of a cosmetic or pharmaceutical composition.