WO2006125857A1

WO2006125857A1 - Composition and manufacturing process of cetraria islandica based polymer blend

Info

Publication number: WO2006125857A1
Application number: PCT/FI2006/000166
Authority: WO
Inventors: Mika Tapio Reijonen
Original assignee: Mika Tapio Reijonen
Priority date: 2005-05-26
Filing date: 2006-05-26
Publication date: 2006-11-30

Abstract

A polymer blend, which is used as medicine, implants, wound preparations, herbal preparations, nutrients, cosmetics products, food components or for packing materials comprises of : lichenan or lichenan and Cetraria species lichen other components (1) other from the combination (1); and one or the more other polymers (3); and solvents of polymers (2 and 4) typically water or ethanol or combinations thereof.

Description

COMPOSITION AND MANUFACTURING PROCESS OF CETRARIA ISLANDICA BASED POLYMER BLEND

TECHNICAL FIELD

The invention is the making of polymer blend at least with two polymers, typically biopolymer. The compositions of the blend and process conditions are crucial factors in the polymer science area, which are connected to for example pharmaceutical, surgery, cosmetic and food industries.

BACKGROUND OF THE INVENTION

The Finnish Funding Agency for Technology and Innovation, Tekes had the polymers as the future builders program during 2000-2003 (http://www.tekes.fi/julkaisut/Potra.pdf gotten 26.5.2005) the and the final report describes different using targets, such as articles Biohajoavat polymeerit laakkeiden ja geenien annostelussa ja Tarkkelyspohjaiset polyolit polymeerien raaka-aineina. For example From solvent to aqueous film coating - in the article (http://www.idealcures.co.in/solvents.htm gotten 26.5.2005) is told from the coating, which more often should be water-based. In the article, it is described using of plasticizers and for them connected problems. These are forced often to use in order to increase the flexibility of films, but on the larger amount it generally affects by an opposite way. hi addition to by using the plasticizers, it can arise also other problems, such as in the substances in the film being separating.

SUMMARY OF THE INVENTION

The present invention contains a composition and manufacturing process for the polymer blend based one or more substances from Cetraria islandica, typically lichenan, with other polymer, typically starch, and solvent, such water, for water-soluble, biodegradable and safe applications, like coating processes for example in capsules, microcapsules or nanocapsules, matrixes, scaffolds, or gels, and so the influence of materials as a different protecting and carrier applications. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The target of the invention is to make the polymer blend was able to make suitable for water-based coatings and gels with hydrogen bond networks. According to invention the process and composition do not need preferably plasticizers and it do not need to make derivatives. The polymer blend forms hard, but flexible film, and these properties can easily affects on the ratio of polymers and on the process conditions, such as with the temperature and pressure. In addition, the formed film is not sticky.

Both starch and Icelandic moss ((Cetraria islandica (L.) Ach.), which includes abundance of lichenan, are safe, biodegrable and renewable resources, which the both form from the glucose units, i.e.glucan. So, for example, according to the invention making implants are not forced to cut out from body by surgery operations. A big advantage is that the polymer blend is preferable polysaccharide mixtures, neither for example protein, which can leads many allergy problems and foreign body reactions.

Cetraria islandica includes 50 % water-soluble polysaccharide, including lichenan, which is linear cellulose type b-D-glucose polymer and isolichenan, which is linear starch type a- D-glucose polymer. These polysaccharides have so both the properties of the starch and cellulose. In addition, lichenan is also in other lichens and in some plants. Pollutants and heavy metals can be removed with the help of the modern technology, and make as needed the sensitive tests, and in Finland is possible to collect abundant Cetraria islandica from the slight pollutant fallout areas. Fortunately, Cetraria islandica is fast growing compared to other lichen species. It belongs to bush like lichens and the rate of growth about 1 cm/y, and of course, the biotechnological manufacturing processes are possible. For example in Scandinavia, Russia, the USA and Canada Cetraria islandica in are available big, easily and quickly collected carpets, which are able cut part for example by a lawnmower way. At the moment Islandic moss is used only little for benefit.

Cetraria islandica is a safe material. In the directive 2002/46/EC it is said that Cetraria islandica is including as a characteristic nutrient substance, (in English http://www.elintarvikevirasto.fi/english/p3544.pdfin Finnish http://www.elintarvikevirasto.fi/yrittajalle/p3487.pdf gotten 26.5.2005 on page 3 In addition, the polysaccharides from Cetraria islandica are shown itself having antimicrobic effects (Rational approach to fractionation, isolation, and characterization of polysaccharides from the lichen Cetraria islandica. Kramer P, Wincierz U, Grubler G; Tschakert J, Voelter W, Mayer H. Arzneiπήttel-Forschung (1995 Jun), 45(6), 726-31), when often it is forced to to increase conservation material, and on the other hand the conservation material can be together incompatibility with other materials.

Cetraria islandica are shown to to be antioxidant (Ilhami Gulcin, Munir Oktay, O. Irfan Kufrevioglu, AH Asian. Determination of antioxidant activity of lichen Cetraria islandica (L) Ach. Journal of Ethnopharmacology 79 (2002) 325-329).

The recently published US patent 6,878,199 Bowde et al. April 12, 2005 biodegradable or compostable containers on page 2 in the lines 21-22 and 44-45 are written that many attempts are made using of the starch in materials, but suitable combination has not achieved. Also in this patent it is not presented the blend of starch and lichenan.

The properties of starch are tried to affect for example with the temperature, such as using over 100 ⁰C and by using plasticizers, such as in the US patent 5,569,692 Bastioli et.al. Biodegradable compositions and films or moulded articles obtained therefrom.

Also celluloses are tried to use with other polymers for example with chitosan, such as Makoto Hasegawa, Akira Isogai, Fumihiko Onabe, Makoto Usuda, Rajai H. Atalla. Characterization of cellulose-chitosan blend films. Journal of Applied Polymer Science, Volume 45, Issue 11 , pages 1873- 1879, 2003.

Cereal glucans has been studies much, for example in the patent CNl 324216 Method for isolating beta-glucan composition from oats and products and therefrom, but the protein of corns are difficult get away from the product. These proteins cause allergy reactions. The acid materials of Cetraria islandica get away by basic processes, for example with NaOH aqueous solution. In addition, it is possible to crush and after boiling the solution is bright, but little brown. After cooling it is geeling, and can with cold water, where lichenan does not dissolve. The gel can be used or then it can be precipated for example with ethanol. Starch is different depending on plant sources, such as from potato, rice, sago, soy and cereal species, and of cource these belonging under the field of the invention. Potato starch is cheap and it is glutein-free products. Studies from the potato starch structure it made for example in the university of Helsinki published thesis (http

://emesis.helsmki.fi/julkaisut/mat/fysik/pg/ikonen/perunata.pdf gotten 26.5.2005). In the lichen, the polysaccharides are not in grain, where there are also protein, and so the purification is complex in grains. In the lichen, polysaccharides forms a flexible skeleton. Glutein-free diet must be followed all through life. Sensitivity to glutein is permanent, although symptoms become smaller and intestinal villi improves with the right diet.

Non-animal sourced solutions are pressed to make, so for example from cow carcass to get gelatine it could be to invented alternatives for these using. Lichenan and for example with starch formed blend is a non-animal sourced and neither petrochemical products.

Polymer, such as polysaccharide can modify by chemical, physical and chemical-physical ways. The polymer can make changes by increasing desired groups, whereby the properties of the polymers change. Some important factors for drugs diffusion are for example copolymerization, cross linkages in the polymers and the crystallinity of the polymers. In the invention it can easily affects lichenan and other polymer the properties of the polymer blend, for example on the potato starch ratio or using of the isolated material, such as using as different ratio of amylose and amylopectin or only from another of these, i.e.only amylose or amylopectin or rich products of these.

The properties of the forming film and hereby also for example material controlled release is affected both on the composition, especially on the polymers relationship, and on the process conditions, for example in spraying and temperature. Because of the good binder¹ properties, polymer blend suits for example medicines, paints and glues as a component. The renewable natural resources based the environmentally friendly glues, e.g. for paper products and fibre materials. The polymeric blend can be used to prepare both solution and dispersion glues and hot melting glues. In addition, polymer blend can use as ecological packing materials for example in blisters. Film forming materials are for example gelatine, gum acacia, starch, polyvinylpyrrolidone PVP, carboxymethyl cellulose CMC, hydroxyethylcellulose, methyl cellulose, polyvinyl alcohol PVA, polyacrylic acid, polyetylen, polyamide (nylon), cellulose acetate, cellulose nitrate, silicones, waxes and grease such as paraffin, beeswax, stearine, myristine, palrnitine and lauric acid, lauryl, cetyl, stearyl , myristyylialcohol, shellac, cellulose acetatftalate, cellulose acetatbutyrate and cellulose acetatesuccinate. For example hydroxypropyhnethylcellulose needs plasticizers , example polyethylenglycol or glycerol, and here is as danger separating of the materials. On other hand cellulose has not meant to be human organs eatable, which a human being is not able to melt.

The micro, nano and so on, encapsulation are meant a method, where the small particles of the solid material, liquid drops, or gaseous material is being coated with the polymer or other suitable material by forming consistent film. The manufacturing methods of the microcapsule are many, where the most important are in situ layer polymerization and coaservation technologies. By the microencapsulation can be affected to properties of medicine properties and on the microcapsules are many most important applications in the drug industry. Microcapsules are used extensively in many trade areas such as in the agriculture, medical industry, pharmaceutical industry and in the biotechnology. Micro encapsulation improves appreciable enzyme stability and extends the duration of the effect. Also cells can be capsulated.

In the US patent 6,613,733 Barnabas et al. presented opposite starch free composition.

In the US patent 6,358,580 Mang et. al. presented in the claim 1 b) adds the water superabsorbent synthetic polymer.

Starch does not have compatibility problems (Handbook of pharmaceutical excipients, Arthur H. Kibbe, 3th edition, 2000, the USA) and it is inexpensive, and this extremely much tried for example its possibility of hard and flexible film forming properties. Starch is light, colourless, fine and odourless powder, such as also lichenan. Nowadays mainly corn starch and potato starch are used in tablets.

Polymers are used medicine area to many to different applications, such as to stabilize emulsion or suspension conditions, flocculating promoting materials, coating or as the binder material, packing material, for example medicine blisters and many different ways in controlling drug release. Polymers are used also trandermal medication to release drug in a controlled way. Preparation types are depot plaster, which drug can be in matrix or controlled by diffusion of film or combinations of thereof.

Plasma substitutes with the help of expanders will normalize from the loss of blood caused the deficit of the volume and for example in accidents. As the plasma substitutes are being used macromolecules including colloid solution. As the plasma substitute using from the colloid is being required, that the physical and chemical composition are near the possibly, organs the composition of the own blood plasma. Polymer capsules can also use to transport built genes or drug defined places in the body. The film structure can include chemical mark such as, dust polyethyleoxide like marker. This is recognized only in the specified cell. After the medicine giving, to the patient, polymer capsule finds its road to the cell where there is comparable a chemical mark as on the capsule.

EXAMPLES

EXAMPLE 1 50 g dried Cetraria islandica (Fig 1. (1)) was put 40Og to the boiling water (Fig 1. (2)).

This blend 1 in Fig .1 was given to boil 15 min under magnetic stirring. It made mixture of 20 potato starch (Fig 1. (3)) (Finnamyl Oy, Finland) and 20 g cold water (Fig 1. (4)), and after that the blend 2 in Fig. 1 was cast sieve (0,59 mm) through, and from this hot solution taken 20 ml was put to four 100 ml decanter glass, which added 1, 2, 3 or 4 g of the blend 1. It was given be under warming magnetic stirrer for 3 min and was cast forming the polymer blend in Fig 1. to the Petri vases, which diameter was 94 mm. These blends were given dry room temperature, whereby formed different properties owing films. The film, where was added 3 g , was made the tensile strength examination of the film by the material test device (Lloyd Ltd., England) The film was cut lcm x 1.5cm strip to the jaws. The film was pulled lOmm/min at speed. In the picture 2 it shows the obtained load-time curve. The thickness of the film was 0.026 mm, which was measured on the digital micrometer (Sony digital indicator U30, Japan). EXAMPLE 2

Lichenan extracted from Cetraria islandica such as Kramer P, Wincierz U, Grubler G; Tschakert J, Voelter W₅ Mayer H. Rational approach to fractionation, isolation, and characterization of polysaccharides from the lichen Cetraria islandica. Arzneimittel- Forschung (1995 Jun), 45(6), 726-731 presenting, except that now it was used alkaline aqueous solution of NaOH in washing until aqueous solution was without brown color, and then it was washed with fresh water and dried in room temperature.. Acids materials, such as tannine acids were got out before boiling and this risk to the acid hydrolysis is not, and in temperature being at the maximum + 100 ⁰C, an so the degraradation of the polysaccharide will not happen. The industry is pressed to avoid for example the use of the ether, which is shown in the article Kramer P, Wincierz U, Grubler G; Tschakert J, Voelter W, Mayer H. Rational approach to fractionation, isolation, and characterization of polysaccharides from the lichen Cetraria islandica. Arzneimittel-Forschung (1995 Jun), 45(6), 726-731. As the problem is, that during drying lichenan, it changes for the brown or for the black color, and researchers uses for example ether. In this invention especially is being avoided the use of the ether, when generally aqueous or/and ethanol including mass it is yet wet, then it will add another polymer or polymer, typically starch or its fraction, like making mixed crystals. Another possibility is let be typically for a week time room temperature in ethanol (96 %), whereby after that during drying it does not darken. Also cold drying e.g. freeze and spray drying and for example fluid nitrogen is possible to use. In the example it was made 3 g of corn starch (Ph.Eur.) and 3 g lichenan on ethanol (96 %) moisture, when that was dried out on the filter for 2 minutes. It was added 100 g distilled water, and the blend was heated on the heat plate under magnetic stirring for 20 minutes, after then 50 ml distilled water was added. Then the 70 ⁰C blend was added slowly 2Og 23 ⁰C 1 %

(weight/weight) ibuprofen in ethanol (96 %) magnetic to the glass slide and it was dried on the heat air, and after that was taken by light microscope pictures from this dried from the blend (Picture 3. a) and from the crystallized ibuprofen from ethanol (Picture 3. b)), which was as a starting material.

EXAMPLE 3

The same blend in the example 2 in 70 ⁰C it was cast to teflon moulds (3 cm x 11 cm) 1O g mixture and was given to dry room temperature overnight , after then measured film tensile strength with the material test device (Lloyd Ltd, England). The film was cut 2 cm x 2 cm strip to the as attached jaws. The curve of load and time is shown Picture 4.

EXAMPLE 4

The 3 cm x 2 cm cut by the example 3 films were put to dissolve 80 ml distilled water in the 100 ml decanter glass on the heat plate under magnetic stirrer for 20 minutes, where the film dissolved slowly. This can easily regulate with lichenan-starch ratio, and get appreciably different properties of dissolution of gel strengths.

For those skilled in the arts are clear that the invention is not limited to the presented details, such for example the using of the polymers can be coating, painting and polishing area. Also the making of the mixture and drying can happen in many different way for example spray and freeze drying or different mixture order and different conditions, such as high or low pressure and high or low temperature. In the polymer chemistry it is known many manufacturing processes, which are suitable for water-based coating and other applications. In addition, the polymer blend can be solid, gel, liquid or gas in manufacturing process and the form of the final product can be solid, semisolid or liquid and desirable fractions of molecules. Alternatives of solvents are not restricted, but for example acetone can use. Instead of the precipitation with ethanol, it can do also with other substances, but because ethanol is cheap and safe, it is preferably used. One way is to make the mixture of wet lichenan and other polymer, like starch, and so the problem of darkening is not happening.

The chemical and physical modifications of polymers are well known in skilled workers. Also polymer technologies such solvent casting, salt-leaching, laminating, melt molding, extrusion, 3-D printing, spray drying, lyophilization, using supercritical CO2 fluid and phase separation are well known.

Although in the claim 1, wherein the lichenan is typically for a week time been typically in the strong ethanol solution (50-96 %), and lichenan does not darken in its drying after that, such otherwise it would happen for example without example using ether. Time, like a week time is not restricted, and it can longer or faster like using higher temperature.

In addition, lichenan can be from nature or synthetically, semisynthetically or biotechnically produced or combinations thereof. The composite can include other material, such the promoting material of bone forming and wounds, for example glass, SiO₂, P2O5, Na₂O, silicate, calcium, fluoride compounds and drug, such as antibiotics.

The crucial innovative step is making the hydrophilic polymer blend by the simple process and preferable not using many polymers or other substances, like no plasticizers other than water.

PICTURES

PICTURE 1. The schematic chart of the manufacturing process.

PICTURE 2. The tensile strength of the film was measured with the material test device (Lloyd Ltd, England), where x-axel is time (s) and y-axel is load (N).

PICTURE 3. a) light microscope photos polymer blend for ibuprofen in coating, b) ibuprofen without the polymer blend and c) a measuring stick, and in the picture a visible length is 6 mm.

PICTURE 4. The tensile strength examination of the film was measured with the material test device (Lloyd Ltd, England), where x-axle is time (s) and y-axle is load (N).

Claims

1. A polymer blend, which is used as medicine, implants, wound preparation, herbal preparation, nutrients, cosmetics product, food component or for packing materials comprises of

- lichenan or lichenan and Cetraria species lichen other components (1) other from the combination (1), and

- one or the more other polymers (3) and

- solvents of polymers (2 and 4) typically water or ethanol or combinations thereof.

2. The composition according to the claim 1 other polymer (3) is starch, for example potato starch, pregelatinized starch, modified starch, amylose or amylopectine, or derivates or degradation products, or combinations thereof.

3. The composition according to the claim 1 other polymer (3) is cellulose, microcrystalline cellulose, for example hydroxypropylmethylcellulose or these derivatives, such as ester, ether or cross bound, semisynthetic, synthetic, natural or biotechnologically produced polymer, for example rubber, tragant, gelatine, carragen, inuline, dextrins, gum acacia, agar, agarose, alginate, polyvinylalcohol, oligosacchraride, for example inuline, frukto or oligosaccharide, derivates of these, for example chitosan, or derivates or degradation products, or combinations thereof.

4. The composition according to the claim 1 the polymer blend has good film formation properties.

5. The composition according to the claim 1, wherein the polymer blend (1) uses in hydrophilic material with other hydrophilic substances, such for peptide and protein coating or as a matrix, a scaffold or a gel or as other drug carrier systems.

6. The composition according to the claim 1, wherein the polymer blend (1) can be used as an antioxidant excipient.

7. The process according to the claim 1 the polymer lichenan is typically 0.1-25 weight % as water mixture and the other polymer is typically 0.1-25 weight % as water mixture in the manufacturing stage.

8. The process according to the claim 1 lichenan (2) is wet and mixed with the polymer (3) as moistured typically with ethanol or water or or combinations thereof, or lichenan is in gel form before mixing with other polymer or polymers, which is as solid, gas, solution or gel form or combinations thereof.

9. The process according to the claim 1 lichenan (2) is typically for a week time been typically in the strong ethanol solution (50-100 %), and lichenan does not darken in its drying after that, such as otherwise would happen for example without example ether.

10. The process according to the claim 1 Cetraria species (2) is purified with NaOH aqueous solution and after boiling in water forming wet lichenan or precipitated from ethanol and yet wet, mixing with other polymer (3).