Patent 6,743,775

We have now found that fixation of suitable types of drugs to microdispersed or microfibrillar PAGA, and salts, complex salts, or intermolecular polymer complexes thereof, preferably as prepared according to the method disclosed in PCT IE/98/00004, can be used as a means for preparing drug dosage forms with a significantly protracted effect and a reduced toxicity.

A prolongation of the effect of a drug fixed to this type of polymer chain makes it possible to reduce the amounts dosed and the frequency of dosing and thereby makes the therapy more comfortable for the patient and reduces potential systemic toxicity of the drug, the latter issue being especially of concern with, for instance, certain types of antibiotics or cytostatics.

When the polymer matrix is biodegradable. The matrix, insoluble at the origin, can then be degraded by hydrolysis or an enzyme-assisted hydrolysis in the organism whereby it slowly releases the active substance fixed to the ionogenic groups of the structural units of the biopolymer and makes it free to permeate through biological membranes.

We have found that microdispersed and microfibrillar PAGA, containing uronic carboxyl groups in the polysaccharidic polymer chain, owing to it's small particle size, high porosity and high specific surface area, and a fully open inner surface, appears to be an ideal biopolymer suitable for physicochemical fixation of a number of biologically active substances.

The open inner surface makes it possible for the molecules of the active substance to uniformly penetrate into the polymer matrix and to get uniformly fixed thereto by way of formation of either a simply salt of an acetate type or a complex salt. This uniformity, in turn, provides for a uniform release of the active substance and for the uniformity of it's effect in the organism.

Though an appropriate selection of the amount of the active substance, selection of further cations fixed to the polysaccharidic polymer chain, and possibly introduction of a certain density of cross links within the chain, it is possible to influence and vary the rate of the release from the polymer matrix. A pronounced prolongation of the drug effect and reduction of systemic toxicity with, for example, cytostatic drugs can be achieved, and the release of the active substance from the matrix can be well controlled.

Last but not least, a concomittant contribution to the reduction of drug toxicity can be attained owning to the release of glucuronic acid, which is a detoxication agent of a mammalian organism, simultaneously occurring during the biodegradation of the polymer matrix.

According to the invention there is provided a slow release formulation including a biocompatible anionic polysaccharide material containing glucuronic acid in the polymer chain.

Preferably at least 5% of the basic structural units are glucuronic acid.

Preferably the polysaccharide material is polyanhydroglucuronic acid, biocompatible salts thereof, copolymers thereof, or a biocompatible intermolecular complex thereof.

In a preferred embodiment of the invention the biocompatible intermolecular polymer complex is a complex of:

an anionic component comprising a linear or branched polysaccharide chain containing glucuronic acid; and

a non protein cationic component comprising a linear or branched natural, semi-synthetic or synthetic oligomer or polymer.

Preferably at least 5% of the basic structural units of the anionic component are glucuronic acid.

The cationic component preferably contains nitrogen that either carries a positive charge or wherein the positive charge is induced by contact with the polysaccharidic anionic component.

The cationic component may be selected from derivatives of acrylamide, methacrylamide and copolymers thereof. In this case the cationic component is selected from polyacrylamide, copolymer of hydroxyethylmethacrylate and hydroxypropylmetacrylamide, copolymers of acrylamide, butylacrylate, maleinanhydride and/or methylmetacrylate.

In one embodiment the cationic component is a cationised natural polysaccharide.

Preferably the polysaccharide is a starch, cellulose or gum.

The gum is preferably guargumhydroxypropyltriammonium chloride.

Alternatively the cationic component is a synthetic or semi-synthetic polyamino acid. In this case preferably the cationic component is polylysin, polyarginin, or .alpha.,.beta.-poly-[N-(2-hydroxyethyl)-DL-aspartamide].

In another embodiment the cationic component is a synthetic anti-fibrinolytic.

In this case preferably the anti-fibrinolytic is a hexadimethrindibromide (polybren).

Alternatively the cationic component is a natural or semi-synthetic peptide.

In this case preferably the peptide is a protamine, gelatine, fibrinopeptide, or derivatives thereof.

In another embodiment the cationic component is an aminoglucane or derivatives thereof.

In this case preferably the aminoglucane is fractionated chitin or its de-acetylated derivative chitosan. The aminoglucane may be of microbial origin or is isolated from the shells of arthropods such as crabs.

In an especially prepared embodiment of the invention the anionic component is polyanhydroglucuronic acid and/or bicompatible salts and/or copolymers thereof.

Most preferably the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain from 8 to 30 percent by weight of carboxyl groups, at least 80 percent by weight of these groups being of the uronic type, at most 5 percent by weight of carbonyl groups, and at most 0.5 percent by weight of bound nitrogen.

Preferably the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain at most 0.2 percent by weight of bound nitrogen.

In a preferred embodiment the molecular mass of the polymeric chain of the anionic component is from 1x10³ to 3x10⁵ Daltons.

Most preferably the molecular mass of the polymeric chain of the anionic component ranges from 5x10³ to 1.5x10⁵ Daltons.

In one embodiment of the invention the content of carboxyl groups is in the range of from 12 to 26 percent by weight, at least 95 percent of these groups being of the uronic type.

Preferably the anionic component contains at most 1 percent by weight of carbonyl groups.

In a preferred embodiment the carbonyl groups are intra- and intermolecular 2,6 and 3,6 hemiacetals, 2,4-hemialdals and C2-C3 aldehydes.

In a preferred embodiment the cationic component is gelatine.

In another preferred embodiment the cationic component is chitosan.

The composition may include at least one biocompatible biologically active substance.

Alternatively or additionally the composition includes at least one biologically acceptable adjuvant.

The composition may include at least one pharmaceutically active adjuvant.

In this case the adjuvant may be an anti-ulcer agent such as an antibiotic which is active against Helicobacter pylori e.g. clarithyromycin and/or a H₂ -antagonist e.g. cimetidine.

The composition may also include bismuth salt.

The composition is preferably in a form for oral administration.

The composition may be in the form of a tablet, pellet, capsule, granule, or microsphere.

We have now found that by preparing polymeric intermolecular complexes (IMC) of glucuronoglucanes, notably microdispersed PAGA, prepared especially according to PCT IE 98/00004 it is possible to enhance the haemostatic effect of the final products on this basis and the properties of the temporary wound cover formed after the haemostasis is achieved such as its flexibility and resistance to cracking on movable parts of the body.

It is also possible to upgrade physicomechanical properties of the final products on this basis. Such IMCs make it possible to prepare application forms whose manufacture from a pure PAGA or their simple salts is extremely difficult. Such application forms includes non-woven textile-like structures or polymeric films. To modify or upgrade the physical mechanical properties it is sufficient to use even a relatively small amount of polymeric counterion while it is possible to obtain suitable application properties within a broad concentration range of the components. The ratio of the glucuronoglucane to polymeric counterion can be 0.99:0.01 to 0.01:0.99.

Another advantage of glucuronoglucane based IMCs is the possibility to control their biological properties such as varying the degree of haemostatis, resorption time, or immunomodulative properties, and the like.

Polymeric cations suitable to form IMCs with glucuronoglucanes prepared for example according to PCT IE 98/00004 may roughly be subdivided to the following groups:

1. Synthetic biocompatible nitrogen-containing oligomers and polymers.

a) Derivatives of acrylamide and methacrylamide and their copolymers [such as polyacrylamide, copolymer of hydroxyethylmetacrylate and hydroxypropylmetacrylamide, copolymer of acrylamide, butylacrylate, maleinanhydride, and methylmetacrylate, and the like], or else cationised natural polysaccharides such as starches, celluloses, or gums such as guargumhydroxypropyltriammonium chloride.

b) Synthetic or semi-synthetic polyaminoacids such as polylysin, polyarginin, .alpha.,.beta.-poly-[N-(2-hydroxyethyl)-DL-asparamide. Synthetic antifibrinolytics hexadimethrindibromide (polybren) can also be included in this group.

2. Natural or semi-synthetic peptides such as gelatine, protamines, or fibrinopeptides, and their derivatives.

3. Natural aminoglucanes such as fractionated chitin and its de-acetylated derivative chitosan, of microbial origin or isolated from the shells of arthropods such as crabs.

In preparing IMCs on the basis of PAGA according to the invention these three groups of substances can be combined to obtain required properties of the final product.

In general it can be said that IMCs using substances from 1a and 1b would preferably be used to prepare various types of highly absorbant biocompatible dressing materials in the form of nonwovens, films, plasters, and pads.

IMCs using the substances from 2 and 3 may serve as efficient haemostatic agents for internal applications in the microfibrillar form, in the microdispersed form as dusting powders, in the form of films, granules, tablets or non-woven textile-like structures. Those preparations also display antiadhesive properties.

We have also found out that in the form of film-like cell culture matrices the latter IMCs incorporating PAGA and salts thereof as prepared according to PCT IE 98/00004 have a favourable effect on the growth of fibroblasts and keratinocytes.

While it is also possible to create IMCs using structural scleroproteins of the collagen type as disclosed in WO 9800180A, it is preferable to use the above mentioned groups of substances because of the possibility of contamination of the final product by telopeptides, viruses or pyrogens. Collagen can affect in an uncontrolled manner, the immune response of the organism because formation of antibodies can be provoked by any portion of the collagen structure even though the main determinants occur in the terminal regions of the collagen macromolecule. Removal of telopeptides only partially solves the antigenicity problem (Michaeli et al: Science, 1969, 166, 1522).

By preparing IMCs according to the invention it is possible to essentially enhance properties of the originally prepared glucoronoglucanes such as 1,4 .beta. PAGA. For instance an intermolecular complex salt of PAGA and gelatine in one single production step can be used to prepare final products in the form of a non woven, film, microdispersed granules, or dispersions. In contrast to collagen, suitably hydrolysed gelatine is well tolerated, has no toxicity or side effects and it is a much less costly raw material. We have found out that this complex has very good haemostatic properties being about 40% higher than the original PAGA calcium sodium salt. This is despite the fact that the gelatine itself only displays a haemostatic effect after an addition of thrombin [Schwartz S. I. et al.: Principles of Surgery, St.Louis: McGraw Hill Co, 1979, p. 122-123]. In this case the absorption in the organism can be controlled by changing the composition of the complex within the range from tens of hours to several months. With an advantage this complex with a higher haemostatic efficiency can be used as an embolisation or microembolisation product. It can also be used to prepare haemostatic layers of highly absorbent multi-layer dressings or resorbable plasters, though more costly polybren or protamines could also be applied.

An important advantage of these IMCs is the fact that the compounds can be prepared within a single manufacturing operation using the hydrolytic process described in PCT IE 98/00004 which makes these products cost effective.

These IMCs can further be modified by biologically active and/or biologically acceptable substances. Because the IMCs prepared by the present procedure are either of a microdispersed or microfibrillar nature, the active substances tend to be bound uniformly and also are uniformly released in the organism without the need for other adjuvants such as micrcrystalline waxes or stearates. However, the addition of such adjuvants is not excluded.

Biologically active substances which can be incorporated into the IMC may involve, for instance, antibiotics carrying at least a weak positive charge in the molecule such as cephalosporins (cephotaxin), aminoglycosides (neomycin, gentamycin, amikacin), penicillins (tikarcilin) or macrolides (erythromycin, clarithromycin) and the like.

In cases where the calcium/sodium salt of PAGA or its IMC complexes according to the invention are used as microembolisation or embolisation agents in regional chemotherapy of malign tumours, suitable types of cytostatics such as adriamycin or derivatives of 1,4-diaminoanthrachinone can be incorporated. It is also possible to use the IMCs as detaching ligands for platinum(II) based cytostatics.

Biologically acceptable substances used for modification of the IMCs include, for instance, glycerol and its polymers (polyglycerols); mono, di, and certain triglycerides; polyethyleneglycols; monopropyleneglycol; block copolymers of polyethyleneoxides and polypropyleneoxides (Pluronic); starches; cyclodextrines; polyvinylalcohols; cellulose and its derivatives; in general, substances that, in the concentrations used, are not irritating or toxic for the living organism while being capable of further optimising the physicomechanical properties of the final product based on the IMCs according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention will be more clearly understood from the following description thereof given by way of example only.

EXAMPLES OF POLYMER COMPLEXES OF GLUCURONOGLUCANES

EXAMPLE 1

Material

long-fibre cotton--medicinal cotton wool oxidised by N_x O_y (proprietary)

                C₆ OOH              18.8% b/w
                ash content           <0.1% b/w
                .SIGMA. C=O               0.6% b/w

20% solution Na₂ CO₃ (Lachema, a.s. Neratovice)

CaCl₂.6H₂ O anal.grade (Lachema, a.s. Neratovice)

demineralised water 2 .mu.S

ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)

acid acetic anal.grade (Lachema, a.s. Neratovice)

H₂ O₂ anal.grade 30% (Lachema, a.s. Neratovice)

N-HANCE 3000 guargumhydroxypropyltriammoniumchloride (Aqualon-Hercules)

Equipment

mixer: bottom stirring, 150 l (duplicator), stainless steel EXTRA S

vibrating screen: stainless steel, 150 mesh

rotary air pump: rotor diameter 150 mm

turbostirrer: ULTRA TURAX (Janke-Kunkel)

beaker: 5 l

pH meter PICCOLO

thermocouple thermometer

Procedure

30 g of N-HANCE 3000 were placed into and 5 l beaker and 3 l of demineralised water 2 .mu.S were added. Contents of the beaker were intensely stirred for 30 minutes. The pH value was adjusted to less than 4.5 by addition of an acetic acid solution leading to a viscosity rise.

60 l of demineralised water 2 .mu.S were introduced into a mixer. Then 3 kg of CaCl₂.6H₂ O anal.grade were added and the contents heated up to a temperature of 50^oC. under stirring. On dissolution of the calcium chloride the stirring was interrupted and 2.7 kg of the raw oxidised cotton wool were introduced. The mixer was closed and the contents were agitated for 120 seconds. Then the pH value of the contents was adjusted by addition of a 20% solution of Na₂ CO₃ to 6-6.5 and 13 kg of H₂ O₂ 30% were introduced. The fibre suspension was slowly agitated for 10 minutes. Then the pH value was readjusted to 4.5-5.0 and the prepared viscous solution of N-HANCE 3000 was introduced. The contents of the mixer were stirred intensely for 30 seconds. Subsequently 60 l of synthetic rectified ethanol conc. 98% were introduced into the mixer. After another 15 seconds from adding the ethanol the contents of the mixer were transferred onto a vibrating screen, and the supernatant. Liquid was filtered off. The filtration cake was redispersed in the mixer in 60 l of a mixture of 18 l of synthetic rectified ethanol conc. 98% and 42 l of demineralised water 2 .mu.S. The fibre suspension was filtered again on the vibrating screen.

The isolated material thus prepared may further serve to prepare final products of the nonwoven type via a wet or dry process.

                            Analysis:
                Ca content                 4.0% b/w
                Na content                 1.8% b/w
                .SIGMA. C=O content              0.0% b/w
                COOH content              20.7% b/w

Example 2

Material

oxidised short-fibre cotton (Linters--Temming) (proprietary)

                C₆ OOH              16.8% b/w
                ash content          <0.15% b/w
                .SIGMA. C=O               2.6% b/w

20% solution Na₂ CO₃ (Lachema, a.s. Neratovice)

CaCl₂.6H₂ O anal.grade (Lachema, a.s. Neratovice)

redistilled water (PhBs 1997)

ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)

isopropanol 99.9% (Neuberg Bretang)

H₂ O₂ anal.grade 30% (Lachema, a.s. Neratovice)

gelatine (PhBs 1997)

Equipment

turbostirrer: ULTRA TURAX (Janke-Kunkel)

sulphonation flask 11

heater 1.5 kW

laboratory centrifuge: 4000 rpm

thermostated water bath

pH meter PICCOLO

glass thermometer

rotary vacuum dryer or hot-air dryer

Procedure

Into a 1 sulphonation flask equipped with a turbostirrer and a heater, 400 ml of redistilled H₂ O were placed, 15.73 g of CaCl₂.6H₂ O were added and on dissolution, 40.0 g of 20% Na₂ CO₃ solution were introduced under stirring. Subsequently, 50 g of oxidised Linters were added to the white emulsion formed and the contents were heated up to 95^oC. and the stirring intensity set to a maximum. After 10 minutes, 30 g of 30% H₂ O₂ were added into the flask and the hydrolysis continued for another 10 minutes. The contents were then cooled down to 60^oC. on a water bath and the pH of the system was adjusted to a value of 4.5-5.0 by addition of 20% solution of Na₂ CO₃. Furthermore, gelatine solution (10 g of gelatine in 70 g of redistilled H₂ O) warmed up to 50^oC. was added and let to react for another 20 minutes. The flask contents were then cooled down to 30^oC. in a water bath and 626 ml of synthetic rectified ethanol conc. 98% were added gradually under intense stirring. The suspension of IMC thus formed was isolated using a laboratory centrifuge. The supernatant liquid was filtered away and the cake was redispersed into 250 ml of 50% ethanol. The system was centrifuged again and after the separation of the supernatant liquid, the IMC was redispersed into 250 ml of synthetic rectified ethanol conc. 98% and let to stay for 4 hours. It was then centrifuged again, redispersed into 99.9% isopropanol, and let to stay for a minimum of 10 hours at 20^oC. The gel formed was centrifuged again and the product was dried in a rotary vacuum dryer or a hot-air dryer.

The product can be used, for instance, for microembolisation, for preparation of haemostatic dusting powders, for manufacture of polymer drugs, e.g. based on cytostatics, or for preparation of spheric particles for macroembolisation.

                            Analysis:
                content Ca                   4.4% b/w
                content Na                   2.7% b/w
                content .SIGMA. C=O              0.0% b/w
                content COOH                20.5% b/w
                content N                    1.8% b/w

EXAMPLE 3

Material

oxidised short-fibre cotton (Linters--Temming) (proprietary)

                C₆ OOH              16.8% b/w
                ash content          <0.15% b/w
                .SIGMA. C=O               2.6% b/w

NaOH anal.grade (Lachema, a.s. Neratovice)

redistilled water (PhBs 1997)

ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)

isopropanol 99.9% (Neuberg Bretang)

H₂ O₂ anal.grade 30% (Lachema, a.s. Neratovice)

gelatine (PhBs 1997)

Equipment

turbostirrer: ULTRA TURAX (Janke-Kunkel)

sulphonation flask 11

heater 1.5 kW

laboratory centrifuge: 4000 rpm

thermostated water bath

pH meter PICCOLO

glass thermometer

rotary vacuum dryer or hot-air dryer

Procedure

Into a 1 1 sulphonation flask equipped with a turbostirrer and a heater, 400 ml of redistilled H₂ O were placed, and 8 g of NaOH were added. On dissolution, 50 g of oxidised Linters were added, the contents were heated up to 70^oC. and the stirring intensity set to a maximum. After 20 minutes, 40 g of 30% H₂ O₂ were added into the flask, temperature was increased to 85^oC., and maintained for another 10 minutes. The contents were then cooled down to 50^oC. on a water bath and gelatine solution (10 g of gelatine in 70 g of redistilled H₂ O) warmed up to 50^oC. was added to the hydrolysate. The temperature was decreased to 25-30^oC. and the pH of the system was checked and adjusted to a value of 6.0-6.5. Subsequently, 626 ml of synthetic rectified ethanol conc. 98% were added gradually under intense stirring. The suspension of IMC thus formed was isolated using a laboratory centrifuge. The supernatant liquid was filtered away and the cake was redispersed into 250 ml of 50% ethanol. The system was centrifuged again and after the separation of the supernatant liquid, the IMC was redispersed into 250 ml of synthetic rectified ethanol conc. 98% and let to stay for 4 hours. It was then centrifuged again, redispersed into 99.9% isopropanol, and let to stay for a minimum of 10 hours at 20^oC. The gel formed was centrifuged again and the product was dried in a rotary vacuum dryer or a hot-air dryer.

                            Analysis:
                Na content                   3.8% b/w
                .SIGMA. C=O content              0.0% b/w
                COOH content                22.5% b/w
                N content                    2.7% b/w

EXAMPLE 4

Material

oxidised short-fibre cotton (Linters--Temming) (proprietary)

                C₆ OOH              16.8% b/w
                ash content          <0.15% b/w
                .SIGMA. C=O               2.6% b/w

20% solution Na₂ CO₃ (Lachema, a.s. Neratovice)

CaCl₂.6H₂ O anal.grade (Lachema, a.s. Neratovice)

redistilled water (PhBs 1997)

ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)

isopropanol 99.9% (Neuberg Bretang)

H₂ O₂ anal.grade 30% (Lachema, a.s. Neratovice)

chitosan, degree of deacetylation 92% (Henkel)

Equipment

turbostirrer: ULTRA TURAX (Janke-Kunkel)

sulphonation flask 11

heater 1.5 kW

laboratory centrifuge: 4000 rpm

thermostated water bath

pH meter PICCOLO

glass thermometer

rotary vacuum dryer or hot-air dryer

Procedure

Into a sulphonation flask, 250 ml redistilled H₂ O were placed, and 5 g of NaOH were added. On dissolution, 25 g of oxidised Linters were introduced under stirring, the temperature increased to 50^oC. and the stirring intensity set to a maximum. After hydrolysing for 15 minutes, 35 g of 30% H₂ O₂ were gradually added to the system and the temperature was maintained at 50^oC. for another 20 minutes. The content were cooled down to 30^oC. and 400 g of highly viscous 5% solution of chitosan were added. The flask contents were then intensely stirred for another 10 minutes, and the pH of the system was adjusted, by addition of NaOH, to a value of 7.0. Subsequently 300 ml of synthetic rectified ethanol conc. 98% were added under stirring. The suspension of IMC thus formed was isolated using a laboratory centrifuge. The supernatant liquid was filtered away and the cake was redispersed into 250 ml of 50% ethanol. The system was centrifuged again and after the separation of the supernatant liquid, the IMC was redispersed into 250 ml of synthetic rectified ethanol conc. 98% and let to stay for 4 hours. It was then centrifuged again, redispersed into 99.9% isopropanol, and let to stay for a minimum of 10 hours at 20^oC. The gel formed was centrifuged again and the product was dried in a rotary vacuum dryer or a hot-air dryer.

                            Analysis:
                Na content                   1.8% b/w
                .SIGMA. C=O content              0.0% b/w
                COOH content                10.4% b/w
                N content                    2.8% b/w

EXAMPLE 5

Material

oxidised short-fibre cotton (Linters--Temming) (proprietary)

                C₆ OOH              16.8% b/w
                ash content          <0.15% b/w
                .SIGMA. C=O               2.6% b/w

NaOH anal.grade (Lachema, a.s. Neratovice)

HCl 39% anal.grade (Lachema, a.s. Neratovice)

redistilled water (PhBs 1997)

ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)

isopropanol 99.9% (Neuberg Bretang)

H₂ O₂ anal.grade 30% (Lachema, a.s. Neratovice)

gelatine (PhBs 1997)

Ambroxol (H. Mack, Germany)

Equipment

turbostirrer: ULTRA TURAX (Janke-Kunkel)

sulphonation flask 21

heater 1.5 kW

laboratory centrifuge: 4000 rpm

laboratory pin mill ALPINE (35 000 rpm)

thermostated water bath

pH meter PICCOLO

glass thermometer

rotary vacuum dryer or hot-air dryer

Procedure

Into a sulphonation flask, 400 ml redistilled H₂ O were placed, and 8 g of NaOH were added. On dissolution, 50 g of oxidised Linters were introduced under stirring, the temperature increased to 70^oC. and the stirring intensity was set to a maximum. After hydrolysing for 20 minutes, 40 g of 30% H₂ O₂ were gradually added to the system and the temperature was increased to, and maintained at, 85^oC. for another 10 minutes. The content were cooled down to 50^oC. in a water bath, and gelatine solution (2 g of gelatine in 70 g of redistilled H₂ O) warmed up to 50^oC. was added to the hydrolysate. The temperature was decreased to 25-30^oC. and the pH of the system was checked and adjusted to a value of 1.6-1.8 by addition of 39% HCl. Under intense stirring, a solution of Ambroxol (25 g of ambroxolium hydrochloride in 500 ml of redistilled H₂ O) was added gradually. After agitating for 5 minutes the pH value was adjusted to 4.3-4.6 by adding 5% NaOH solution, and 626 ml of synthetic rectified ethanol conc. 98% were added under intense stirring. The suspension of Ambroxol containing IMC thus formed was isolated using a laboratory centrifuge. The supernatant liquid was filtered away and the cake was redispersed into, subsequently, 800 ml of 60% ethanol and 250 ml of 98% ethanol, wherein it was let to stay for a minimum of 10 hours. The system was centrifuged again and the product was dried at 40^oC. in a rotary vacuum dryer or a hot-air dryer. A white to slightly yellowish powder was obtained and further desagglomerated on an Alpine pin mill.

The product serves for the preparation of a mucoregulatory drug with a prolonged action.

                            Analysis:
                Na content                   4.6% b/w
                .SIGMA. C=O content              0.0% b/w
                COOH content                14.8% b/w
                N content                    1.9% b/w

Claim 1 of 38 Claims

What is claimed is:

1. A slow release formulation including a biocompatible anionic polysaccharide material containing glucuronic acid in a polymer chain of the polysaccharide material.

____________________________________________
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