DE19712708A1 - Dried hydrocolloid or hydrogel based on polysaccharide(s) - Google Patents

Abstract

Dried hydrocolloid and/or hydrogel with few contaminants is claimed, which has a density of 0.05 - 1.50 g/cm<3> and a residual water content of 1 - 80 wt.%, and is optionally in a structured surface form. The hydrocolloid/hydrogel is based on non-modified and/or modified natural, biotechnologically manufactured and/or semi-synthetic polysaccharides and optionally contains 0.01 - 60 wt.% of additives. The novelty is that drying of the hydrocolloid/hydrogel takes place using microwave energy and optionally the thermal energy from heated gases or infrared radiation. Also claimed is a method for producing the dried hydrocolloid/hydrogel, in which microwave energy preferably makes up 10 - 95 % of the total energy used to dry the gel and where the frequency of the microwaves is preferably 2.4 - 2.5 GHz. The microwaves are continuous or in modulated or impulse form.

Description

The invention relates to dried, low-contamination hydrocolloids and / or Hydrogels based on polysaccharides for use in pharmacy, cosmetics, Medical technology and biotechnology.

Soluble colloids in the form of hydrocolloids and insoluble colloids in the form of Hydrogels based on polysaccharides are known.

The drying of the hydrocolloids or Hydrogels can lead to an undesirable drop in molecular weight and undesirable lead to chemical changes compared to the starting product.

Known drying processes for polysaccharides are thermal drying through heat convection and freeze drying in a vacuum.

WO 95 25751 describes the production of fabrics from the polysaccha rid hyaluronic acid by hot air drying. The production of freeze-dried Biomatrices based on natural and modified polysaccharides are the subject from DE 43 28 329. These biomatrices have a cavity structure into which Liquids can penetrate quickly and freely. Freeze drying at The production of collagen sponges is described in the patents DE 27 34 503, DE 29 43 520 and DE 40 28 622. The drying process also delivers here a spongy structure of the biomatrix. The manufacture of fabrics with a porous structure based on hyaluronic acid and hyaluronic acid derivatives Freeze drying is the subject of DE 40 24 180.

The disadvantages of thermal drying of polysaccharides The inhomogeneous drying process and the thermal form convection Damage to the polysaccharides due to molecular weight degradation and chemical Changes. With short drying times, local overheating results because  the product dries on the surface first. The existing outer hard dry crust complicates the further drying process inside the Materials, chemical damage from molecular weight degradation and chemical damage occur Changes such as decarboxylations occur and the results are inhomogeneous Products related to moisture content. Longer drying times at lower temperatures result in more uniform products in terms of Moisture content, however, usually lead to heat unstable polysaccharides considerable molecular mass degradation combined with oxidative Changes and a decrease in material properties, especially the elastic properties. Another consequence of long drying times can be in the microbial contamination of the polysaccharides and the associated Degradation by microorganisms exist.

The disadvantages of freeze-drying polysaccharides are sponge-like structure of freeze-dried products. Into the cavities of the Freeze-dried polysaccharides can handle liquids quickly and freely penetrate and thus a spontaneous decay of the network of the matrix bring about. Through this instant effect, the property of water and Active substance storage of the matrix quickly removed.

For coatings, compact surface layers with good Material properties and long-term stability required, sponge-like structures are unsuitable for this application.

The aim of the invention is therefore dried hydrocolloids and / or hydrogels Basis of polysaccharides, which is characterized by a high product homogeneity are low in contamination and only one compared to the starting products have a small drop in molecular weight and at most slightly change chemically changed.

The object of the invention was achieved by dried low-contamination hydrocolloids and / or hydrogels, optionally in the form of fabrics, with a density of 0.05 to 1.50 g / cm ³ and a residual water content of 1 to 80% by mass based on unmodified and / or modified natural, bio-technically produced and / or semi-synthetic polysaccharides and, if appropriate, 0.01 to 60% by mass, based on the hydrocolloids and / or hydrogels, of additives, dissolved, the drying of the hydrocolloids and / or hydrogels under the action of the thermal Energy from microwaves and possibly the thermal energy from heated gases and / or IR emitters has been carried out evenly and gently while largely maintaining the initial molar mass.

Have the dried low-contamination hydrocolloids and / or hydrogels as a result of the microwave treatment, bacterial counts of maximum 100 germs / g dried hydrocolloid or hydrogel.

The unmodified and / or modified natural, biotechnologically produced and / or semi-synthetic polysaccharides are preferably unmodified and / or modified pectins, chitins, chondroitins, heparins, starches, dextrans, Pullulane, Xanthane, Welane, Rhamsane, Curdlane, Alginate, Carrageenane, Keratans, hyaluronic acids, dermatans, gellans, schizophyllans and / or Polysaccharides from carob flour, agar, Arabic gum, tragacanth, guar gum, Fenugreek gum, Locust bean gum and / or Tara gum.

Examples of modified polysaccharides are carboxymethyl-strong, Hydroxyethyl starch, dialdehyde starch, pectin esters, chitosans, etherified guar gum, acetylated hyaluronic acids, hyaluronic acid esters and cross-linked or partially cross-linked Hyaluronic acids.

The additives optionally contained are preferably 0.1% by mass to 25% % By mass of film-forming binders and / or thickeners, 0.01% by mass to 0.25 Mass% preservative, 1 mass% to 30 mass% stability-improving fibrous carrier materials and / or stability-improving carrier materials in the form of textile and / or grid-like fabrics, 0.05 to 10 mass% Minerals, 0.05 to 3 mass% micelle-forming substances, 1 to 25 mass% Plasticizers, 0.05 to 30% by mass cosmetic and / or pharmaceutical  Active substances, 1 to 30 mass% vehicle for active substances, 0.05 to 2 mass% antioxidant dantien, 0.05 to 2% fragrances and / or 0.05 to 5% by mass of dyes, whereby the proportions each relate to the hydrocolloids and / or hydrogels.

The film-forming binders and / or thickeners consist of plastics and / or semi-synthetic modified natural substances, preferably from starch ethers, Sodium alginate, cellulose derivatives such as carboxymethyl cellulose, cellulose ether, Cellulose esters and alkyl celluloses, polyvinyl acetate, polyvinyl alcohol, partially saponified Polyacrylic acid esters and / or partially saponified polymethacrylic acid esters. A is particularly preferred film-forming binder and / or thickener Carboxymethyl cellulose due to the reversible water solubility and good Compatibility, especially in medical and cosmetic applications.

Examples of suitable preservatives are p-hydroxybenzoic acid, Benzyl alcohol and propylene glycol. For medical and cosmetic applications Applications where skin irritation has to be excluded are p-Hy droxybenzoic acid ester and sorbic acid are particularly suitable.

The stability-improving fibrous carrier materials and / or stability improving carrier materials in the form of textile and / or grid-like Sheets preferably consist of cellulose, cellulose esters, calciumal ginate, wool, cotton, silk, polyamides, polyesters, polyethers, polyvinylal alcohol and / or polyolefins. These carrier materials increase the mechanical Dry stability of the dried hydrocolloids and hydrogels, the selection of the The shape of the carrier materials depends on the application, e.g. B. are Sewing thread nonwoven fabrics on the basis of cotton suitable carrier materials for Hydrocolloids with active ingredient properties in wound care.

Suitable minerals as additives in dried hydrocolloids and Hydrogels are aluminum hydroxide, magnesium hydroxide, zinc oxide, calcium carbonate, talc, bentonite, silica and / or wollastonite. These minerals stabilize the hydrocolloid or the hydrogel and / or regulate with medication  applications, the electrolyte balance on the corresponding application Job.

Examples of micelle-forming substances are higher alcohols such as cetyl alcohol, Stearyl alcohol and wool wax alcohols, sodium lauryl ether sulfate, fatty acid amides, Sodium salts of fatty acids and lecithin. Are preferred as micelle-forming Substances non-ionic emulsifiers such as polyglycol esters and polyglycol ethers.

Suitable plasticizers as flexibilizing additives in dried hydro Colloids and hydrogels are glycerin, glyceryl alkyl ether acetate, polyethylene glycol diethylhexoate, 2-ethylhexyl p-hydroxybenzoate, stearyl citrate and polyvinyl methyl ether. Glycerin is coming for medical and cosmetic applications suitable.

Examples of cosmetic and pharmaceutical active ingredients are essential oils, Corticosteroids, pyribenzamines, pilocarpine nitrate, tyrothricin, folic acid, Nicotinic acid amide, nicotinic acid ester. Vitamins such as are preferably used Vitamin A, Vitamin B1, Vitamin B6, Vitamin E and skin penetration-promoting agents such as polyoxyethylene nonylphenol.

As a vehicle for the transport of active ingredients, the dried hydrocolloids and / or contain hydrogels as additives, liposomes are suitable.

Examples of suitable antioxidants are thiodipropionic acid, tocopherol and α lonon. Ascorbic acid is particularly suitable.

The fragrances can be composed of natural fragrance complexes, in particular essential oils, as well as synthetic uniform fragrances such as limonene, Phellandrene, cinnamon alcohol, fenchyl alcohol or geraneol exist. Prefers become fragrance substances based on essential oils.

As additives for marking and coloring in the dried hydrocolloids and / or hydrogels contained dyes are preferably natural vegetable.  

As additives for marking and coloring in the dried hydrocolloids and / or hydrogels contained dyes are preferably natural vegetable Dyes such as alkanna, calendula, crocus, indicum, carotene, lactoflavin, Chlorophyll and santalum rubrum, color pigments such as barium sulfate, zinc oxide, Titanium dioxide and iron oxide as well as synthetic dyes, e.g. B. on triphenyl methane-based or anthraquinone-based.

Under the influence of the thermal energy of Microwaves and possibly the thermal energy of heated gases and / or IR radiators dried hydrocolloids a number average molecular weight of at least 75% of the number average molecular weight is used as the starting product put hydrocolloids. Determining the number average molecular weight of Hyddro Colloids can be measured by GPC analysis in conjunction with light scattering measurements [Orvisky, E., Chromatographia (1994), 39 (5/6), 366-368; Vercruysse, K, J. Chromatogr., Pt. B Biomed.Appl. (1994), 656 (1), 179-190].

According to the invention, the low-contamination hydrocolloids and / or hydrogels dried evenly and gently while largely maintaining the starting molar mass are produced, optionally in the form of sheet-like structures, with densities in the range from 0.05 to 1.50 g / cm ³ and a residual water content of 1 to 80 % By mass based on unmodified and / or modified natural, biotechnologically produced and / or semi-synthetic polysaccharides and optionally 0.01 to 60% by mass, based on the hydrocolloids and / or hydrogels, of additives and optionally 0.1 to 10% by mass, based on the hydrocolloids and / or hydrogels, of blowing agents, after a drying process under the action of the thermal energy of microwaves and, if appropriate, the thermal energy of heated gases and / or IR radiators.

In the event of additional exposure to the thermal energy of heated gases and / or IR emitters when drying hydrocolloids and / or hydrogels, the thermal energy of the micro acts  waves simultaneously and / or after exposure to thermal energy heated gases and / or IR emitters. The ratio of micro wave energy to the temperature and flow rate of the gas selected so that the proportion of microwave energy in the drying of the hydrocolloids total energy used is 95 to 10%. The for drying the Hydro Colloidal gases are preferably wholly or partly in the Heat exchanger of the microwave generators heated.

It is advantageous that dried hydrocolloids and / or hydrogels can also be produced in foamed form by the process according to the invention. Examples of blowing agents which the hydrocolloids and / or hydrogels may contain during drying to adjust the porosity and density in the production of foamed dried materials, are gas-releasing blowing agents such as azodicarbonamide or cyanuric acid trihydrazide, volatile hydrocarbons and halogenated hydrocarbons such as pentane, isobutane, Monofluorotrichloromethane or difluoromonochloromethane or gases such as nitrogen, argon or carbon dioxide. Dried foamed hydrocolloids or hydrogels with densities in the range from 0.50 to 1.50 g / cm ³ generally do not require any additional blowing agents, since the density of the closed-cell foamed material or the porosity of the open-cell foamed material due to the energy input Microwave treatment and the resulting diffusion kinetics of water vapor can be controlled. The foam density or the porosity of the dried material determines the swelling or absorption rate during application.

The introduction of the thermal energy of microwaves with a frequency of preferably 2.4 to 2.5 GHz takes place according to the invention as a continuous power or as modulated and / or pulsed power. The applicable one Modulation and / or pulse shape and the amplitude of the microwave energy by determines the required properties of the specific dried material. So extensive void-free foils require low microwave power and / or short microwave pulses and long pauses. The pulse duration of the microwave Len irradiation according to the invention is 10 to 95% of the period of the Performance profile.  

For applications that require the drying of thin layers, the Application of applicators that represent single or multimode resonators partial.

Furthermore, the use of several differently coupled resonators beneficial to the changing dielectric properties of the drying material to meet the required microwave power on appropriate place and / or at the appropriate time act on the material to let. When using a microwave tunnel with multiple feeds the coupling of the different feed points according to the dry Degree of efficiency and the required drying rate set up.

When using single or multi-mode resonators with a known mode shape can transport the material to be dried through the resonator required modulation of the microwave radiation by adjusting the The length of the resonator and the transport speed take place.

The low-contamination hydrocolloids and / or hydrogels dried evenly and gently under the influence of the thermal energy of microwaves while largely maintaining the starting molar mass, with a density of 0.05 to 1.50 g / cm ³ and a residual water content of 1 to 80 mass%, optionally in Form of sheet-like structures, based on natural, biotechnologically produced and / or semi-synthetic polysaccharides and optionally 0.01 to 60% by mass, based on the hydrocolloids and / or hydrogels, of additives are in particular as cosmetics, for topical ophthalmic, dermal and / or transdermal application of active ingredients, in particular as a "drug delivery system", as components for implants, as components for the treatment of arteriosclerosis, arthritis, thromboses and / or traumatic complaints, for promoting angiogenesis, wound healing and anti-inflammatory processes and as a support matrix for use in cell culture technology k suitable.

The application is preferably in the form of coated and / or impregnated carrier materials, in particular fabrics, knitted fabrics, nonwovens,  Knitted or cushion-like fabrics as well as in the form of gels, membranes, Films, microspheres, ointments and / or foams.

Another application of under the influence of thermal energy Microwaves evenly and gently while largely maintaining the Starting molar mass of dried low-contamination hydrocolloids and / or Hydrogels with a residual water content of 1 to 80% by mass form the Improve the lubricity of drugs, products and devices Glass, ceramics, plastics and / or natural materials, especially prosthetic ones Products, catheters, ultrasound probes and endoscopic instruments. The Increased lubricity results from the water absorption of the colloids in the Coating when hydrated. The increased lubricity causes Reduction of the irritation of the epidermis in the medical application and This particularly facilitates the insertion of catheters into body openings.

The hydrocoloids or act in coated drugs Hydrogels simultaneously as a "drug delivery system".

The invention is illustrated by the following examples:

example 1

Housing of ultrasonic measuring heads with a surface of approx. 85 cm ² of polypropylene continuously pass through a dipping station which contains a coating formulation of 22 g hyaluronic acid, 12 g carboxymethyl cellulose, 4 g glycerol and 0.3 g sorbic acid dissolved in 1 l water, and subsequently a 2 at a throughput speed of 0.17 m // min. 5 m long microwave tunnel with four, depending on the degree of drying of the material, differently adapted feed points with a total power consumption of approx. 8.5 kW, through which the air heated to 40 to 45 ° C is led from the heat exchangers of the microwave generators. The resulting abrasion-resistant coating of the measuring head housing has a thickness of 250 µm, a water content of 12% by mass and shows no discoloration as a result of the heat treatment.

Example 2

For the production of shoe insert material against sweaty feet is on a 3.5mm thick cotton fabric soaked in a 0.05M calcium chloride solution is an aqueous highly viscous solution containing 2% by weight carboxymethyl cellulose, 5 Mass% alginic acid, 10 mass% guar gum, 2 mass% sodium hyaluronate, 0.05 Mass% aluminum stearate, 0.01 mass% Isodorant® and 1mM phosphate buffer contains, doctored in the form of an 8mm thick layer and at one Throughput speed of 0.25m / min. in the microwave tunnel according to example 1 dried. The residual water content of the coated cotton fabric is 5.5 Dimensions%.

Example 3

A 5% solution of hyaluronic acid benzyl ester (molar mass weight average by GPC analysis 2.8 × 10 ⁶ ) is applied to the Teflon-coated conveyor belt of the microwave tunnel according to Example 1 and, after passing through the microwave tunnel at 0.08 m / min, as 750 μm Peeled off film with a residual water content of 8.5%.

GPC analysis of the peeled-off film gives a weight-average molecular weight of the dried hyaluric acid benzyl ester of 2.4 × 10 ⁶ .

Example 4

0.5 ml / cm ^{2 of} a sodium hyaluronate solution are applied to the inner base of cell culture bottles made of polyethylene (diameter 75 mm) and distributed evenly by a vibrating device. The cell culture bottles pass at 0.55 m / min through the microwave tunnel according to Example 1 and subsequently through a sterilization and packaging station. The analysis of the sodium hyalurate coating dried in the cell culture bottles by the action of microwaves shows a water content of 16.5% by mass. The bottles are used for the cultivation of cell cultures, in particular for the cultivation of keratinocytes.

Claims (10)

1. Dried low-contamination hydrocolloids and / or hydrogels with a density of 0.05 to 1.50 g / cm ³ and a residual water content of 1 to 80% by mass, where appropriate in the form of fabrics, based on unmodified and / or modified natural, biotechnologically produced and / or semi-synthetic poly saccharides and optionally 0.01 to 60% by mass, based on the hydrocoloid and / or hydrogels, of additives, characterized in that the drying of the hydrocolloids and / or hydrogels under the action of the thermal energy of Microwaves and, where appropriate, the thermal energy of heated gases and / or IR radiators has been carried out uniformly and gently while largely maintaining the initial molar mass. 2. Dried low-contamination hydrocolloids and / or hydrogels according to claim 1, characterized in that the unmodified and / or modified natural, biotechnologically produced and / or semi-synthetic polysaccharides Pectins, chitins, chitosans, chondroitins, heparins, starches, dextrans, pullulans, Xanthane, Welane, Rhamsane, Curdlane, Alginate, Carrageenane, Keratane, Hyaluronic acids, dermatans, gellans, schizophyllans and / or polysaccharides Carob flour, agar, Arabic gum, tragacanth, guar gum, fenugreek gum, Locust bean gum and / or tare gum. 3. Dried hydrocolloids and / or hydrogels according to claim 1 and 2, characterized characterized in that the additives 0.1 mass% to 25 mass% film-forming Binders and / or thickeners based on plastics and / or semi synthetic modified natural products, in particular cellulose derivatives, 0.01  % By mass to 0.25% by mass of preservatives, especially p- Hydroxybenzoic acid ester and / or sorbic acid, 1 mass% to 30 mass% stabili fibrous carrier materials which improve the performance and / or improve the stability Backing materials in the form of textile and / or grid-like fabrics, 0.05 up to 10 mass% minerals, 0.05 to 3 mass% micelle-forming substances, in particular nonionic emulsifiers, 1 to 25 mass% plasticizer, esp special glycerin, 0.05 to 30 mass% cosmetic and / or pharmaceutical Active ingredients, especially vitamins and / or skin penetration-promoting agents, 1 to 30 mass% vehicle for active substances, in particular liposomes, 0.05 to 2 mass% Antioxidants, especially ascorbic acid 0.05 to 2% fragrances, in particular essential oils and / or 0.05 to 5% by mass of dyes, each based on the Hydrocolloids and / or hydrogels. 4. Dried hydrocolloids and / or hydrogels according to claim 1 to 3, characterized characterized in that the stability-improving additives fibrous carrier materials and / or stability-improving carrier material materials in the form of textile and / or lattice-like fabrics made of cellulose, Cellulose esters, calcium alginate, wool, cotton, silk, polyamides, polyesters, Polyethers, polyvinyl alcohol and / or polyolefins exist. 5. Dried hydrocolloids according to claim 1 to 4, characterized in that the dried hydrocolloids a number average molecular weight of at least 75% of Molecular weight number average of the hydrocolloid used as the starting product have. 6. Process for the production evenly and gently while largely maintaining the initial molar mass of dried low-contamination hydrocolloids and / or hydrogels with a residual water content of 1 to 80 mass% and a density of 0.05 to 1.50 g / cm ³ , optionally in the form of fabrics, based on unmodified and / or modified natural, biotechnologically produced and / or semi-synthetic polysaccharides and optionally 0.01 to 60% by mass, based on the hydrocolloids and / or hydrogels, of additives according to one or more of claims 1 to 5 and optionally 0 , 1 to 10% by mass, based on the hydrocolloids and / or hydrogels, of blowing agents, characterized in that the drying takes place under the action of the thermal energy of microwaves and, if appropriate, the thermal energy of heated gases and / or IR radiators. 7. Method of manufacturing evenly and gently with extensive preservation the initial molar mass of dried low-contamination hydrocolloids and / or Hydrogels according to claim 6, characterized in that the action of the thermal energy of the microwaves simultaneously and / or after exposure to the thermal energy from heated gases and / or IR emitters and that Ratio of microwave energy to temperature and to the throughput of the Gases is set so that the proportion of microwave energy to the Drying of the hydrocolloids total energy used is 95 to 10% and the gases used to dry the hydrocolloids are preferably entirely or are partially heated in the heat exchanger of the microwave generators, wherein the frequency of the microwaves is preferably 2.4 to 2.5 GHz. 8. Process for the production evenly and gently with extensive preservation the initial molar mass of dried low-contamination hydrocolloids and / or Hydrogels according to claim 6 and 7, characterized in that the action of the thermal energy of microwaves with a frequency of preferably 2.4 to 2.5 GHz as a continuous output or as a modulated and / or pulsed output is introduced, the modulation in whole or in part by the transport of the  Hydrocolloids by single or multi-mode resonators with one or more Microwave feed points is realized and the pulse duration of the microwaves irradiation is 10 to 95% of the period of the performance profile. 9. Use of low-contamination hydrocolloids and / or hydrogels dried with the density of 0.05 to 1.50 g / cm ³ and a residual water content of 1 to 80 mass under the influence of the thermal energy of microwaves evenly and gently while largely maintaining the starting molar mass %, optionally in the form of fabrics, based on unmodified and / or modified natural, biotechnologically produced and / or semi-synthetic polysaccharides and optionally 0.01 to 60% by mass, based on the hydrocolloids and / or hydrogels, of additives, according to a or more of claims 1 to 8 as cosmetics, for topical ophthalmic, dermal and / or transdermal application of active ingredients, as components for implants, as components for the treatment of arteriosclerosis, arthritis, and / or trauma-related complaints, for promoting angiogenesis, wound healing and anti-inflammatory processes and as a matrix for the egg use in cell culture technology, the application being in the form of coated and / or impregnated carrier materials, in particular woven, knitted, non-woven, knitted or cushion-like materials, and in the form of gels, membranes, films, microspheres, ointments and / or foams. 10. Application of under the influence of the thermal energy of microwaves evenly and gently while largely maintaining the initial molar mass dried low-contamination hydrocolloids and / or hydrogels with a Residual water content from 1 to 80% by mass based on unmodified and / or modified natural, biotechnologically produced and / or semi-synthetic Polysaccharides and optionally 0.01 to 60 mass%, based on the Hydrocolloids and / or hydrogels, additives, according to one or more of the  Claims 1 to 8 for improving the lubricity of drugs, Products and devices made of glass, ceramics, plastics and / or natural materials, in particular of prosthetic products, catheters, ultrasound measuring heads and endoscopic instruments.