Background of the invention The main active principle in the solid composition of matter involved in the present invention is selected from chitosan, its derivatives or salts thereof. Chitosan is a well-known polysaccharide which is composed of 4)-linked N-acetyl-D-glucosamine and D-glucosamine units.

Chitosan is manufactured by alkaline treatment of chitin, a polymer forming the shell of inter alia insects and crustaceans. Commercially, chitosan is recovered from crab-and shrimpshells that are waste products from the fishing industry. When treating chitin with alkali, usu- ally sodium hydroxide, N-deacetylation takes place, i e acetamido groups are converted to amino groups, as the chitin is transformed to chitosan. By controlling the al- kaline treatment of chitin it is possible to manufacture chitosans with varying degrees of N-acetylation.

Physical properties of chitosan, its derivatives and salts thereof, which properties affect its utility, de- pend on the degree of N-acetylation, the Mw, the molecu- lar weight distribution and the distribution of N-acetyl groups. Furthermore, different acid addition salts and derivatives of chitosan exhibit different properties.

It is also known that chitosan, its derivatives and salts thereof are biologically active and inter alia show anti-microbial properties.

Chitosan and derivatives and salts thereof are used in many forms, such as in solutions for the control of microbial growth. Examples of such solutions are solu-

tions used as teat-dipping agents to prevent onset of mastitis in lactating cattle, as in e g WO 98/48627, as well as solutions for other anti-microbial uses.

One problem encountered in the use of solutions of chitosan, or of derivatives or salts thereof, is lack of stability of such solutions, especially when stored at elevated temperatures.

The dissolution of chitosan, or of derivatives or salts thereof, or indeed of any polysaccharide, is often problematic when performed without vigorous stirring. In- stead of dissolving, the polysaccharide material will form lumps with a gel-like shell efficiently prohibiting further dissolution of the material.

Furthermore, transportation of dilute solutions of chitosan, or of derivatives or salts thereof, is expen- sive and involves handling problems in preparation and use. Also, storage facilities for dilute solutions can be costly and therefore disadvantageous.

Another possibility to solve storage and transporta- tion problems would be to prepare concentrated solutions.

However, this is not possible since chitosan forms very viscous solutions already at a low concentration, pre- venting the preparation of highly concentrated solutions.

Another problem with chitosan solutions, and especially concentrated solutions, is that the viscosity decreases over time, due to hydrolytic degradation.

Summary of the invention The present invention has for a main object to pro- vide effervescent solid compositions of matter compris- ing, as an active principle, a substance selected from chitosan, its derivatives and salts thereof.

Another object of the invention is to provide such a composition of matter, thereby avoiding transportation and storage of aqueous solutions or suspensions of the active principle, since such solutions or suspensions can be easily prepared by the consumer at the time of use.

Yet another object of the invention is to provide such compositions of matter, which are stable in storage for a prolonged time before use thereof.

A further object of the invention is to provide solid compositions of matter comprising a substance se- lected from chitosan, its derivatives and salts thereof, which substances are otherwise not readily dissolved or suspended, which compositions are readily dissolved or suspended in aqueous liquid.

Still another object of the invention is to provide effervescent solid compositions of matter comprising, in addition to a substance selected from chitosan, its de- rivatives and salts thereof, a substance selected from heparin, heparan sulfate, dextran sulfate and other nega- tively charged polysaccharides or polymers.

A further object of the invention is to provide solid compositions of matter, such that solutions or sus- pensions made thereof, when used as teat-dipping agents, upon drying will form films on the areas treated.

Another object of the present invention is the pro- vision of methods for wound-healing treatment of mammals.

Still another object of the invention is to provide a method for prophylactic or wound-healing treatment of lactating animals prone to develop or suffering from mas- titis, particularly cows.

For these and other objects which will be evident from the following disclosure, the present invention pro- vides an effervescent solid composition of matter com- prising as an active component a substance selected from chitosan, its derivatives and salts thereof and a second component capable of releasing C02 in an acidic environ- ment.

The composition of matter according to the invention preferably contains less chitosan, or derivative or salt thereof, than 50% by weight of chitosan, more preferably less than 25% by weight of chitosan. In keeping with the objects of the invention, this preferred proportion of

chitosan, or derivative or salt thereof, in the composi- tion of matter is mainly dictated by the capacity for dissolution or suspension of the active ingredient by the second component and the acidic environment, when the composition is placed in an aqueous liquid. The content of chitosan, or of derivatives or salts thereof, has to be sufficiently low, compared to the content of effer- vescing components in the composition of matter, for dis- solution to occur. The percentage referred to above is thus the percentage of chitosan in relation to effervesc- ing components. Surprisingly, it has been found by the present inventors that the relation between the quantity of effervescence-generating components and chitosan, or derivatives or salts thereof, is critical for the disso- lution of the composition in an aqueous liquid. As stated above, most chitosan qualities will not dissolve without vigorous stirring, even in large amounts of aqueous liq- uid and after long times. This also holds true if the proportion of chitosan is too large in relation to the quantity of effervescing components. The dissolution rate of chitosan, or derivatives or salts thereof, in the com- position of matter according to the invention thus de- pends on efficient mixing caused by release of C02 from the effervescent components, as well as on the final pH of the solution, as described in detail below.

If chitosan derivatives or salts are used that are more easily dissolved than chitosan itself, the percent- age thereof may be increased. The same is true for chito- san, or derivatives or salts thereof, of different mo- lecular weights, low-molecular weight qualities being more easily dissolved or suspended.

The preferred quality of the chitosan, or derivative or salt thereof, used in the composition of matter ac- cording to the invention depends on the specific area of use. This in turn will influence the concentration of chitosan, or derivative or salt thereof, that is pre- ferred.

To obtain maximum anti-microbial efficiency, in those embodiments of the invention where this is desired, it is preferred that the chitosan, or derivative or salt thereof, has a degree of deacetylation of no less than about 50%, preferably no less than about 80%, and par- ticularly no less than about 85%. However, an upper limit of the deacetylation degree of about 95% is preferred, mainly due to practical and economic aspects of the preparation of chitosan, or derivative or salt thereof.

Thus, a preferred composition of matter according to the invention comprises chitosan, or derivative or salt thereof, having a deacetylation degree within the range from about 85% to about 95%, but the upper limit of 95% may be exceeded by compositions that still come within the scope of the present invention. This may occur for example if an economical process of obtaining chitosan of such high degree of deacetylation is made available.

Then, chitosan having a deacetylation degree of up to 99% or more may be obtainable, and may well be used in compo- sitions according to the present invention.

The viscosity of an aqueous solution of a certain concentration of chitosan, or derivative or salt thereof, can be modified by using qualities of chitosan, its de- rivatives or salts thereof with different weight average molecular weights (Mw). In the present invention, chito- san, or derivative or salt thereof, with a molecular weight of between 1 kDa and 2000 kDa is preferred.

The preferred particle size of the chitosan, or de- rivative or salt thereof, used is less than 850 ßm, more preferably less than 250 Am (60 mesh). If chitosan, or derivative or salt thereof, of another particle size is used, or if the molecular weight of the chitosan, or de- rivative or salt thereof, is such that dissolution of particles is difficult, the particles may be ground to a smaller size prior to use.

In a composition of matter according to the inven- tion, said second component is preferably a carbonate,

e g selected from alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, alkaline earth metal bicarbonates, ammonium carbonate, and ammo- nium bicarbonate.

Said second component has the capacity to release C02 in an acidic environment. This acidic environment may be provided as an aqueous solution with a low pH, e g an acetic acid solution, in which the composition of matter is placed. In preferred embodiments, however, release of COs is obtained through the use of a third component of the solid composition, which is selected from solid acids and mixtures thereof.

In such embodiments, said second and third component of the composition of matter according to the invention can be regarded as an"effervescent couple". The effer- vescent couple thus comprises at least one component ca- pable of releasing C02 in an acidic environment (the sec- ond component of the composition of matter) and at least one solid acid (the third component), preferably a solid organic acid. The couple renders effervescence upon mix- ing with an aqueous solution, as the components of the couple combine to produce carbon dioxide. The effervesc- ing action also aids in mixing the other ingredients of the composition to achieve even dispersion and solubili- sation throughout the solution.

In those embodiments of the invention that employ a solid acid, or mixture of solid acids, as a third compo- nent, it is preferred to use a solid organic acid, or mixtures of solid acids comprising at least one solid or- ganic acid. Preferably, this is a weak organic acid that provides a certain buffering effect resulting in a less varying pH in a solution or suspension prepared by disso- lution or suspension of the solid composition according to the invention. For the purposes of preparing a solu- tion or suspension for use on the teats of lactating ani- mals, a non-toxic, mono-carboxylic acid, e g a non-toxic a-hydroxy acid, is preferred, glycolic acid being the

most preferred for this application. In other applica- tions, the preferred solid organic acid may be an a- hydroxy acid or an acid other than a-hydroxy acids, in- cluding ascorbic acid. In most biological applications, the solid acid will need to exhibit properties such as non-toxicity and pharmaceutical acceptability. The pKa of the solid acid is preferably below 7, a pKa below 5 being even more preferred.

A particularly preferred composition of matter ac- cording to the invention is constituted by the active component being selected from chitosan, its derivatives and salts thereof, the second component being an alkali metal bicarbonate, and the composition further comprising a third component which is glycolic acid.

In the composition of matter according to the inven- tion, the contents of acid thereof is preferably in stoi- chiometric excess over the contents of said second compo- nent.

Where the active component is an acid addition salt of chitosan and the composition contains a solid acid, or mixture of solid acids, as third component, said stoichiometric excess is based on said third component together with the acid of addition.

Where the composition of matter according to the in- vention contains chitosan as such as active principle and a solid acid, or mixture of solid acids, as third compo- nent, said stoichiometric excess refers to the contents of the third component over the second component.

The composition of matter, according to those em- bodiments of the invention that contain a solid acid, or mixture of solid acids, as third component, preferably has an acid content such that, when the composition is dissolved or suspended in the appropriate amount of aque- ous liquid, the pH of the solution or suspension is below about 7, so that the chitosan of the composition is read- ily dissolved. More preferably, the pH value is in the range of from about 2 to about 6.8, the lower limit being

dictated mainly by the desired properties of the solution or suspension. For applications wherein the solution or suspension is to be applied to the skin of an animal or human subject, the pH range is even more preferably from about 4 to about 6.8, the lower limit here being dictated by the sensitivity of the area to which the solution or suspension is to be applied.

When the composition is dissolved or suspended in the appropriate amount of liquid, the pH of the solution or suspension can optionally be further stabilised by use of a pH buffering system, which in certain applications of the present invention will need to be non-toxic and pharmaceutically acceptable. Examples of preferred buff- ering systems include the acetic acid system and buffer systems of other monovalent acids, e g lactic acid.

The acidic pH of the liquid provides a suitable en- vironment for dissolution or suspension of chitosan, or of a derivative or salt thereof, as well as a suitable environment for C02 release from the second component.

Inventively, these two effects operate in a synergistic manner to facilitate the dissolution or suspension of chitosan, or derivative or salt thereof, in the liquid.

The composition of matter according to the invention may additionally contain heparin, heparan sulfate, dex- tran sulfate or another negatively charged polysaccharide or polymer. It may also be preferred to include neutral polymers, e g cellulose, in the composition of matter ac- cording to the invention, since such polymers may confer desired properties to a solution or suspension made from the composition, in terms of e g improved clarity or vis- cosity.

The composition of matter according to the present invention can be presented in different forms, e g pow- der, granules, pellets, capsules or tablets of suitable size, prepared by standard methods well known to the skilled person. An additional component of the composi- tion, e g any of the negatively charged polysaccharides

mentioned in the previous paragraph, may be added as a separated coating around a core consisting of the main components of the composition of matter, forming a dragee, or as a part of a tablet containing more than one compartment.

The composition of matter according to the present invention may optionally further comprise pharmaceuti- cally acceptable excipients known to the skilled person, e g binders, diluents, surfactants, lubricants, disinte- grants, anti-microbial agents, detergents and colouring agents.

The composition of matter according to the present invention is preferably kept in moisture-proof or air- tight packages or containers, e g welded aluminum con- tainers, etc. Transportation of products in a dry form and in moisture-proof packets makes it more difficult to contaminate the product. Further, such compositions are much less expensive to transport than compositions in liquid form. In many cases, the effectiveness of active ingredients is prolonged in a dry, rather than liquid, state due to increased stability of the ingredients in the dry state.

The composition of matter according to the invention is thus especially practical when it is used for the preparation of solutions or suspensions, which retain their activity for only a short time after preparation thereof, since said solutions or suspensions may be pre- pared shortly or even immediately before use.

According to one preferred embodiment, the composi- tion of matter according to the present invention is kept in one separate, moisture-proof container, while an ef- fervescent composition of matter comprising heparin, heparan sulfate, dextran sulfate or another negatively charged polysaccharide or polymer is kept in another separate container. Thus, the contents of the two con- tainers may be used simultaneously or at separate in- stants. Another possibility is the provision, in such a

second, separate container, of a liquid, e g glycerol, that confers desired properties, e g a skin conditioning effect, to the resulting solution or suspension.

The composition of matter according to the present invention can be used as a medicament. In particular, the composition of matter according to the present invention can be used for the manufacture of an aqueous solution or suspension for treatment of dermal wounds in mammals in- cluding man. Furthermore, the composition of matter ac- cording to the present invention can advantageously be used for the manufacture of an aqueous solution or sus- pension for prophylactic or wound-healing treatment of mastitis in lactating animals.

The present invention also relates to a method for treatment of a mammal suffering from a dermal wound, which method comprises the steps of: a) admixing an effervescent solid composition of matter according to the present invention with an aqueous liquid to form a solution or suspension thereof; b) contacting the dermal wound of said mammal with said solution or suspension to provide such treatment.

The present invention also relates to a method for prophylactic or wound-healing treatment, or both, of a lactating animal prone to develop or suffering from mas- titis. The method comprises the steps of: a) admixing an effervescent solid composition of matter according to the present invention with an aqueous liquid to form a solution or suspension thereof ; b) contacting teats of said animal with said solu- tion or suspension to provide such treatment.

The methods according to the invention, described immediately above and having regard to mastitis, suitably take place in connection with milking operations. Consid- ering the daily milking, the application is suitably per-

formed twice or thrice a day after milking. In certain cases it may be preferable to apply the solution before milking, considering the risk of transferring micro- organisms during the milking process. The method of the invention is very well suited for such a pre-milking treatment, as the risk of transferring non-desirable com- ponents into the milk is minimised through the use of a chitosan-containing solution or suspension. Chitosan, or derivative or salt thereof, is preferably present in the solution or suspension in an anti-microbially active con- centration.

Preferably, in the methods of the invention, an ef- fervescent composition of matter is used which comprises components that provide a skin conditioning effect on skin. Such components may be glycolic acid as the third component, or glycerol as an additive, but other skin conditioning components are possible.

In such methods it is preferred that said composi- tion of matter is used in an amount resulting in a solu- tion or suspension having a concentration of chitosan of up to and including about 2% (weight/volume), the upper limit being mainly dictated by economic and practical considerations. The most preferable concentration of chi- tosan in said solution or suspension is about 1% (w/v).

A particularly preferred composition of matter for use in the methods for prophylactic or wound-healing treatment according to the invention comprises a combina- tion of chitosan, or derivative or salt thereof, and one or more of the additional substances heparin, heparan sulfate and dextran sulfate, whereby solutions or suspen- sions made thereof when used as teat-dipping agents upon drying will form particularly water-resistant films on the areas treated.

Other applications of use for the composition of matter according to the invention than that of the meth- ods described above are possible. In such applications, solutions or suspensions having even lower concentra-

tions, e g down to about 0.1% (w/v) of chitosan, may prove active and effective. In such cases, lower concen- trations naturally offer advantages in terms of economy.

Examples of preferred embodiments The present invention will in the following be il- lustrated in connection with non-limiting examples. In said examples parts and percentages refer to weight if not otherwise stated.

Compositions with other dissolution times than those reported can easily be prepared by changing the ratio be- tween chitosan, or derivative or salt thereof, and effer- vescent couple. The form of the composition of matter, e g powder, granules, pellets, capsules or tablets, will also affect the dissolution time. Also, the pressure ap- plied when preparing tablets affects the dissolution time of a resulting tablet.

Materials The chitosan used in the following examples was of commercial grade, having a deacetylation degree of 84- 99%. Likewise, the heparin used was of commercial grade.

TABLET EXPERIMENT-EXAMPLES 1-5 Preparation of tablets The tablets of the examples below were prepared in laboratory scale by mixing and grinding of the included chemicals into fine particles. For compression of stan- dard size tablets, a standard FTIR press was used. Larger tablets were compressed in a specially adapted press made from a plastic tube with a lid and bottom. Materials were transferred into the tube and the lid fitted. The device was then placed in a press designed for production of FTIR tablets, whereupon the materials were compressed at approximately 3 tons for 30-60 seconds.

The tablets of the examples below had diameters in the range from about 13 to about 40 mm, with thicknesses of about 2,3 or 7 mm, depending on the amount of mate- rial present in the tablet.

Dissolution times refer to solutions that are not stirred during dissolution of tablets.

EXAMPLE 1 The compositions of Table 1 were prepared by mixing chitosan or an acid addition salt thereof with a solid acid and sodium bicarbonate. Solid preparations of powder or tablets were formed as described above.

TABLE 1 Chitos an Chitos an HCl Sodium bicar- Composition (g) (g) Acid bonate (g) A 1.0 2.0 g glycolic acid 2.0 B 1.0 2.2 g glycolic acid 2.0 C 1.0 1.6 g benzoic acid 1. 0 D 1.0 1.8 g salicylic acid 1.0 E 1.0 5.6 g ascorbic acid 2.4 F 1.0 20 g citric acid 1.8 G 3.0 3.0 g glycolic acid 3.0 H 1.0 2.0 g glycolic acid 1.8 J 0.5 1.0 g glycolic acid 0.9 K 2.0 4.0 g glycolic acid 3.5 L 1.0 2.3 g glycolic acid 2.0 EXAMPLE 2 The solid compositions A-F of Table 1 were admixed with 100 ml tap water at ambient temperature. The solid composition G of Table 1 was admixed with 300 ml tap wa- ter at ambient temperature. Thus, chitosan or its acid addition salt was added in an amount corresponding to 1.0% (weight/volume) of the total volume. The time from addition of the composition until it was fully dissolved was recorded and is shown Table 2, as is the pH value of each resultant solution.

TABLE 2 Composition pH Dissolution time (h) A 4.7 1 B 5. 5 0.8 C 5. 2 over nighta D 4.9 over nighta E 5.1 5b F 2.3 0.03 G 4.7 5.5

aNot completely dissolved after 2 h, completely dissolved after 16 h bMost of the material is dissolved after 10 minutes, completely dis- solved after 5 h EXAMPLE 3 The solid compositions H-K of Table 1 were admixed with 100 ml tap water at ambient temperature. Thus, chi- tosan was added in an amount corresponding to from 0.5% to 2.0% (w/v) of the total volume. The time from addition of the composition until it was fully dissolved was re- corded and is shown in Table 3, as is the pH value of each resultant solution.

TABLE 3 Composition % Chitosan pH Dissolution time (h) H 1.0 5.3-5.5 0.8 J 0.5 5.5-5.8 0.2 K 2.0 5.3-5.4 1.5

EXAMPLE 4 A tablet was prepared containing 0.02 g heparin, 0.1 g glycolic acid, and 0.1 g sodium bicarbonate. The tablet

was dissolved in 100 ml tap water at ambient temperature.

The solid composition L of Table 1 was admixed with the solution.

Thus, chitosan was added in an amount corresponding to 1. 0% (w/v) of the total volume. The time from addition of the composition until it was fully dissolved was ap- proximately 45 minutes. The resulting solution contained 1.0% (w/v) chitosan and 0.02% (w/v) heparin, pH 5.0.

EXAMPLE 5 A tablet was prepared containing 1.0 g chitosan and 1. 75 g sodium bicarbonate. The tablet was dissolved in 100 ml of a solution of 6% acetic acid at ambient tem- erature.

The tablet was completely dissolved in approximately 10 minutes.

GRANULATION EXPERIMENT-EXAMPLES 6-17 In all of the examples below, chitosan granulate is added to water in an amount yielding solutions of 1% by weight of chitosan. In those cases (examples 12-17) where heparin is added to water, the amount thereof corresponds to 0.02% by weight in the final solutions.

EXAMPLE 6 100.3 g chitosan, 198.0 g glycolic acid and 175.3 g NaHC03 were mixed for one minute in a Kenwood mixer, and granulated with 21.5 g of an aqueous solution of ethanol (70%). The granulate was dried in a heating cabinet for 4 h at 50°C, and then sieved through a 1. 3 mm hand sieve.

Finally, the granulate was mixed for 40 minutes in a Tur- bula mixer.

When 4.7 g of the granulate was dissolved in 100 ml of water, a yellow solution was obtained. With stirring,

the granulate was dissolved within 30 seconds. Some foam- ing occurred.

EXAMPLE 7 49.9 g chitosan and 99.3 g glycolic acid were mixed for one minute in a Kenwood mixer, and granulated with about 9 g of an aqueous solution of ethanol (70%). The granulate was dried in a heating cabinet for 3 h at 50°C, and then sieved through a 1.3 mm hand sieve. 87.8 g Na- HC03 was added, and the final granulate was mixed for 20 minutes in a Turbula mixer.

The granulate exhibited a strong effervescent reac- tion when mixed with water, dissolving in a clear, slightly yellow solution.

EXAMPLE 8 50.0 g chitosan and 88 g NaHCO3 were mixed in a Tur- bula mixer for 10 minutes. 99.3 g glycolic acid were added, and the mixing was continued for another 10 min- utes. Subsequently, the mixture was sieved through a 1.3 mm sieve.

The granulate was relatively easily dissolved in wa- ter, and a slightly yellow and not completely clear solu- tion was obtained.

EXAMPLE 9 49.6 g chitosan, 50.1 g lactose, 99.7 g glycolic acid and 87.8 g NaHCO3 were granulated with 17 g of an aqueous solution of ethanol (70%) in a Kenwood mixer. The resulting granulate was dried for 4 h at 50°C in a drying cabinet. Finally, the granulate was sieved through a 1.3 mm sieve.

When enough granulate was added to water to form a 1% chitosan solution, part of the granulate floated on the surface of the water, and it was necessary to aid dissolution by stirring.

EXAMPLE 10 100 g chitosan and 150 g lactose were granulated with 100 g of an aqueous povidone solution (10%) in a Kenwood mixer. The granulate was dried for 2.5 h at 50°C in a drying cabinet, before being sieved through a 1. 5 mm sieve.

50 g of the resulting granulate, 45 g glycolic acid and 35 g NaHC03 were then mixed in a Turbula mixer for 10 minutes. 6.5 g of the mixture was added to 100 ml of wa- ter, giving a solution of 1% by weight chitosan. The granulate dissolved fast during intensive foaming when stirred, giving an almost clear solution with a pH of 3.7.

EXAMPLE 11 50 g chitosan, 100 g lactose and 120 g glycolic acid were granulated with 72 g of an aqueous solution of etha- nol (70%) in a Kenwood mixer. The granulate was dried for 4 h at 50°C in a drying cabinet, before being sieved through a coarse sieve.

5.4 g of the resulting granulate was mixed with 1.7 g NaHCO3. When placed in water, this mixture was relatively easily dissolved. Some of the material sunk to the bottom of the vessel, and a calm effervescent reac- tion started. All of the material was dissolved after one hour, yielding a solution with a pH of 4.4. After 24 h the solution was totally clear and the pH value 4.24.

EXAMPLES 12-17 Preparation of heparin granules: 2.00 g heparin and 10.0 g lactose were mixed with a spoon. 2 g of an aqueous povidone solution (20%) was added as granulation liquid during stirring using a noz- zle. The resulting granulate was dried for 2 h at 60°C in a drying cabinet and then sieved through a 1.5 mm sieve, yielding a fine white-grey powder.

Preparation of chitosan granules: 50 g chitosan, 100 g lactose and 120 g glycolic acid were granulated with 72 g of an aqueous solution of etha- nol (70%) in a Kenwood mixer. The granulate was dried for 4 h at 50°C in a drying cabinet, before being sieved through a coarse sieve.

Preparation of chitosan-heparin solutions: In examples 12-17,0.12 g of the heparin granulate obtained above was placed in 100 ml of distilled water at a temperature of 22°C. pH measurements were used to moni- tor the dissolution process. Next, the chitosan granulate obtained above was added. In examples 12,14 and 16, the chitosan granulate was mixed with NaHCO3 prior to addi- tion of the powder to the heparin solution. In examples 13,15 and 17, the NaHCO3 was added separately a few sec- onds after the addition of chitosan to the heparin solu- tion.

The results are shown in Table 4 below. In all exam- ples, the material was totally dissolved, yielding solu- tions of 0.02% by weight of heparin and 1% by weight of chitosan.

TABLE 4 Chitosan Heparin granulate NaHCO3 granulate pH Example pH of heparin (minutes after addition) (g) (g) (g) Addietin solution Mixed dry with the 12 0.12 6.8 5.4 1.7 5.4 (30) chitosan granulate 13 0.12 7.7 5.4 1.7 Separately 4.3 (45) Mixed dry with the 14 0.12 - 5.4 1.5 4.7 (-) chitosan granulate 15 0.12 6.7 5.4 1.7 Separately 4.1 (90) Mixed dry with the 16 0.12 6.9 5.4 2.1 5.2 (90) chitosan granulate 17 0.12 7.2 5.4 2.1 Separately 5.5 (90)