JPH06211623A - Freeze-drying biomatrix - Google Patents

Abstract

PURPOSE: To provide a freeze-dried biomatrix which is prepd. by compounding natural polysaccharides or denatured polysaccharides and further, water at specific ratios, has a skin moistening effect, less consumes active substances and is suitable for carrier materials, etc., of the active substances of medicines and cosmetics. CONSTITUTION: This biomatrix is obtd. by freeze drying the aq. polysaccharide soln. Namely, the biomatrix contains 10 to 80 wt.% natural polysaccharides and 20 to 90 wt.% denatured polysaccharides. More preferably the biomatrix contains the natural polysaccharides and/or the denatured polysaccharides at 25 to 70 wt.% and the water at 5 to 15 wt.%, more particularly 10 wt.%. The natural polysaccharides are preferably pectin, alginate, carrageenin, agar, Carob (Ceratonia siliqua. L.) flour, etc., and the denatured polysaccharides are film formable binders, such as carboxymethyl cellulose. Fibrous components for improving the stability at dry and/or cosmetic or medicine active substances may be incorporated into this matrix. The matrix does not necessitate the use of skin stimulative substances, such as antiseptics, dyestuff and perfume, and is thus advantageous.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD 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,
Suitable as carrier material for active substances in medicine and cosmetics.

[0002]

Freeze-dried biomatrix is known in the art, in particular as collagen sponge.

For example, US 2 610 625 and US 3 157 524
, And DE 26 25 289, non-reticulated collagen sponges are produced from freeze-dried collagen aqueous solutions, or they are foamed with water-miscible organic solvents. Is produced by removing water from. The easily processable product having a sponge-like structure produced in this way swells and decomposes immediately upon addition of water. This product is never stable under humid conditions.

Water-resistant collagen-based water-resistant sponges prepared by adding a cross-linking agent are described in DE 27 3
4 503, 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 medium and contains residues of the crosslinking agent used. This cross-linking agent not only causes irritation to sensitive skin, but also penetrates into the skin as a low molecular weight substance and causes an undesired reaction in the body.

According to the method described in DE-OS 40 28 622, it is possible to produce a collagen sponge which is crosslinked without using a chemical additive 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 dipping, tanning, meat removal and peeling of the silver film of salt-preserved raw material are first performed. Then, the raw material is purified by an alkali treatment and an acid treatment immediately after that to remove the non-collagen impurities.

[0006] In certain consumer groups, for example, for religious or ethical reasons, there is a growing tendency to not use animal materials at all. Furthermore, when using animal materials, there is a risk that the product may contain immunogens or pathogens.

The use of plant-derived substances in pharmacy or as cosmetics is a known technique. In the area of pharmacy, for example, calcium alginate has been used for wound treatment (eg Sorbalgon® / Hartman).
n). Also, the use of plant-based biopolymers for cosmetic skin treatment has long been known (The Chemistry and
Technology of Pectin, Reginald H. Walter, Chapter 12, 2
51-264, and Investigating the Nutritional, M
edicinal and Cosmetic Values of Seaweeds and their
Extracts, Koyama, Hayatsu, Yamoto, Ph. D. Morsy,
Erde International, pp. 85-106). However, the conventional commercial products using the above-mentioned vegetable biopolymer as a raw material have not been very kind to users. Traditionally used biopolymer mixtures are prone to dust generation,
It is not easy to handle because it is difficult to dissolve in water, resulting in a non-uniform mixture.

[0008]

SUMMARY OF THE INVENTION The present invention relates to a lyophilized biomatrix based on natural and modified polysaccharides, the use of which is for topical and transdermal administration of pharmaceutical and cosmetic agents.

The lyophilized biomatrix of the present invention comprises
It is suitable for producing a formulation which is easier to control than known formulations and which can release the active substance to the skin more appropriately. In this freeze-dried biomatrix,
Due to the absence of interactions, the transport route in the skin is not obstructed, the transport route is short because no obstructive substances (e.g. lipids) are used, and the ease of dose setting, i.e. the higher concentration of active substance The potency of the agent is higher.

Therefore, consumption of the active substance can be saved by using the freeze-dried biomatrix of the present invention. Also,
Skin irritants (eg preservatives, pigments, fragrances, emulsifiers)
The use of can be avoided altogether.

[0011]

The object of the present invention is to produce a biomatrix, preferably based on non-animal substances, particularly preferably using only non-animal substances, which biomatrix is a galenic pharmaceutical ( galenischen Sy
Like the collagen sponge of stem), it does not contain a preservative, a cross-linking agent and a fragrance, and can achieve skin moisturization without irritation. In addition, this biomatrix appears to be suitable for transdermal administration of drug and cosmetic agents.

This problem is solved according to the invention by a biomatrix produced by freeze-drying an aqueous polysaccharide solution. The biomatrix according to the invention contains 10 to 80% by weight of natural polysaccharides and 20 to 90% by weight of modified polysaccharides. Preferably, this 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.
contains. When necessary, the biomatrix of the present invention may contain the components shown below.

In contrast to other drying methods such as spray-drying and air-drying, the freeze-drying method is a sponge-like biomatrix which has a convenient property (immediate effect) that allows rapid reconstitution. The water supply results in a biomatrix that spontaneously forms a gel.

The natural polysaccharides are preferably selected from the group consisting of pectin, alginates, carrageenins, agar and locust bean flour.

Examples of the modified polysaccharide include cellulose derivatives such as cellulose ether. Preferably, a film-forming binder such as carboxymethyl cellulose or its derivatives is used. Carboxymethyl cellulose can be combined in an advantageous manner with other cellulose ethers, polyesters or polyvinyl alcohols.

The freeze-dried biomatrix according to the invention exhibits a sponge-like structure with fine pores and is produced in a preferred embodiment from plant-derived materials.

The polysaccharides used according to the invention can be combined with proteins of plant origin in an advantageous manner. Furthermore, as additional polysaccharides, glucose aminoglycans such as hyaluronic acid, hyaluronic acid derivatives, and chondroitin sulfate are also used.

In the lyophilization of the polysaccharide mixture, unlike the dispersion of collagen, it is not necessary to consider the isoelectric point,
For example, hyaluronic acid can be mixed in with almost no problem. The freeze-dried biomatrix of the present invention is mainly composed of polysaccharides, namely 1. Natural polysaccharides 2. It consists of modified polysaccharides. This matrix further includes 3. 3. Fiber components and / or to improve dry stability. Cosmetic or medicinal agents can be included.

In a preferred embodiment of the invention, the biomatrix solution or suspension used for the production of the freeze-dried biomatrix is 0.25 to 2.5% by weight, preferably 0.9.
To 1.9 wt% natural polysaccharide and 0.5 to 2.5 wt%, preferably 0.9 to 1.6 wt% modified polysaccharide, demineralized water is added to adjust to 100%. In addition, 0.05 to 0.7
5% by weight, preferably 0.12-0.23% by weight of the fiber component, and / or 0.0025 to 0.5% by weight, depending on the intended use,
Preferably 0.12 to 0.17% by weight of cosmetic and / or pharmaceutically active substances can be added to this mixture.

In a particularly preferred embodiment, the suspension for producing the freeze-dried biomatrix further comprises a micelle-forming substance such as isoparaffin in a total amount of 0.1-1.5% by weight, preferably 0.17-0.81% by weight. And

The polysaccharides used in the present invention, especially those of vegetable origin, have the properties of protective colloids. Possible modified polysaccharides are film-forming binders, which on the one hand have an affinity for the natural polysaccharides and, on the other hand, also for the incorporated fiber components. The use of carboxymethylcellulose has the advantage that a product with reversible water solubility can be obtained, and carboxymethylcellulose is non-toxic and is also an additive as a cosmetic base.
It is also internationally recognized as (binder, thickener, protective colloid). In addition, carboxymethyl cellulose can be combined with other cellulose ethers in an advantageous manner, so that a lyophilized biomatrix with various properties can be produced.

As the fiber component, cellulose ester,
Mention may be made of polyester, polyamide, polyvinyl alcohol, wool, cotton, silk and viscose fibers. Viscose fibers are particularly preferred here. The fiber component has a length
3-30 mm, fineness 1-6 dtex is desirable (1 d
tex = 7.85 · 10 ^-3 ρd ² ; ρ = density g / cm ³ , d = diameter μm). In a major embodiment of the invention, the lyophilized biomatrix comprises 3-30% by weight, more preferably 3-15% by weight of the fiber component.

The use of viscose fibers is preferred because it is the most hydrophilic fiber component normally used and most suitable for the production of soluble products. Viscose fiber, like other widely used components of the biomatrix of the present invention, is a non-toxic modified polysaccharide. Therefore, it has a very high affinity for other components, and as a result, even a small amount of the fiber component contributes to the stabilization of the matrix. The suitably used viscose is approved for use in cosmetics and pharmaceuticals.

The matrix according to the invention has a moisturizing action 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, which can be penetrated into the stratum corneum or promoted in a desired form only by the skin moisturizing action of the polysaccharide. The freeze-dried biomatrix according to the invention is in a particularly preferred embodiment
Cosmetics as active substances, drugs as active substances,
It can be used for transdermal administration.

The cosmetically active substances include, for example, many products such as vitamins, proteins, water-soluble plant extracts, liposomes and the like.

The biomatrix according to the invention is suitable in an advantageous manner for the special care of the face and body skin, the use as a face mask being particularly preferred in this case.

In contrast to the collagen sponges known in the art, the freeze-dried biomatrix of the invention spontaneously shrinks into a gel when an aqueous solution is added, but the collagen sponge containing the active substance is galenische.
n System), osmotic diffusion liberates additional active agents on selected areas of the skin. The lyophilized biomatrix according to the invention can be used for topical or transdermal administration of an agent, in a preferred embodiment the biomatrix is used as a wound dressing (e.g. for hemostasis) or in a particularly preferred embodiment. Used as a drug delivery system.

The rapid transdermal transport of skin-active substances is promoted as the degree of water infiltration of the stratum corneum is increased, and also by using a freeze-dried biomatrix having a main component having a skin moisturizing action. . In this case, the low-molecular-weight substance added to the biomatrix or the aqueous solution diffuses in the epidermis from a part having a high concentration of the biomatrix supersaturated in water to a part having a low concentration. Molecules that are relatively permeable include short-chain peptides, ATP, urea and substances such as electrolytes.

The above-mentioned ideal transdermal transport conditions, on the other hand, are also undesired and extremely dangerous because they permeate through the stratum corneum barrier and also apply to the low molecular weight substance, which induces skin irritation. Hazardous substances that have been confirmed to have irritating effects include cosmetic preservatives and fragrances, and surface-active substances commonly used in commercial emulsions. A feature of the freeze-dried biomatrix according to the invention is that these substances do not have to be used fully and preferably at all.

In the conventional xerogel, the matrix structure is largely changed after dehydration, and the distance between the constituents is the same as the bond distance of atoms. In contrast to this, the biomatrix gel (instantaneous) according to the present invention is used. gel)
Form pores, the solvent penetrates quickly and freely into the pores, and the biomatrix network
It spontaneously collapses in situ. Freeze-drying forms a capillary structure, similar to water removal by sublimation from food ingredients such as coffee and tea, so that condensate becomes very quick and the desired immediate effect is obtained.

A substance having many polar groups (cellulose /
When using (proteins), aqueous solvents tend to form strong cross-links with these polar groups, which affects their solubility and diffusion properties. When sufficient water is added (the cross-linking structure is canceled), the polymer matrix returns to its original state, and the mobility of the water atom and the active substance in the matrix increases (VNR Pillai, M. Mutter, Natu
rwissensch. 1981, 68, 558-566). This effect found in the freeze-dried biomatrix according to the invention has great significance when used in cosmetics and on the biokinetics and permeability of cosmetic active substances.

Further, the freeze-dried biomatrix according to the present invention forms a water-resistant matrix when a certain amount of calcium ion is added to water used as a solvent to completely or partially replace sodium ion of alginate. Is possible.

Due to the naturally formed calcium alginate structure, such an amount of biomatrix can be stabilized such that only a certain portion of the polymer transitions to the gel state.

In addition, the stabilizing effect of calcium ions can be utilized in a particularly advantageous way for using the biomatrix of the present invention as a face mask. In this case, the freeze-dried biomatrix of the skin can first disintegrate to gel by the addition of humidity.
The gel can subsequently be transferred to a soft, 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.

Hydrophilic fibrous material (eg viscose fiber)
The matrix can be further stabilized by adding This greatly improves the stability during drying, which facilitates handling of the matrix (molding, correction of position, etc.) when used for skin protection, for example.

A feature of the freeze-dried biomatrix of the present invention which does not contain a fiber component is that it is completely invisible when rubbed on the skin when used in cosmetics,
On the other hand, in a biomatrix containing structural fibers, insoluble fibers remain on the skin and must be removed after makeup.

In any case, the use of fibers or stabilization with calcium ions allows the hardness of the freeze-dried biomatrix to be adjusted appropriately and the product to be adapted to the desired application range. It can be handled easily and practically.

In a further preferred embodiment of the freeze-dried biomatrix according to the invention, micelle-binding biomatrix materials are mixed and prepared. This material is present in the lyophilized biomatrix in an amount of 4-30% by weight, preferably 5-20% by weight. In the vegetable immediate-reactive biomatrix, for example, isoparaffin can be used as a micelle forming substance. This isoparaffin can build a cohesive structure by micelle formation, thereby creating a stable gel.

In particular, the biomatrix according to the invention is free of perfumes, pigments and preservatives.

The freeze-dried biomatrix of the invention is also characterized by the fact that it contains 0.1 to 20% by weight, in a preferred embodiment, of a cosmetic and / or pharmaceutical agent.
3 to 10% by weight, easy to add. It is advantageous to be able to enclose the active substance in capsules, such as liposomes or liposome-like vesicles.

The freeze-dried biomatrix of the present invention comprises
For example, it has the following advantages over known biopolymers:

For its production, only natural substances and components derived from living organisms whose properties have been well elucidated are used. The use of skin-irritating substances (eg preservatives, pigments, fragrances, emulsifiers) can be avoided altogether.

Avoiding the interaction of the substances used in the production of the biomatrix according to the invention by the very small number of substances used and the absence of kinetics inside the biomatrix by dehydration (freeze-drying). You can

Since the composition of the freeze-dried biomatrix of the present invention is clear, the chemical composition of the substance used
Physical and biological analyzes are easy and therefore immediately lend themselves to consistent quality control of products using this biomatrix.

The lyophilized biomatrix is suitable for the production of a formulation which is easier to control and which more appropriately releases the active substance to the skin, compared to the formulation known as Galenik-Systeme. ing. Therefore, with this freeze-dried biomatrix, for example, the dose of a drug having a narrow safety margin and high potency of a vitamin A derivative or a semi-finished product thereof can be made more accurate. In this freeze-dried biomatrix, there is no interaction, so the transport route in the skin is not obstructed, the transport route is short because no obstacle substances (such as lipids) are used, and the ease of dose setting, that is, the concentration of the active substance is By being able to be higher, the potency of conventional agents will be higher.

Therefore, consumption of the active substance can be saved by using the freeze-dried biomatrix of the present invention.

In producing the freeze-dried biomatrix of the present invention, first, a natural polysaccharide and a modified polysaccharide and, if necessary, a desired cosmetic or pharmaceutical active substance are added to a homogeneous mixture in an aqueous solvent. And then the mixture is cooled. A gel is formed on cooling.

Then, a fiber component is added to this gel, if necessary, and stirred to disperse it uniformly. After stirring, the mixture is cooled again at, for example, 1 ° C., and then poured into a mold. Within this mold, the initial gel structure is reformed and subsequent freeze-drying produces a collagen sponge-like structure.

Freezing is an important process step as the first step in the subsequent formation of the biomatrix, and in the present invention,
Preferably, low temperatures accelerate freezing in this step. The cryogenically frozen gel is then freeze-dried under high vacuum to freeze separate and evaporate the solvent (sublimation). An important feature of freeze-drying is the ability to form pores without affecting volume. Furthermore, there is an effect that a quick reconstitution is obtained, and this effect is known as an immediate effect based on the quick reconstitution.

In a preferred embodiment of the invention, a dry mixture of natural and modified polysaccharides is first prepared and stirred in water. After cooling the premix to 10 ° C., the fiber component, the cosmetic active ingredient and / or the pharmaceutical ingredient and / or the micelle-forming substance are dispersed in the premix. The resulting mixture is -10 to -40 ° C, preferably-
Freeze at 20 ° C for 0.5 to 4 hours, preferably 1 to 3 hours in a flat form. The thickness of the flat plate is 0.5 to 3.5 cm,
It is preferably 1.5 to 2.0 cm. The size of the pores generally depends on the freezing rate during freezing. In some cases, after the plate was subjected to intermediate treatment at -10 to -25 ° C,
It is lyophilized under a vacuum of about 0.5 to 3.0 mbar, warming to a range between 0 and 120 ° C. The freeze-drying process preferably lasts 15 to 35 hours. After that, the flat plate is divided and processed.

After the freeze-drying process, the water content of the freeze-dried biomatrix obtained by the above method is preferably 5%.
It is preferably in the range from 1 to 15%, especially 10%.
The dry concentration of the raw material used for the production of the freeze-dried biomatrix of the present invention, ie the concentration of the component mixture in demineralized water, is about 1 to 5%.

Next, the present invention will be described in more detail based on examples.

[0053]

【Example】

Example 1 The following substances are used in the production of freeze-dried biomatrix: Carboxymethylcellulose 13.5g Sodium alginate 13.5g Viscose fiber 1.5g Aloe extract 1.5g Water (demineralized) 970.0g First, carboxymethylcellulose and sodium alginate. A powder mixture of is prepared and dispersed in water with stirring. This mixture (premix I) is cooled to 10 ° C. A mixture of viscose fiber and aloe extract is evenly dispersed in Premix I. Then, this mixture was filled in an aluminum mold (maximum thickness of about 2 cm) and then in a salt water bath at -20 ° C.
Freeze for about 90 minutes. Remove the frozen plate from the aluminum mold and leave it in a low temperature room at -20 ℃ for 24 hours. The 2 cm thick plate is freeze dried at 1.5 mbar. In this case, first 1
Heat at 20 ° C for 12 hours. Then, freeze-drying is continued at 100 ° C. and 80 ° C. for 9 hours each. The dried plate is then divided into 1 mm thick and the usual tests are carried out.

(Example 2) For the production of a freeze-dried biomatrix containing a micelle forming substance, a method similar to the method described in Example 1 is used.

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.

(Example 3) To produce a freeze-dried biomatrix containing no fiber component, sodium alginate 16.5 g, carboxymethylcellulose 13.5 g, and demineralized water 970.0 were prepared in the same manner as in Example 1.
Use g.

[0057]

INDUSTRIAL APPLICABILITY The freeze-dried biomatrix of the present invention is suitable for producing a preparation which is easier to control and more appropriately releases the active substance to the skin than the known preparations. Only natural substances with well-characterized properties and bio-derived components are used in its production, so that the use of skin-irritating substances can be completely avoided and it also contributes to the constant quality control of the product. Further, since the types of substances used are small, it is possible to avoid the interaction of the substances used.

Therefore, by using the freeze-dried biomatrix of the present invention, the concentration of the active substance can be increased and the consumption amount of the active substance can be saved.

Continued front page (72) Inventor Wolfgang Zberack 48727 Bierbeck, Federal Republic of Germany 39727 Münsterstraße 39 (72) Inventor Tudeneck Eckmeyer Weinham 69469, Federal Republic of Germany Rote Tulum Strasse 28 (72) Inventor Petra Thebes-Schwarzer Germany Federal Republic of Münster 48163, Osterstraße 73

Claims (23)

[Claims] 1. A freeze-dried biomatrix containing 10 to 80% by weight of a natural polysaccharide and 20 to 90% by weight of a modified polysaccharide. 2. The freeze-dried biomatrix according to claim 1, which contains 25 to 70% by weight of the natural polysaccharide, 25 to 70% by weight of the modified polysaccharide, and 5 to 15% by weight of water. 3. The natural polysaccharide is pectin, alginic acid,
Freeze-dried biomatrix according to claim 1 or 2, selected from the group consisting of carrageenan, agar and locust bean flour. 4. The freeze-dried biomatrix according to claim 1, which contains a film-forming binder as the modified polysaccharide. 5. The freeze-dried biomatrix according to claim 1, which contains a cellulose ether derivative as the modified polysaccharide. 6. The freeze-dried biomatrix according to claim 5, further comprising cellulose ester, polyester or polyvinyl alcohol as a fiber component. 7. The biomatrix is 3 to 30% by weight.
7. The freeze-dried biomatrix according to claims 1 to 6, which comprises the fibers of: 8. The biomatrix is 3 to 15% by weight.
The freeze-dried biomatrix according to claim 7, which contains the fiber of. 9. The freeze-dried biomatrix according to claim 6, wherein the fiber is selected from the group consisting of cellulose ester, polyester, polyamide, polyvinyl alcohol, wool, cotton, silk and viscose fiber. 10. The fiber has a length of 3 to 30 mm and a fineness of 1
10. The freeze-dried biomatrix according to claims 6-9, which is from 6 to 6 dtex. 11. The freeze-dried biomatrix according to claim 1, wherein the biomatrix further contains a protein of plant origin. 12. The freeze-dried biomatrix according to claim 1, wherein the biomatrix further contains glucose aminoglycan. 13. The freeze-dried biomatrix according to claim 12, wherein the glucose aminoglycan is selected from the group consisting of hyaluronic acid, hyaluronic acid derivatives or chondroitin sulfate. 14. The freeze-dried biomatrix according to claim 1, wherein the biomatrix contains a substance capable of forming micelles. 15. The freeze-dried biomatrix according to claim 14, wherein the micelle-forming substance is isoparaffin. 16. The biomatrix is a drug and / or
Alternatively, it contains a cosmetic active substance.
The freeze-dried biomatrix according to. 17. The freeze-dried biomatrix according to claim 16, wherein the biomatrix contains 0.1 to 20% by weight of the active substance. 18. The freeze-dried biomatrix according to claim 16 or 17, wherein the biomatrix contains 3 to 10% by weight of the active substance. 19. Freeze-dried biomatrix according to claims 15 to 18, wherein the active substance is present in capsule form. 20. The lyophilized biomatrix according to claim 19, wherein the agent is encapsulated in liposomes or liposome-like vesicles. 21. The freeze-dried biomatrix according to claim 1, wherein the biomatrix is made water resistant by calcium ions. 22. Use of the lyophilized biomatrix according to claims 1 to 21 for the use of an agent for external and / or transdermal administration. 23. Use of the freeze-dried biomatrix according to claim 22 as a wound dressing.