JP4067580B2 - Freeze-dried biomatrix - Google Patents

Description

[0001]
[Industrial application fields]
The present invention relates to a freeze-dried biomatrix having a skin moisturizing action, which biomatrix mainly consists of polysaccharides and at the same time is suitable as a carrier material for pharmaceutical and cosmetic active substances.
[0002]
[Prior art]
In the technical field, freeze-dried biomatrix is especially known as a collagen sponge.
[0003]
For example, as described in US 2 610 625 and US 3 157 524 and DE 26 25 289, non-mesh-bonded collagen sponges can be produced from aqueous collagen solutions by lyophilization or mixed with water. It is manufactured by removing water from a foamed collagen mass using an organic solvent. The product having an easily processable sponge-like structure produced in this way swells and decomposes as soon as water is added. This product is never stable under humid conditions.
[0004]
Water-resistant sponges based on water-resistant collagen produced with the addition of crosslinking agents are described, for example, in DE 27 34 503, DE 29 43 520 and DE 32 03 957. The collagen sponge produced by the method of DE-PS 32 03 957 is stable in aqueous solvents and contains the residue of the used cross-linking agent. This cross-linking agent not only causes irritation to sensitive skin, but also penetrates into the skin due to its low molecular weight and causes unwanted reactions in the body.
[0005]
According to the method described in DE-OS 40 28 622, it is possible to produce a collagen sponge which is crosslinked without using chemical additives and is stable even in an aqueous solvent. This collagen sponge is also a pure natural product. In this case, for example, an animal raw material such as bovine or porcine skin or bovine Achilles tendon is used, and normal pretreatments such as soaking, tanning, stripping and stripping of the silver film are first performed. Next, the raw material is purified by alkali treatment and acid treatment immediately thereafter to remove non-collagenous impurities.
[0006]
In certain consumer groups, there is an increasing tendency to use no animal ingredients at all, for example for religious or ethical reasons. Furthermore, when using animal raw materials, there is a risk that the product contains immunogens or pathogenic substances.
[0007]
The use of plant-derived substances in pharmacy or as cosmetics is a known technique. In the pharmaceutical field, for example, calcium alginate is used for wound treatment (eg Sorbalgon® / Hartmann). In addition, the use of plant biopolymers for cosmetic skin treatment has long been known (The Chemistry and Technology of Pectin, Reginald H. Walter, Chapter 12, pp. 251-264, and Investigating the Nutritional, Medicinal and Cosmetic Values of Seaweeds and their Extracts, Koyama, Hayatsu, Yamoto, Ph. D. Morsy, Erde International, 85-106). However, conventional commercial products made from the above-mentioned plant biopolymers are not very friendly to users. Conventionally used biopolymer mixtures are not easy to handle because they tend to generate dust and are not easily dissolved in water, resulting in a heterogeneous mixture.
[0008]
SUMMARY OF THE INVENTION
The present invention relates to a lyophilized biomatrix based on natural and modified polysaccharides, whose use is for topical and transdermal administration of pharmaceutical and cosmetic agents.
[0009]
The lyophilized biomatrix of the present invention is suitable for the production of a formulation that is easier to control and more appropriately releases the agent to the skin compared to known formulations. In this lyophilized biomatrix, there is no interaction so that the transport route in the skin is not obstructed, the transport route is short because no obstacle substance (e.g. lipid) is used, and the ease of dose setting, i.e. the concentration of the active substance is reduced. By being able to be higher, the efficacy of conventional agents is higher.
[0010]
Therefore, the consumption of the active substance can be saved by using the freeze-dried biomatrix of the present invention. Also, the use of skin irritating substances (eg preservatives, pigments, fragrances, emulsifiers) can be completely avoided.
[0011]
[Structure of the invention]
The object of the present invention is to produce a biomatrix, preferably on the basis of a non-animal substance, particularly preferably using only a non-animal substance, this biomatrix being a collagen of the Galenischen System Like a sponge, it does not contain preservatives, crosslinking agents and fragrances and can achieve skin moistening without irritation. Furthermore, this biomatrix appears to be suitable for transdermal administration of pharmaceutical and cosmetic agents.
[0012]
This problem is solved by the present invention by a biomatrix produced by freeze-drying an aqueous polysaccharide solution. The biomatrix according to the present invention contains 10 to 80% by weight of natural polysaccharide and 20 to 90% by weight of modified polysaccharide. Preferably, the biomatrix contains 25 to 70% by weight of natural and / or modified polysaccharides, 5 to 15% by weight of water, more preferably 10% by weight. If necessary, the biomatrix of the present invention may contain the components shown below.
[0013]
In contrast to other drying methods such as spray drying and air drying, lyophilization methods are a sponge-like bio-matrix with convenient properties (immediate effect) that can be quickly condensed, i.e. by supplying water. A biomatrix that naturally forms a gel is obtained.
[0014]
The natural polysaccharide is preferably selected from the group consisting of pectin, alginate, carrageenan, agar and locust bean flour.
[0015]
Examples of the modified polysaccharide include cellulose derivatives such as cellulose ether. Preferably, a film-forming binder such as carboxymethylcellulose or a derivative thereof is used. Carboxymethyl cellulose can be combined in an advantageous manner with other cellulose ethers, polyesters or polyvinyl alcohol.
[0016]
The lyophilized biomatrix according to the invention exhibits a sponge-like structure with fine pores, and in a preferred embodiment is produced from a plant-derived material.
[0017]
The polysaccharides used in the present invention can be combined in an advantageous manner with proteins of plant origin. Furthermore, as additional polysaccharides, glucose aminoglycans such as hyaluronic acid, hyaluronic acid derivatives or chondroitin sulfate are also used.
[0018]
In the lyophilization of the polysaccharide mixture, unlike the collagen dispersion, it is not necessary to consider the isoelectric point, and therefore, for example, hyaluronic acid can be mixed almost without any problem. The lyophilized biomatrix of the present invention mainly comprises polysaccharides, i.e. 1. Natural polysaccharides Consists of modified polysaccharides. This matrix further includes
3. 3. Fiber components to improve dry stability and / or Cosmetic or pharmaceutical agents can be included.
[0019]
In a preferred embodiment of the invention, the biomatrix solution or suspension used for the production of the lyophilized biomatrix is 0.25 to 2.5% by weight, preferably 0.9 to 1.9% by weight of natural polysaccharides and 0.5 to 2.5% by weight. Preferably, it contains 0.9 to 1.6% by weight of modified polysaccharide and is adjusted to 100% by adding demineralized water. Furthermore, 0.05 to 0.75% by weight, preferably 0.12 to 0.23% by weight of fiber components, and / or 0.0025 to 0.5% by weight, preferably 0.12 to 0.17% by weight of cosmetic and / or pharmaceutical agents, depending on the intended use, It can be added into this mixture.
[0020]
In a particularly preferred embodiment, the suspension for producing the lyophilized biomatrix is further comprised of 0.1 to 1.5% by weight, preferably 0.17 to 0.81% by weight, of micelle-forming substances such as isoparaffin in the total amount.
[0021]
The polysaccharides used in the present invention, especially those of plant origin, have the properties of protective colloids. A modified polysaccharide may be a film-forming binder, which on the one hand has an affinity for natural polysaccharides and on the other hand may also have an affinity for incorporated fiber components. The use of carboxymethylcellulose has the advantage that a product with reversible water solubility is obtained, and carboxymethylcellulose is non-toxic, both as a cosmetic base and as an additive (binder, thickener, protective colloid). Internationally recognized. Also, carboxymethyl cellulose can be combined with other cellulose ethers in an advantageous manner, so that lyophilized biomatrix with various properties can be produced.
[0022]
Examples of the fiber component include cellulose ester, polyester, polyamide, polyvinyl alcohol, wool, cotton, silk, and viscose fiber. Here, viscose fibers are particularly preferred. The fiber component preferably has a length of 3 to 30 mm and a fineness of 1 to 6 dtex (1 dtex = 7.85 · 10 ⁻³ ρd ² ; ρ = density g / cm ³ , d = diameter μm). In a main embodiment of the invention, the lyophilized biomatrix contains 3 to 30% by weight, more preferably 3 to 15% by weight of fiber components.
[0023]
The use of viscose fibers is preferred because it is the most hydrophilic fiber component normally used and is most suitable for the production of soluble products. Viscose fibers are non-toxic modified polysaccharides as well as other widely used components of the biomatrix of the present invention. Therefore, the affinity for other components is very high, and as a result, even a small amount of fiber component contributes to the stabilization of the matrix. The suitably used viscose can be used for both cosmetics and pharmaceuticals.
[0024]
The matrix according to the present invention has a skin moisturizing effect on its own and is therefore particularly suitable for use in care cosmetics. At the same time, it is also useful as a carrier substance for skin active substances. The skin active substances can only penetrate into the stratum corneum by the skin moisturizing action of the polysaccharide, or are promoted in a desired form. The lyophilized biomatrix according to the invention can be used for transdermal administration, in a particularly preferred embodiment, with cosmetics as agents and drugs as agents.
[0025]
Examples of cosmetic active substances include many products such as vitamins, proteins, water-soluble plant extracts, and liposomes.
[0026]
The biomatrix according to the invention is suitable for special care of the skin of the face and body in an advantageous manner, in which case use as a face mask is particularly preferred.
[0027]
In contrast to collagen sponges known in the art, the lyophilized biomatrix of the present invention shrinks spontaneously into a gel when added with an aqueous solution, but is similar to the galenischen system of collagen sponges that contain active substances. In addition, the osmotic diffusion liberates additional active substances in certain parts of the skin. The lyophilized biomatrix according to the invention can be used for topical or transdermal administration of the agent, and in a preferred embodiment this biomatrix is used as a wound dressing (eg for hemostasis) or in a particularly preferred embodiment. Used as a drug delivery system.
[0028]
The rapid transdermal transport of the skin active substance is promoted as the stratum corneum is soaked in water, and is promoted by using a freeze-dried biomatrix using a main component having a skin humidifying action. In this case, the low molecular weight substance added to the biomatrix or the aqueous solution diffuses in the epidermis from a portion where the concentration of the supersaturated biomatrix is high to a portion where the concentration is low. Molecules that are relatively easy to penetrate include substances such as short peptides, ATP, urea and electrolytes.
[0029]
The ideal transdermal delivery conditions described above, on the other hand, apply to the low molecular weight material when penetrating from the stratum corneum barrier, which is undesirable and extremely dangerous because it induces skin irritation. Hazardous substances that have been confirmed to have an irritating action include cosmetic preservatives and perfumes, and surfactants that are commonly used in commercial emulsions. A feature of the lyophilized biomatrix according to the invention is that these substances do not need to be used fully and preferably at all.
[0030]
In the conventional xerogel, the matrix structure changes greatly after dehydration, and the distance between the constituent elements is the same as the bond distance of atoms, but in contrast, the biomatrix gel (instant gel) according to the present invention is In order to form pores, the solvent quickly and freely penetrates into the pores and the biomatrix network spontaneously collapses in situ. By freeze-drying, a capillary structure is formed as in the case of water removal by sublimation from food materials such as coffee and tea, so that condensate becomes very quick and the desired immediate effect is obtained.
[0031]
When using substances with many polar groups (cellulose / protein), aqueous solvents tend to form strong crosslinks with these polar groups, thereby affecting dissolution and diffusion properties. If enough water is added (cancelling the cross-linked structure), the polymer matrix returns to its original state, which increases the mobility of water atoms and active substances in the matrix (VNR Pillai, M. Mutter, Naturwissensch. 1981, 68, 558-566). This effect seen in the freeze-dried biomatrix according to the present invention has a great significance for cosmetic use and in vivo kinetics and permeability of cosmetic active substances.
[0032]
In addition, the lyophilized biomatrix according to the present invention can form a water-resistant matrix by adding a certain amount of calcium ions to water used as a solvent, for example, by completely or partially replacing sodium ions of alginate. To do.
[0033]
Due to the naturally formed calcium alginate structure, such an amount of biomatrix can be stabilized so that only a certain portion of the polymer moves into the gel state.
[0034]
In addition, the stabilizing effect of calcium ions can be utilized in a particularly advantageous manner for using the biomatrix of the present invention as a face mask. In this case, the lyophilized biomatrix of the skin can first disintegrate into a gel by the addition of humidity. Subsequently, the gel can be transferred to a soft and separable gel film by supplying calcium ions. For example, spraying a calcium lactate solution allows the gel to be easily peeled or removed from the skin.
[0035]
The matrix can be further stabilized by adding a hydrophilic fiber material (eg viscose fibers). As a result, the stability during drying is greatly improved, so that the handling of the matrix (molding, position correction, etc.) when used for skin protection, for example, is facilitated.
[0036]
A feature of the freeze-dried biomatrix of the present invention that does not contain a fiber component is that when it is used in cosmetics, it is completely invisible when rubbed into the skin, whereas a biomatrix that contains structural fibers contains insoluble fibers. It remains on the skin and must be removed after makeup.
[0037]
In any case, the use of fibers or stabilization with calcium ions can adequately adjust the firmness of the lyophilized biomatrix and adapt the product to the desired application range, but this is necessary. Easy and practical handling is possible.
[0038]
In a further preferred embodiment of the lyophilized biomatrix of the present invention, the biomatrix material capable of micelle binding is prepared by mixing. This material is present in the lyophilized biomatrix by 4-30% by weight, preferably 5-20% by weight. In a plant immediate-reactive biomatrix, for example, isoparaffin can be used as a micelle-forming substance. This isoparaffin can build a bonded structure by micelle formation, thereby creating a stable gel.
[0039]
In particular, the biomatrix of the present invention is free of fragrances, pigments and preservatives.
[0040]
Also, as a feature of the lyophilized biomatrix of the present invention, cosmetic and / or pharmaceutical agents can be easily added from 0.1 to 20% by weight, in a preferred embodiment, from 3 to 10% by weight. Advantageously, the agent can be placed in a capsule such as a liposome or a liposome-like vesicle.
[0041]
The lyophilized biomatrix of the present invention has, for example, the following advantages compared to known biopolymers.
[0042]
For its production, only natural substances and biological components with well-characterized properties are used. The use of skin irritants (eg preservatives, pigments, fragrances, emulsifiers) can be completely avoided.
[0043]
Interaction of the used substances can be avoided by the fact that there are very few kinds of substances used for the production of the biomatrix of the present invention and there is no kinetics inside the biomatrix due to dehydration (lyophilization).
[0044]
Since the composition of the lyophilized biomatrix of the present invention is clear, the chemical, physical and biological analysis of the materials used is easy, so that the quality of the product using this biomatrix is constant. Useful for management immediately.
[0045]
The lyophilized biomatrix is suitable for the production of formulations that are easier to control and more appropriately release the agent to the skin compared to the formulation known as Galennik-Systeme. Therefore, this freeze-dried biomatrix makes it possible to make the dosage of a highly effective drug with a narrow safety margin of, for example, vitamin A derivatives and semi-finished products thereof more accurate. In this lyophilized biomatrix, there is no interaction so that the transport route in the skin is not obstructed, the transport route is short because no obstacle substance (e.g. lipid) is used, and the ease of dose setting, i.e. the concentration of the active substance is reduced. By being able to be higher, the efficacy of conventional agents is higher.
[0046]
Therefore, the consumption of the active substance can be saved by using the freeze-dried biomatrix of the present invention.
[0047]
When producing the lyophilized biomatrix of the present invention, first, natural polysaccharides and modified polysaccharides are added, and optionally the desired cosmetic or pharmaceutical agents are added and mixed uniformly in an aqueous solvent. The mixture is then cooled. A gel forms upon cooling.
[0048]
Next, a fiber component is added to the gel as the case may be, and the mixture is stirred and dispersed uniformly. After stirring, after cooling again at, for example, 1 ° C., the mixture is poured into a mold. In this formwork, the original gel structure is reformed and the subsequent freeze-drying produces a structure similar to a collagen sponge.
[0049]
Freezing is an important processing step as a first step in the subsequent formation of the biomatrix, and in the present invention, the freezing is preferably accelerated at a low temperature in this step. The low temperature frozen gel is then lyophilized under high vacuum to freeze separate and evaporate the solvent (sublimation). An important feature of lyophilization is the ability to form pores without affecting volume. In addition, there is an effect that quick condensate can be obtained, and this effect is known as an immediate effect based on promptness and condensate.
[0050]
In a preferred embodiment of the invention, a dry mixture of natural and modified polysaccharide is first prepared and stirred in water. After the premix is cooled to 10 ° C., the fiber component, cosmetic agent and / or pharmaceutical ingredient, and / or micelle-forming material are dispersed in the premix. The resulting mixture is frozen in a flat formwork at −10 to −40 ° C., preferably −20 ° C., for 0.5 to 4 hours, preferably 1 to 3 hours. The thickness of the flat plate is 0.5 to 3.5 cm, preferably 1.5 to 2.0 cm. The size of the pores generally depends on the freezing speed during freezing. In some cases, the plate is intermediately treated at −10 to −25 ° C., then warmed to a range between 80 ° C. and 120 ° C., and freeze-dried under a vacuum of about 0.5 to 3.0 mbar. The lyophilization process preferably continues for 15 to 35 hours. Thereafter, the flat plate is divided and processed.
[0051]
After the lyophilization process, the water content of the lyophilized biomatrix obtained by the above method is preferably in the range of 5 to 15%, in particular 10%. The dry matter concentration of the raw material used in the production of the freeze-dried biomatrix of the present invention, that is, the concentration of the component mixture in demineralized water is about 1 to 5%.
[0052]
Next, the present invention will be described in more detail based on examples.
[0053]
【Example】
Example 1
The following materials are used in the production of lyophilized biomatrix:
Carboxymethylcellulose 13.5g
Sodium alginate 13.5g
Viscose fiber 1.5g
Aloe extract 1.5g
970.0 g of water (demineralized)
First, a powder mixture of carboxymethyl cellulose and sodium alginate is prepared, and this is dispersed in water while stirring. The mixture (premix I) is cooled to 10 ° C. Disperse the mixture of viscose fiber and aloe extract evenly in premix I. The mixture is then filled into aluminum molds (maximum thickness of about 2 cm) and frozen in a brine bath at −20 ° C. for about 90 minutes. Remove the frozen plate from the aluminum mold and leave it in a low temperature room at -20 ° C for 24 hours. The 2 cm thick plate is lyophilized at 1.5 mbar. In this case, it is first heated at 120 ° C. for 12 hours. Thereafter, freeze-drying is continued for 9 hours at 100 ° C. and 80 ° C., respectively. The dried plate is then divided into 1 mm thicknesses and subjected to normal testing.
[0054]
(Example 2)
For the production of a lyophilized biomatrix containing a micelle-forming substance, a method similar to the method described in Example 1 is used.
[0055]
10.5 g carboxymethylcellulose
10.5 g sodium alginate
2.0 g viscose fiber
2.0 g liquid paraffin
3.0 g squalene
2.0 g polyproxy- (15) -stearyl ether
970 g demineralized water.
[0056]
(Example 3)
In the production of a lyophilized biomatrix that does not contain a fiber component, 16.5 g of sodium alginate, 13.5 g of carboxymethylcellulose, and 970.0 g of demineralized water are used in the same manner as described in Example 1.
[0057]
【The invention's effect】
The lyophilized biomatrix of the present invention is suitable for the production of a formulation that is easier to control and more appropriately releases the agent to the skin compared to known formulations. The production uses only natural and well-derived components with well-characterized properties, so that the use of skin-irritating substances can be completely avoided and helps to maintain a consistent quality control of the product. In addition, since the types of substances used are small, the interaction of the used substances can be avoided.
[0058]
Therefore, when the freeze-dried biomatrix of the present invention is used, the concentration of the active substance can be increased and the consumption of the active substance can be saved.

Claims (25)

A lyophilized biomatrix consisting of 10 to 80% by weight sodium alginate, 20 to 90% by weight carboxymethylcellulose and water. The sodium alginate from 25 to 70 wt%, the present carboxymethyl cellulose 70% by weight 25, and the water that exists in the 5 to 15 wt%, lyophilized biomatrix according to claim 1. The freeze-dried biomatrix according to any one of claims 1 to 2 , for use in external application and / or transdermal administration of an active ingredient. The lyophilized biomatrix according to any one of claims 1 to 3 , for use as a wound dressing.   (I) 10 to 80% by weight of sodium alginate;
  (Ii) 20 to 90% by weight of carboxymethylcellulose;
  (Iii) water; and
  (Iv) A fiber component selected from the group consisting of cellulose ester, polyester, polyamide, polyvinyl alcohol, wool, cotton, silk and viscose fiber.
A freeze-dried biomatrix. 6. The lyophilized biomatrix of claim 5, wherein the sodium alginate is present at 25 to 70% by weight, the carboxymethylcellulose is present at 25 to 70% by weight, and the water is present at 5 to 15% by weight. The lyophilized biomatrix according to any one of claims 5 to 6, wherein the lyophilized biomatrix contains 3 to 30% by weight of fiber components. The lyophilized biomatrix according to any one of claims 5 to 7, wherein the lyophilized biomatrix contains 3 to 15% by weight of fibers. The freeze-dried biomatrix according to any one of claims 5 to 8, wherein the fiber has a length of 3 to 30 mm and a fineness of 1 to 6 dtex. The lyophilized biomatrix according to any one of claims 5 to 9, for use in topical and / or transdermal administration of an active ingredient. The lyophilized biomatrix according to any one of claims 5 to 10, for use as a wound dressing.   (I) 10 to 80% by weight of sodium alginate;
  (Ii) 20 to 90% by weight of carboxymethylcellulose;
  (Iii) water;
  (Iv) a fiber component selected from the group consisting of cellulose ester, polyester, polyamide, polyvinyl alcohol, wool, cotton, silk and viscose fibers; and
  (V) one or several components selected from the group consisting of glucose aminoglycans, micelle-forming substances, calcium ions, active pharmaceutical ingredients and active cosmetic ingredients
A freeze-dried biomatrix. 13. A lyophilized biomatrix according to claim 12, wherein the sodium alginate is present at 25 to 70% by weight, the carboxymethylcellulose is present at 25 to 70% by weight, and the water is present at 5 to 15% by weight. 14. A lyophilized biomatrix according to any one of claims 12 to 13, wherein the lyophilized biomatrix contains 3 to 30% by weight of fiber components. 15. A lyophilized biomatrix according to any one of claims 12 to 14, wherein the lyophilized biomatrix contains 3 to 15% by weight of fibers. The freeze-dried biomatrix according to any one of claims 12 to 15, wherein the fiber has a length of 3 to 30 mm and a fineness of 1 to 6 dtex. The lyophilized biomatrix according to any one of claims 12 to 16, wherein the glucose aminoglycan is selected from the group consisting of hyaluronic acid, hyaluronic acid derivatives or chondroitin sulfate. The freeze-dried biomatrix according to any one of claims 12 to 17, wherein the micelle-forming substance is isoparaffin. 19. A lyophilized biomatrix according to any one of claims 12 to 18, wherein the active ingredient is present at 0.1 to 20% by weight. 20. A lyophilized biomatrix according to any one of claims 12 to 19, wherein the active ingredient is present in 3 to 10% by weight. 21. A lyophilized biomatrix according to any one of claims 12 to 20, wherein the active ingredient is present in capsule form. The lyophilized biomatrix according to any one of claims 12 to 21, wherein the active ingredient is encapsulated in liposomes or liposome-like vesicles. The lyophilized biomatrix of any one of claims 12 to 22, wherein the biomatrix contains calcium ions. 24. A lyophilized biomatrix according to any one of claims 12 to 23 for use in topical and / or transdermal administration of an active ingredient. 25. A lyophilized biomatrix according to any one of claims 12 to 24 for use as a wound dressing.