IE83675B1 - Polymer complexes with polysaccharide comprising glucuronic acid residues - Google Patents
Polymer complexes with polysaccharide comprising glucuronic acid residuesInfo
- Publication number
- IE83675B1 IE83675B1 IE1999/0613A IE990613A IE83675B1 IE 83675 B1 IE83675 B1 IE 83675B1 IE 1999/0613 A IE1999/0613 A IE 1999/0613A IE 990613 A IE990613 A IE 990613A IE 83675 B1 IE83675 B1 IE 83675B1
- Authority
- IE
- Ireland
- Prior art keywords
- complex
- synthetic
- content
- cationic component
- imc
- Prior art date
Links
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- 229920001282 polysaccharide Polymers 0.000 title claims description 6
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- 150000004804 polysaccharides Polymers 0.000 title claims description 6
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- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 210000000987 Immune System Anatomy 0.000 description 1
- 210000002510 Keratinocytes Anatomy 0.000 description 1
- 210000003127 Knee Anatomy 0.000 description 1
- 229940041033 Macrolides Drugs 0.000 description 1
- 229960000564 Nitrofurantoin Drugs 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229940068917 Polyethylene Glycols Drugs 0.000 description 1
- 229920001451 Polypropylene glycol Polymers 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- 206010040882 Skin lesion Diseases 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 206010046577 Urinary tract infection Diseases 0.000 description 1
- 210000002700 Urine Anatomy 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 231100000494 adverse effect Toxicity 0.000 description 1
- 229960000880 allobarbital Drugs 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000181 anti-adherence Effects 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 230000001754 anti-pyretic Effects 0.000 description 1
- 230000000840 anti-viral Effects 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000012598 cell culture matrix Substances 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 239000011365 complex material Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 108091005892 fibrous proteins Proteins 0.000 description 1
- 102000034337 fibrous proteins Human genes 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 101700000038 mpas Proteins 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical class CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002110 toxicologic Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
Description
Polmromlxswith ol hri mriin rni irsids
Introduction
Oxidised cellulose and its derivatives have been widely used in medicine and
pharmacy since the first preparation by Chait and Kenyon [Sh0rygin P P., Chait
E.V.: Zh. obshch. chim. 7, 188 (1937); Yackel E.C., Kenyon W.O.: J Am. Chem.
Soc. 64, 121 (1942)].
Other types of haemostatics and antifibrinolytics have been introduced, however,
oxidised cellulose especially in the highly pure form of a polyanhydroglucuronic
acid and their copolymers (PAGA), and notably salts thereof, is used in various
medicinal applications as a completely resorbable semi—synthetic polymer with
minimum adverse effects in the organism. This is true for both the basic substance
prepared according to GB 709684; US 4,100,341, or salts thereof prepared according
to more recent patents, such as.: CS AO 242920; EP 0659440Al and PCT IE
98/00004.
It is known that after application of oxidised cellulose to stop surface bleeding a rigid
scab is formed. especially on movable parts of the body, such as knees, fingers or
ankles. This may be a disadvantage because it can crack and lead to renewed
bleeding. Using a haemostat according to PCT IE 98/00004 this disadvantage can be
partially overcome by altering the technological conditions of the manufacture (such
as increasing the amount of crosslinks) which brings about increased accumulation
of the body fluids in the substance and thereby the flexibility of the wound cover is
optimised.
Within the last two decades, during investigations of various types of
polysaccharides, it was established that during their biodegradation in the living
Nemec J ., Sedlmayer P., Vortel V.: Report on Toxicological Investigation of a New
Drug Preparation “Mikrocel” Internal report, Research Institute for Pharmacy and
Biochemistry, Praha, branch Pardubice-Rosice and Labem, 1984: Burhcard W.:
Polysacharide. Eigenschaften and Nutzung, Springer—Verlag, Berlin. Heidelberg,
New York, Tokyo, p. 144 (1985); US 5,166,137]. Depending on the type of bond in
the main glycosydic chain, on the value of the degree of polymerisation, on the
presence of various functional groups, and the degree of ionisation thereof, on the
type of structural units, and the type of salt or a complex salt thereof, these
polysaccharides affect the immune system of the organism. It seems for instance
that glucanes bonded by an 1,3 |3 bond have immunomodulative properties while 1,4
[5 bonded glucanes suppress tumorous growth. There are however exceptions to these
rules. An important factor underlying these properties is the presence of the
glucuronic acid in the chain.
It is known that a large proportion of bonds between individual substances occurring
in living organisms is of a non—covalent nature, such as hydrogen bonds, van der
Waals forces, or bonds of an ionic character especially with biopolymers. These
bonds create so-called intermolecular polymeric complexes (IMC) such as for
example, heparin — peptides. In general these complexes represent a new class of
macromolecular substances formed by association of individual polymer chains into
macromolecules through secondary bonding interactions. According to the nature of
the interactions these complexes can be subdivided into polyelectrolytc complexes,
hydrogen bonded complexes, stereo complexes and charge transfer complexes.
These types of complexes have a number of common properties, notably an
organised supermolecular structure and the ability to create other higher
supermolecular entities. The characteristic feature is their ability to undergo
restructuring depending on the conditions prevailing in their environment. Further
they are capable of undergoing interpolymer substitution reactions and it is
especially due to this latter ability that the IMCs in their behaviour come close to
imitating biochemical processes occurring in living organisms.
The invention in particular involves the use of polyanhydroglucuronic acids and salts
thereof. The term polyanhydroglucuronic acid and salts there of as used herein also
includes copolymers thereof, especially with anhydroglucose. This is hereinafter
referred to as PAGA.
Co—pending patent application WO 98/33822 describes particular
polyanhydroglucuronic acids and salts thereof and a method of preparing such
compounds. In particular therefore, the term polyanhydroglucuronic acids and salts
thereof includes the acids and salts referred to in this co—pending application.
Statements of Invention
According to the invention there is provided a biocompatible intermolecular polymer
complex of:
an anionic component comprising polyanhydroglucuronic acid [PAGA]
wherein at least 5% of the basic structural units are glucuronic acid said
PAGA being prepared by partially or completely hydrolysing and
neutralising in an oxidative environment a polyanhydroglucuronic acid-
containing material; and
a non protein cationic component comprising a linear or branched natural,
semi—synthetic or synthetic oligomer or polymer.
In a preferred embodiment of the invention the cationic component is a synthetic
biocompatible nitrogen—containing oligomer or polymer that either carries a positive
charge or wherein the positive charge is induced by contact with the polysaccharidic
anionic component.
In one case the cationic component is ielected from derivatives of acrylamide,
methacrylamide and copolymers thereof. Preferably the cationic component is
selected from polyacrylamide, copolymer of hydroxyethylmethacrylate and
hydroxypropylmetacrylamide, copolymers of
acrylamide, butylacrylate,
maleinanhydride and/or methylmetacrylate.
In another case the cationic component is a synthetic or semi—synthetic polyamino
acid. Preferably the cationic component is polylysin, polyarginin, or or, [3—poly-[N-
(Z—hydroxyethy1)—DL—aspartamide].
In a further embodiment the cationic component is a synthetic anti-fibrinolytic. The
anti—fibrinolytic may be a hexadimethrindibromide (polybren).
In a still further embodiment the cationic component is a natural or semi—synthetic
peptide. Preferably the peptide is a protamine, gelatine, fibrinopcptide, or
derivatives thereof.
In a further case the cationic component is an aminoglucane or derivatives thereof.
Preferably the aminoglucane is fractionated chitin or its de—acety1ated derivative
chitosan. The aminoglucane may be of microbial origin or is isolated from the shells
of arthropods such as crabs.
In this case preferably the polyanhydroglucuronic acid and salts thereof contain in
their polymeric chain from 8 to 30 per cent by weight of carboxyl groups, at least 80
per cent by weight of these groups being of the uronic type, at most 5 per cent by
weight of carbonyl groups, and at most 0.5 per cent by weight of bound nitrogen.
Preferably the polyanhydroglucuronic acid and salts thereof contain in their
polymeric chain at most 0.2 per cent 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, ideally, the molecular mass of the
polymeric chain of the anionic component ranges from 5x103 to 1.5 x 105 Daltons.
In a preferred embodiment the molecular mass of the polymeric chain of the anionic
omponent is from 1 x 103 to 3 x 105 Daltons, ideally the molecualr mass of the
polymeric chain of the anionic component ranges from 5 x 103 to 1.5 x 105 Daltons.
Most preferably the content of carboxyl groups is in the range of from 12 to 26 per
cent by weight, at least 95 per cent of these groups being of uronic type‘
In a preferred embodiment of the invention the anionic component contains at most 1
per cent by weight of carbonyl groups.
The carbonyl groups are preferably intra- and intermolecular 2,6 and 3,6
hemiacetals, 2,4—hemialdals and C2-C3 aldehydes.
The cationic component may be gelatine.
Alternatively the cationic component is chitosan.
The invention also provides a pharmaceutical or cosmetic composition including at
least one biocompatible complex of the invention.
Preferably the composition includes at least one biocompatible biologically active
substance.
The composition may alternatively or additionally include at least one biologically
acceptable adjuvant.
Dail D riin
We have now found that by preparing polymeric intermolecular complexes (IMC) of
glucuronoglucanes, notably microdispersed PAGA, prepared especially according to
WO 98/33822 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 0.99:0.0l to
.0l: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 glucuronoglucancs prepared for
example according to WO 98/33822 may roughly be subdivided into 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.
Synthetic or semi-synthetic polyaminoacids such as polylysin,
polyarginin, oc,[3—poly-[N—(2—hydroxyethyl)—DL—asparamide. Synthetic
antifibrinolytics hexadimethrindibromide (polybren) can also be included
in this group.
Natural or semi-synthetic peptides such as gelatine, protamines, or
fibrinopeptides, and their derivatives.
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.
product.
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
In general it can be said that IMCs using substances from la and lb 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.
_ 8 _
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 WO 98/33822
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 [3 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. This complex has a higher
haemostatic efficiency and 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 WO 98/33822 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 microcrystalline 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 ccphalosporins (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.
The invention will be more clearly understood from the following examples of
polymer complexes of glucuronoglucanes.
Example 1:
Material:
long—fibre cotton ~ medicinal cotton wool oxidised by NXQV
(proprietary)
C6OOH 18.8 % b/w
ash content < 0.1 % b/w
X C=O 0.6 % b/w
% solution NagCO3 (Lachema, a.s. Neratovice)
CaCl2.6H2O analgrade (Lachema, a.s. Neratovice)
demineralised water 2pS
ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)
acid acetic anal. grade (Lachema, a.s. Neratovice)
H202 anal.grade 30% (Lachema, a.s. Neratovice)
N—HANCE 3000 guargumhydroxypropyltriammoniumchloride
(Aqualon — Hercules)
mixer: bottom stirring, 150 litre (duplicator), stainless steel EXTRA
vibrating screen: stainless steel, 150 mesh
rotary air pump: rotor diameter 150 mm
turbostirrer: ULTRA TURAX (Janke—l(unkel)
beaker:5 litre
pH meter PICCOLO
thermocouple thermometer
Pro r :
g of N—HANCE 3000 were placed into a 5 l beaker and 3 1 of demineralised water
2uS were added. The contents of the beaker were intensely stirred for 30 minutes.
The pH Value was adjusted to less than 4.5 by the addition of an acetic acid solution
leading to a viscosity rise.
l of demineralised water 2uS were introduced into a mixer. 3 kg of CaCl2.6H;O
ana1.grade were added and the contents heated up to a temperature of 50°C with
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. The pH value of the contents was adjusted
by addition of a 20% solution of Na2CO3 to 6 — 6.5 and 13 kg of H202 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 1 of synthetic rectified ethanol conc. 98% were introduced
into the mixer. 15 seconds after 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 1 of demineralised water 2uS. 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
2 C20 content 0.0 % b/w
COOH content 20.7 % b/w
Example 2:
: oxidised short—fibre cotton (Linters — Temming) (proprietary)
Equipment:
Procedure:
C6OOH 16.8 % b/w
ash content < 0.15 % b/w
Z C=O 2.6 % b/w
% solution Na2CO3 (Lachema, a.s. Neratovice)
CaC12.6H2O analgrade (Lachema, a.s. Neratovice)
redistilled water (PhBs 1997)
ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)
isopropanol 99.9% (Neuberg Bretang)
H202 analgrade 30% (Lachema, a.s. Neratovice)
gelatine (PhBs 1997)
turbostirrer: ULTRA TURAX (Janke-Kunkel)
sulphonation flask 1 litre
heater 1.5 kW
laboratory centrifuge: 4000 rpm
thermostated water bath
pH meter PICCOLO
glass thermometer
rotary vacuum dryer or hot—air dryer
Into a 1 litre sulphonation flask equipped with a turbostirrer and a heater, 400 ml of
redistilled H20 were placed, 15.73 g of CaCl2.6H2O were added and on dissolution,
40.0 g of 20% NagCO3 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°C with the stirring intensity set to a maximum. After 10 minutes, 30
g of 30% H202 were added into the flask and the hydrolysis continued for another 10
minutes. The contents were then cooled down to 60°C on a water bath and the pH of
the system was adjusted to a value of 4.5 — 5.0 by the addition of a 20% solution of
Na2CO3. A gelatine solution (10 g of gelatine in 70 g of redistilled H20) warmed to
50°C was added and left to react for another 20 minutes. The flask contents were
then cooled to 30°C 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 alllowed stand
for 4 hours. It was then centrifuged again, redispersed into 99.9 % isopropanol, and
left to stand for a minimum of 10 hours at 20°C. The gel formed was centrifuged
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.
:A_n_a.1fl
content Ca 4.4 % b/w
content Na 2.7 % b/w
content X C=O 0.0 % b/w
content COOH 20.5 % b/w
content N 1.8 % b/w
- 14 _
Example 5:
: oxidised short—fibre cotton (Linters — Temming) (proprietary)
C600H 16.8 % b/w
ash content < 0.15 % b/w
Z 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)
H202 anal.grade 30% (Lachema, a.s. Neratovice)
gelatine (PhBs 1997)
Equipment: turbostirrer: ULTRA TURAX (Janke-Kunkel)
sulphonation flask 1 litre
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 litre sulphonation flask equipped with a turbostirrer and a heater, 400 ml of
redistilled H20 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°C and the stirring
intensity set to a maximum. After 20 minutes, 40 g of 30% H202 were added into the
flask, the temperature was increased to 85°C, and maintained for another 10 minutes.
The contents were then cooled to 50°C on a water bath and gelatine solution (10 g of
gelatine in 70 g of redistilled H30) warmed 50°C was added to the hydrolysate. The
temperature was decreased to 25 — 30°C 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 and after the separation of the supernatant liquid, the IMC was
redispersed into 250 ml of synthetic rectified ethanol conc. 98% and left to stand for
4 hours. It was then centrifuged, redispersed into 99.9 % isopropanol, and allowed
stand for a minimum of 10 hours at 20°C. The gel formed was centrifuged 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:
Na content 3.8 % b/w
X C=O content 0.0 % b/w
COOH content 21.5 % b/w
N content 2.7 % b/w
Example 4:
Material: oxidised short-fibre cotton (Linters ~ Temming) (proprietary)
C6OOH 16.8 % b/w
ash content < 0.15 % b/w
Z C=O 2.6 % b/w
% solution N a2CO3 (Lachema, a.s. Neratovice)
CaCl2.6H2O anal.grade (Lachema, a.s. N eratovice)
redistilled water (PhBs 1997)
ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)
isopropanol 99.9% (Neuberg Bretang)
H202 anal. grade 30% (Lachema, a.s. Neratovice)
chitosan, degree of deacetylation 92% (Henkel)
E i m n : turbostirrer: ULTRA TURAX (Janke-Kunkel)
sulphonation flask 1 litre
heater 1.5 kW
laboratory centrifuge: 4000 rpm
therrnostated water bath
pH meter PICCOLO
glass thermometer
rotary vacuum dryer or hot—air dryer
Procedure:
Into a sulphonation flask, 250 ml redistilled H20 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°C and the stirring intensity set to a maximum. After
hydrolysing for 15 minutes, 35 g of 30% H202 were gradually added to the system
and the temperature was maintained at 50°C for another 20 minutes. The contents
were cooled to 30°C 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 the addition of NaOH to a value of 7.0.
Subsequently 300 ml of synthetic rectified ethanol conc. 98% were added with
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 left to stand for 4 hours. It was then
centrifuged again, redispersed into 99.9 % isopropanol, and left for a minimum of 10
hours at 20°C. The gel formed was centrifuged 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:
Na content 1.8 % b/w
X 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)
C6OOH 16.8 % b/w
ash content < 0.15 % b/w
Z 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)
H202 anal.grade 30% (Lachema, a.s. Neratovice)
gelatine (PhBs 1997)
Ambroxol (H. Mack, Germany)
turbostirrer: ULTRA TURAX (Janke—Kunkel)
sulphonation flask 2 l
heater 1.5 kW
laboratory centrifuge: 4000 rpm
laboratory pin mill ALPINE (35 000 rpm)
therrnostated water bath
pH meter PICCOLO
glass thermometer
rotary vacuum dryer or hot—air dryer
Procedure:
Into a sulphonation flask, 400 ml redistilled H20 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°C and the stirring intensity was set to a maximum. After
hydrolysing for 20 minutes, 40 g of 30% H202 were gradually added to the system
and the temperature was increased to, and maintained at, 85°C for another 10
minutes. The content were cooled down to 50°C in a water bath, and gelatine
solution (2 g of gelatine in 70 g of redistilled H20) warmed up to 50°C was added to
the hydrolysate. The temperature was decreased to 25 — 30°C 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 (25g of ambroxolium hydrochloride
in 500 ml of redistilled H20) 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 cone. 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°C 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
X C=O content 0.0 % b/w
COOH content 14.8 % b/w
N content 1.9 % b/w
Example 6:
: oxidised short-fibre cotton (Linters — Temming) (proprietary)
C6OOH 16.8 % b/w
ash content < 0.15 % b/w
Z C:O 2.6 % b/w
% solution Na2CO3 (Lachema, a.s. Neratovice)
CaCl2.6HgO anal.grade (Lachema, a.s. Neratovice)
redistilled water (PhBs 1997)
ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)
isopropanol 99.9% (Neuberg Bretang)
H202 anal.grade 30% (Lachema, a.s. Neratovice)
gelatine (PhBs 1997)
gentamycin sulphate (MERCK)
Equipment: turbostirrer: ULTRA TURAX (J anke—Kunkel)
sulphonation flask 2 litre
heater 1.5 kW
_ -
laboratory centrifuge: 4000 rpm
laboratory pin mill ALPINE (35 000 rpm)
thermostated water bath
pH meter PICCOLO
glass thermometer
hot-air dryer
lyophiliser (Leibold Heraus, Germany)
Pro r :
Into a 2 litre sulphonation flask equipped with a turbostirrer and a heater, 400 ml of
redistilled H2O were placed, 15.73 g of CaCl2.6H2O were added and on dissolution,
40.0 g of 20% Na2CO3 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°C and the stirring intensity set to a maximum. After 10 minutes, 30 g
of 30% H202 were added into the flask and the hydrolysis was continued for another
minutes. The contents were then cooled down to 60°C 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
Na2CO3. A gelatine solution (10 g of gelatine in 70 g of redistilled H20) warmed up
to 50°C was added and let to react for another 20 minutes. The flask contents were
then cooled down to 30°C in a water bath and 40 g of gentamycin sulphate in 600 ml
of redistilled H20 were added gradually within 10 minutes. 626 ml of synthetic
rectified ethanol conc. 98% were then added gradually with intense stirring to the
antibiotic containing IMC suspension formed. 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 and after the separation of the supernatant liquid, the IMC was
redispersed into 250 ml of synthetic rectified ethanol cone. 98% and left for 4 hours.
It was then centrifuged, redispersed into 99.9 % isopropanol, and left for a minimum
of 10 hours at 20°C. The gel formed was centrifuged and the product was dried in a
rotary vacuum dryer or a hot-air dryer.
The product can be used, for instance, for the manufacture of a dusting powder or a
powder spray for the treatment of infected wounds.
Analysis:
Ca content 2.4 % b/w
Na content 1.6 % b/w
Z C=O content 0.0 % b/w
COOH content 9.6 % b/w
N content 2.7 % b/w
Example 7:
Material: long—fibre cotton — medicinal cotton wool oxidised by NXOY
(proprietary)
C6OOH 18.8 % b/w
ash content < 0.1 % b/w
C=O 0.6 % b/w
% solution NagCO3 (Lachema, a.s. Neratovice)
CaC12.6HgO anal.grade (Lachema, a.s. Neratovice)
demineralised water 2pS
ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)
isopropanol 99.9% (Neuberg Bretang)
acid acetic anal.grade (Lachema, a.s. Neratovice)
H202 ana1.grade 30% (Lachema, a.s. Neratovice)
N—HANCE 3000
(Aqualon — Hercules)
polybren (hexadimethrindibromide) (FLUKA)
chlorhexidindigluconate
guargumhydroxypropyltriammoniumchloride
E i m n : mixer: bottom stirring, 1501 (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 litre
pH meter PICCOLO
thennocouple thermometer
Procedure;
g of N-HANCE 3000 were placed into and 5 l beaker and 3 l of demineralised
water 2118 were added. Contents of the beaker were stirred intensely for 30 minutes.
The pH value was adjusted to less than 4.5 by the addition of an acetic acid solution
leading to a viscosity rise.
l of demineralised water 2uS were introduced into a mixer. Then 3 kg of
CaCl2.6HgO anal.grade were added and the contents heated up to a temperature of
50°C 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 the addition of a 20% solution of Na2CO3 to 6 — 6.5 and 13
kg of H202 30% were introduced. The fibre suspension was slowly agitated for 10
minutes. 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. A solution of 35 g of chlorhexidine digluconate in 350 ml of
demineralised water 2uS was then introduced slowly within 10 minutes. Within
another 10 minutes, a solution of polybren containing 120 g of polybren in 1000 ml
of demineralised water 2uS was added. Subsequently 60 l of synthetic rectified
ethanol conc. 98% were introduced into the mixer. 15 seconds after 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
of a mixture of 18 1 of synthetic rectified ethanol conc. 98% and 42 l of
demineralised water 2uS. The fibre suspension was filtered again on the vibrating
screen.
The isolated material thus prepared may further serve to prepare, via a wet or dry
process, final products of the non—woven type having an enhanced haemostatic
activity and a bactericidal effect.
Analysis:
Ca content 3.6 % b/w
Na content 1.9 % b/w
X C=O content 0.0 % b/w
COOH content 18.1 % b/w
N content 0.35 % b/w
Example 8:
Material: oxidised short-fibre cotton (Linters — Temming) (proprietary)
C6OOH 16.8 % b/w
ash content < 0.15 % b/w
Z C=O 2.6 % b/w
% solution Na2CO3 (Lachema, a.s. Neratovice)
CaCl2.6HgO anal. grade (Lachema, a.s. Neratovice)
redistilled water (PhBs 1997)
ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)
isopropanol 99.9% (Neuberg Bretang)
H202 anal.grade 30% (Lachema, a.s. Neratovice)
Chitosan, degree of deacetylation 92% (Henkel)
Clarithromycin lactobionan (Abbott Laboratories, Italy)
_ 24 _
Equipment: turbostirrer: ULTRA TURAX (Janke-Kunkel)
sulphonation flask l litre
heater 1.5 kW
laboratory centrifuge: 4000 rpm
thermostated water bath
pH meter PICCOLO (RTM)
glass thermometer
rotary vacuum dryer or hot-air dryer
dialysing bag (regenerated cellulose)
lyophiliser (Leybold Heraus, Germany)
laboratory pin mill ALPINE (35 000 rpm)
Procedure:
Into a sulphonation flask 250 ml redistilled H20 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°C and the stirring intensity set to a maximum. After
hydrolysing for 15 minutes, 35 g of 30% H202 were gradually added to the system
and the temperature was maintained at 50°C for another 20 minutes. The content
were cooled down to 30°C and 400 g of highly viscous 2% solution of chitosan,
having a pH value of 3.5, 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. During another 10 minutes, a solution of clarithromycin (44 g of
clarithromycin in 456 ml of redistilled H20) was introduced and the pH of the
system was adjusted to a value of 7.0-7.5. Stirring was interrupted, the flask contents
were transferred into a dialysing bag and dialysed against water for 48 hours.
Subsequently the product was isolated by centrifugation, lyophilised, and
disintegrated using the laboratory pin mill ALPINE. (RTM)
The product can be used, for instance, to prepare tablets or granules efficient against
Helicobacter pylori occurring in the gastrointestinal tract.
Analysis;
Na content 4.8 % b/w
X C=O content 0.0 % b/w
COOH content 18.8 % b/w
N content 0.7 % b/w
Example 9:
Legal; oxidised short—fibre cotton (Linters — Temming) (proprietary)
C5OOH 16.8 % b/w
ash content < 0.15 % b/w
Z 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)
H202 anal. grade 30% (Lachema, a.s. Neratovice)
gelatine (PhBs 1997)
Bl(NO3).5HgO (MERCK)
Equipment: turbostirrer: ULTRA TURAX (J anke—Kunkel)
sulphonation flask 2 litre
heater 1.5 kW
laboratory centrifuge: 4000 rpm
thermostated water bath
pH meter PICCOLO (RTM)
glass thermometer
rotary vacuum dryer or hot—air dryer
_ 26 _
Procedure:
Into a sulphonation flask 400 ml redistilled H20 were placed and 8 g of N a0H were
added. On dissolution, 50 g of oxidised Linters were introduced under stirring, the
temperature increased to 70°C and the stirring intensity was set to a maximum. After
hydrolysing for 20 minutes, 40 g of 30% H202 were gradually added to the system
and the temperature was increased to, and maintained at, 85°C for another 10
minutes. The contents were cooled down to 50°C in a water bath, and a gelatine
solution (0.5 g of gelatine in 50 ml of redistilled H20) warmed up to 50°C was added
to the hydrolysate. The temperature was decreased to 25 — 30°C and the pH of the
system was checked and adjusted to a value of 1.6 — 1.8 by addition of 39% HCI. A
freshly prepared solution of BiN03 (54 g of BiN03.5H20 in 746 ml of H20) was
introduced and the temperature maintained for another 15 minutes. The temperature
was decreased to 25 — 30°C and the pH of the system was checked and readjusted to
a value of 5.5 — 6.0. 626 ml of synthetic rectified ethanol conc. 98% were then added
gradually with intense stirring. The Bi0+ containing IMC suspension 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 left for a
minimum of 4 hours. It was then centrifuged again, redispersed into 99.9 %
isopropanol, and left for a minimum of 10 hours at 20°C. The suspension formed
was then centrifuged again and the product was dried in a rotary vacuum dryer or a
hot-air dryer.
The product can be used, for instance, to prepare dusting powders for wound
treatment or tablets for treatment of gastrointestinal tract malfunctions.
Analysis:
Na content 1.9 % b/w
2 C20 content 0.0 % b/w
COOH content 20.0 % b/w
N content < 0.3 % b/w
Bi content 4.7 % b/w
Example 10:
: oxidised short—fibre cotton (Linters — Temming) (proprietary)
Equipment:
Proeedure:
C6OOH 16.8 % b/w
ash content < 0.15 % b/w
X C=O 2.6 % b/w
% solution NagCO3 (Lachema, a.s. Neratovice)
CaCl2.6H2O anal. grade (Lachema, a.s. Neratovice)
redistilled water (PhBs 1997)
ethanol, synthetic rectified conc. 98% (Chemopetrol Litvinov, a.s.)
isopropanol 99.9% (Neuberg Bretang)
H202 anal.grade 30% (Lachema, a.s. Neratovicc)
gelatine (PhBs 1997)
cimetidine hydrochloride (SPOFA)
turbostirrer: ULTRA TURAX (Janke—Kunkel)
sulphonation flask 2 litre
heater 1.5 kW
laboratory centrifuge: 4000 rpm
therrnostated water bath
pH meter PICCOLO (RTM)
glass thermometer
rotary vacuum dryer or hot-air dryer
Into a 1 1 sulphonation flask equipped with a turbostirrer and a heater, 400 ml of
redistilled H20 were placed. 15.73 g of CaCl2.6H2O were added and on dissolution
40.0 g of 20% Na2CO3 solution were introduced with stirring. 50 g of oxidised
_ 28 _
Linters were added to the white emulsion formed and the contents were heated up to
°C and the stirring intensity set to a maximum. After 10 minutes, 30 g of 30%
H202 were added into the flask and the hydrolysis was continued for another 10
minutes. The contents were then cooled down to 60°C 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
Na;CO3. A gelatine solution (10 g of gelatine in 70 g of redistilled H20) warmed up
to 50°C was added and allowed react for another 20 minutes. The flask contents were
then cooled down to 30°C in a water bath and a solution of cimetidine (36 g of
cimetidine hydrochloride in 400 ml of redistilled H20) were added with intense
stirring. The contents were intensely agitated for 10 minutes and 800 ml of synthetic
rectified ethanol conc. 98% were added gradually. 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 and after separation of the supernatant liquid, the IMC was
redispersed into 250 ml of synthetic rectified ethanol conc. 98% and left for 4 hours.
It was then centrifuged again, redispersed into 99.9 % isopropanol, and left for a
minimum of 10 hours at 20°C. 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, to manufacture tablets or granulates for the
treatment of the gastrointestinal tract or other non—malignant ulcerations.
Analysis:
Ca content 4.4 % b/w
Na content 2.7 % b/w
2 C=O content 0.0 % b/w
COOH content 20.5 % b/w
N content 2.1 % b/w
Example 11:
Material: IMC—microdispersed oxidised cellulose (MDOC) complex (as per
above Example 2)
[(2S;2R)aminohydroxyphenylbutenoyl]—L—leucin (Bestatin)
(Boehringer Mannheim, Germany)
redistilled water (PhBs 1997)
methanol, conc. anal. grade (Chemopetrol Litvinov, a.s.)
diethylether (Lachema, a.s. Neratovice)
E i m n : turbostirrer: ULTRA TURAX (Janke-Kunkel)
sulphonation flask 2 1
laboratory centrifuge: 4000 rpm
hot—air dryer
Proeedure:
The IMC—MDOC complex as prepared in Example 2 above was redispersed into
redistilled water in a sulphonation flask using a turbostirrer. A solution of Bestatin in
methanol was added to the flask in an amount sufficient to yield a 10% b/w
concentration of Bestatin in the resulting Bestatin—gelatine—MDOC complex. After
thorough homogenisation, the suspension formed was isolated by centrifugation. The
supernatant liquid was filtered away and the filtration cake was redispersed into
concentrated methanol, centrifuged, redispersed in diethylether, and after being left
for 1 hour, it was dried in a hot—air dryer.
The product, a microdispersed form of a Bestatin—gelatine-MDOC complex, can be
used, for instance, to prepare microembolisation agents used in regional
chemotherapy of malignant tumours or flat dressing structures for wound treatment.
_ 30 -
The following are application examples illustrating some of the uses of the products
produced in examples 1 to 11.
Example A: Preparation of tablets and pellets from IMC—MDOC complex
MDOC = Microdispersed Oxidised cellulose
Material: IMC—MDOC complex — see Example 2
magnesium stcarate (SIGMA)
ascorbic acid (MERCK)
oc—tocoferol acetate (Slovakofarma Hlohovec)
ethanol synthetic rectified (Chemopetrol Litvinov, a.s.)
Equipment: tabletting machine (KORSCH EK 0, Berlin )
blender (Nautamix 300)
c0unter—flow drier BINDER (RTM)
Procedure:
kg of IMC—MDOC complex of composition according to Example 2 were placed
into the blender , and 660 g of micronised ascorbic acid, 1660 g of oc—tocoferol
acetate emulgated in 2500 ml of ethanol, and 1000 g of magnesium slearatc were
added. The mixture was homogenised for 3 hours. It was then dried in a counter-
flow drier at a temperature of 50°C until ethanol was removed.
g of the resulting dry powder were introduced into the tabletting machine, and
the tabletting force was set at a value of 7 kN.
Result:
The tablets prepared were smooth and well cohering and had a weight of 0.5 g.
Disintegration rate of the tablets in a saline F1/1 was 17 minutes at 20°C, and 8
minutes at 37°C.
Application Example:
Patient aged 57, displaying an increased cholesterol content in blood was treated by
MDOC tablets administered orally for 50 days, at a dose of 6 tablets daily. After the
treatment both LDL content and total cholesterol content were significantly reduced.
Blood analysis: before treatment after treatment
Total Cholesterol 7.70 mmol/l 5.70 mmol/l
HDL 1.16 mmol/l 1.30 mmol/l
LDL 4.40 mmol/1 3.30 mmol/l
Triacylglycerols 1.81 mmol/l 1.80 mmol/l
Example B : Preparation of tablets and pellets with IMC—MDOC
complex containing clarithromycin
Material: IMC—MDOC complex — see Example 8
MDOC, particle size 0.1 — 2.0 pm, specific surface area 86m2, COOH
group content 22.2% b/w, Ca content 4.2 % b/w, Na content 3.8 %
b/w
IMC—MDOC complex containing BiO+ - see Example 9
Equipment: laboratory mixer, bottom agitated, 4000 rpm
tabletting machine (KORSCH EK 0, Berlin)
_ 32 -
Procedure:
.5 g of IMC-MDOC containing clarithromycin were placed into the mixer, and 12.0
g of BiO+ salt and 78.5 g of MDOC were added. The vessel was closed, the agitation
set on, and the contents were homogenised for 60 seconds. The homogenised
mixture was then transferred to the storage vessel of the tabletting machine, and the
tabletting force was set to a value of 7.5 kN.
Result;
The tablets prepared were smooth and cohering and had a weight of 0.5 g.
Disintegration rate of the tablets in a saline F 1/1 was 12 minutes at 20°C, and 5
minutes at 37°C.
Indication:
The tablets are indicated for treatment of gastric ulcers. MDOC suppresses formation
of the stomach acidity, adjust the pH value of the environment, and protects the
mucous membranes by forming a gel layer. BiO+ acts as a mild astringens.
Clarithromycin depresses the growth of Helicobacter pylori beyond pathologic
limits.
Example C : Preparation of tablets and pellets with IMC-MDOC complex
containing Ambroxol
Material: MDOC, particle size 0.1 — 2.0pm, specific surface area 86m2, COOH
group content 22.2% b/w, Ca content 4.2 % b/w, Na content 3.8 %
b/W
IMC-MDOC complex containing Ambroxol — see Example 5
microcrystalline cellulose (SIGMA)
hydroxypropylcellulose (Natrosol HHR 250)
magnesium stearate (SIGMA)
Macrogol 400 (SIGMA)
Equipment: laboratory mixer, bottom agitated, 4000 rpm
tabletting machine (KORSCH EK 0, Berlin)
Procedure:
.0 g of MDOC, 42.0 g of IMC—MDOC containing ambroxol, 10.0 g of
microcrystalline cellulose, 2.0 g of magnesium stearate, 1.0 g of Macrogolu 400, and
2.0 g of Natrosol (RTM) HHR250 were introduced into the mixer. The vessel was
closed, agitation (4000 rpm) started and the contents were homogenised for 120
seconds. The homogenised mixture was then transferred to the storage vessel of the
tabletting machine and the tabletting force was set at a value of 5.0 kN.
Result:
The tablets prepared were smooth and cohering and had a weight of 0.5 g.
Disintegration rate of the tablets in a saline F1/1 was 10 minutes at 20°C, and 6
minutes at 37°C.
Indication:
Acute and chronic respiratory diseases involving formation of dense mucus (acute
bronchitis, bronchial asthma), ease of mucus dissolution in rhinofaryngitis. In testing
on volunteers at a dosage rate of 3 tablets per day, ambroxol could still be detected in
the urine at Day 8 after administration.
Example D; Preparation of tablets and pellets with IMC—MDOC complex
containing cimetidine
Material: MDOC, particle size 0.1 - 2.0um, specific surface area 86ml, COOH
group content 22.2% b/w, Ca content 4.2 % b/w, Na content 3.8 %
b/w
IMC—MDOC complex containing Cimetidine - see Example 10
Macrogol 400 (SIGMA)
Equipment: laboratory mixer , bottom agitated, 4000 rpm
tabletting machine (KORSCH EK 0, Berlin )
Procedure:
.0 g of IMC—MDOC containing Cimetidine, 32.0 g of MDOC and 5.0 g of
Macrogolu 400 were introduced into the mixer. The vessel was closed, the agitation
set on, and the contents were homogenised for 60 seconds. The homogenised
mixture was then transferred to the storage vessel of the tabletting machine, and the
tabletting force was set to a value of 7.5 kN.
Result:
The tablets prepared were smooth and well cohering and had a weight of 1.0 g.
Disintegration rate of the tablets in a saline F1/1 was 8 minutes at 20°C, and 6
minutes at 37°C.
Indication:
The tablets are indicated for treatment of gastric ulcers. MDOC suppresses formation
of the stomach acidity, adjust the pH value of the environment, and protects the
mucous membranes by forming a gel layer. BiO+ acts as a mild astringens.
Cimetidine suppresses both basal and simulated secretion of the stomach acid.
Example E: Preparation of rectal suppositories from IMC—MDOC Bi0+ complex
containing aminophenazon and allobarbital
Material: Adeps neutralis (WERBA)
Oleum cacao (WERBA)
IMC—MDOC complex containing BiO+ — see Example 9
Aminophenazonum (SPOFA)
Allobarbitalum (SPOFA)
Equipment: stainless melting tank, agitated, volume 1000 ml, input power 600W
movable support carrying a shaped blister foil
Procedure:
.6 g of Adeps neutralis and 122.6 g of Oleum cacao were introduced into the
melting tank. The contents were heated up to a temperature of 75°C. On melting, 16
g of Allobarbitalum, 117.3 g of Aminophenozonum and 61.33 g of IMC-MDOC
complex containing BiO+ were gradually added under permanent agitation. After
appropriate homogenisation, the mass was cast into a shaped blister foil serving,
when cooled down, as the suppository packaging.
Result:
Suppository of 8 mm diameter, 20 mm length, conical shape, weight 2.25 g.
Indication:
Combined suppositories having antihaemorroidal and analgetic/antipyretic effects.
Example F: Preparation of vaginal suppositories from IMC-MDOC complex
containing gelatine, nitrofurantoin and chlorohexidine
Material: IMC-MDOC complex — see Example 2
gelatina animalis (SIGMA)
1,2—monopropylenglykol (SIGMA)
glycerol, medicinal (MERCK)
nitrofurantoinum (SPOFA) broad spectrum anti—microbial and anti-
inflammatory
chlorohexidine digluconate (FEROSAN) — local bacteriocide
redistilled H20
Equipment: stainless melting tank, agitated, volume 1000 ml, input power 600W
movable support carrying a shaped blister foil
Pro r :
g of redistilled H20, 240 g of medicinal glycerol, 30 g of 1,2—MPG were
introduced into the melting tank and the mixture was heated up to a temperature of
75°C. On melting, 30 g of nitrofurantoinu and 30 g of chlorohexidine were gradually
added under agitation, and the mixture was agitated for another 15 minutes.
Subsequently, 102 g of gelatine animalis were introduced and, after appropriate
homogenisation, 90 g of IMC—MDOC complex were added. The resulting mixture
was agitated for another 15 minutes and then the mass was cast into a shaped blister
foil serving, when cooled down, as the suppository packaging.
Result:
Suppository of 8 mm diameter, 17 mm length, cylindrical shape, weight 2.0 g.
Indication:
Vaginal suppositories for use in treatment of urinary tract infections due to both
grampositive and gramnegative bacterias, displaying a prolonged effect. The IMC-
MDOC present serves to protect the vaginal mucous tissue and to create a natural
microenvironment similar to the action of lactic acid.
Example G: Preparation of dental pins from IMC-MDOC complex containing
bactericidal agent
Material: IMC-MDOC complex - see Example 2
chlorohexidine digluconate (FEROSAN)
ethanol synthetic rectified 98%
Equipment: laboratory mixer 4000 rpm
tabletting machine (KORSCH EK 0, Berlin )
Proeedure:
g of IMC-MDOC complex prepared according to Example 2 were placed into
the mixer and a solution of 1.6 g of chlorohexidine digluconate in 20 g of ethanol
was added under stirring. The mixture was homogenised for 120 seconds, and then
introduced into the tabletting machine equipped with a set of special shaped moulds,
and the tabletting force was set at a value of 5 kN.
Result:
Dental pins of a cone frustrum shape, 15 mm in height and 7 mm in base diameter,
with lateral grooves to facilitate grasping the pin with tweezers.
Indieation:
Treatment of massive postextractional bleeding with simultaneous administration of
a bactericidal agent.
Example H: Preparation of dental pins from IMC-MDOC complex with
antimicrobial agent
Material: IMC—MDOC complex containing chitosan— see Example 4
MDOC, particle size 0.1 — 2.0 um, specific surface area 86 m2/g,
COOH group content 22.2% b/w, Ca content 4.2 % b/w, Na content
3.8 % b/w
polyviny1pyrrolidone—iodine complex PVP—I micronised (lSP—USA)
E i m n : laboratory mixer 4000 rpm
tabletting machine (KORSCH EK 0, Berlin)
Procedure:
g of IMC—MDOC complex, 49 g of MDOC and 1 g of PVP—I complex were
placed into the mixer. The mixture was homogenised for 120 seconds, and then
introduced into the tabletting machine equipped with a set of special shaped moulds,
and the tabletting force was set at a value of 5 kN.
Result:
Dental pins of a cone frustrum shape, 15 mm in height and 7 mm in base diameter,
with lateral grooves to facilitate grasping the pin with tweezers.
Indication:
Treatment of massive postextractional bleeding with simulataneous administration of
an antimicrobial agent.
Example I: Preparation of granules from IMC—MDOC complex containing
clarithromycin
Material: IMC-MDOC complex — see Example 8
MDOC, particle size 0.1 - 2.0 um, specific surface area 86 m2/g,
COOH group content 22.2% b/w, Ca content 4.2 % b/w, Na content
3.8 % b/w
IMC-MDOC complex containing BiO+ - see Example 9
ethanol synthetic rectified 98%
redistilled H20
Equipment: set of vibrating screens with mesh size 100, 150, 200, 250, 350,
ptm
mixer, bottom agitated, vessel size 1000 ml, 8000 rpm, equipped with
a nozzle for inlet of the granulation medium
counter—flow drier BINDER (RTM)
Procedure:
g of MDOC were placed into the mixer, the mixer was closed and the agitation
switched on. A mist of 88% aqueous solution of ethanol was gradually injected into
the mixer at a rate of 10 g/45 seconds. The granulate formed was transferred to the
counter—flow drier and dried at a temperature of 45°C until the humidity content was
reduced below 6% b/w. The dried granules were sieve—screened using the set of
vibrating screens. The individual fractions were packaged into glass vials in amounts
of 0.5 -2.0 g each as required. The preparation was sterilised by y irradiation with a
dose of 25 kGy.
Indieation:
The granules can be used in the treatment of gastric ulcers. MDOC suppresses
formation of the stomach acidity, adjust the pH value of the environment, and
protects the mucous membranes by forming a gel layer. BiO+ acts as a mild
astringens. Clarithromycin depresses the growth of Helicobacter pylori beyond
pathologic limits.
Example ,! ; Preparation of granules from IMC-MDOC complex
Material: IMC—MDOC complex — see Example 2
Equipment: set of vibrating screens with mesh size 100, 150, 200, 250, 350,
um
mixer, bottom agitated, vessel size 1000 ml, 8000 rpm, equipped with
a nozzle for inlet of the granulation medium
counter—flow drier BINDER (RTM)
Procedure:
g of MDOC were placed into the mixer, the mixer was closed and the agitation
switched on. Saturated water vapour was gradually injected into the mixer at a rate of
g/45 seconds. The granulate fonned was transferred to the counter-flow drier and
dried at a temperature of 45°C until the humidity content was reduced below 6%
b/w. The dried granules were sieve—screened using the set of vibrating screens. The
individual fractions were packaged into glass vials in amounts of 0.5 -2.0 g each as
required. The preparation was sterilised by y irradiation with a dose of 25 kGy.
Indication:
The product may be used as a) an embolisation agent, or b) an antilipemicum.
Example K; Preparation of granules from IMC-MDOC complex containing
antimicrobial agent
Material: IMC—MDOC complex — see Example 2
polyvinylpyrrolidone—iodine PVP-I complex micronised (ISP—USA)
l,2—monopropyleneglycol (MERCK)
redistilled H20
ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)
E i m n: set of vibrating screens with mesh size 100, 150, 200, 250, 350, 500
um
mixer, bottom agitated, vessel size 1000 ml, 8000 rpm, equipped with
a nozzle for inlet of the granulation medium
counter—flow drier BINDER (RTM)
Procedure:
g of IMC—MDOC complex, 5 g of PVP—I complex and 5 g of 1,2—MPG were
placed into the mixer, the mixer was closed and the agitation switched on. A mist of
88% aqueous solution of ethanol was gradually injected into the mixer at a rate of
g/50 seconds. The granulate formed was transferred to the counter—flow drier and
dried at a temperature of 45°C until the humidity content was reduced below 6%
b/w. The dried granules were sieve—screened using the set of vibrating screens. The
fraction below 100 um was used to prepare a dusting powder. The higher fractions
were packaged into glass vials in amounts of 0.5 -2.0 g each as required.
Indieation:
Haemostatic preparation with antimicrobial and antiviral effect (powder spray,
dusting powder).
Example L: Preparation of microspheres from IMC-MDOC complex containing
mitoxanthron
Material: IMC—MDOC complex — see Example 3
1,4—bis(hydroxyethylamino-ethylamino-)5,8-
dihydroxyantrachinon (mitoxanthron) (Aliachem a.s.)
ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)
redistilled H20
E i m n ‘ turbostirrer ULTRA TURAX (Janke-Kunkel)
sulphonation flask 1 l
beaker 250 ml
set of vibrating screens with mesh size 100, 150, 200, 250, 350, 500
um
counter-flow drier BINDER (RTM)
vial 10 ml
injection syringe 25 ml
Banging
80 g of redistilled water and 20 g of IMC—MDOC complex were introduced into the
beaker, and the complex was dispersed using the turbostirrer to obtain a colloidal
solution thereof.
ml of 98% ethanol was placed into the sulphonation flask. 1.0 g of mitoxanthron
hydrochloride was placed into the 10 ml vial and dissolved in 5 g of redistilled water.
The solution was then transferred into the sulphonation flask with ethanol under
stirring.
The colloidal solution of IMC—MDOC complex was then gradually introduced into
the mitoxanthron solution by being dropped, via the injection syringe, at a rate of 20
drops per minute into the sulphonation flask. The microspheres were isolated by
filtration from the supernatant liquid, cautiously redispersed into 250 ml of 98%
ethanol and allowed to stay for 4 hours. The ethanol was then removed by filtration
and the microspheres were dried in the counter—flow drier at a temperature of 40°C
until the humidity content was reduced below 3 % b/w. The dry microspheres
containing 50 mg of mitoxanthron per 1 g were sieve-screened using the set of
vibrating screens, and packaged into glass vials in amounts of 0.5 g each.
Indication:
Intraarterial (regional) chemotherapy of malignant tumours where mitoxanthron is
indicated.
Example M: Preparation of microspheres from IMC-MDOC complex containing
mitoxanthron
: MDOC (Ca/Na salt of PAGA), particle size 0.1 - 2.0 mm, specific
surface area 86 m2/g, COOH group content 22.2 % b/w, Ca content
4.2 % b/w, Na content 3.8 % b/w
ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)
redistilled H20
1,2—monopropyleneglycol (Sigma)
sorbitol (Sigma)
isopropanol (Sigma)
Equipment: propeller stirrer, 50 rpm
sulphonation flask 1 l
beaker 250 ml
set of vibrating screens with mesh size 100, 150, 200, 250, 350, 500
um
counter—flow drier BINDER (RTM)
injection syringe 25 ml
Pro r :
g of MDOC Ca/Na salt and 90 g of redistilled H20 were introduced into the
beaker, and dispersed using the propeller stirrer to obtain a colloidal solution.
A cogulating solution was prepared by dissolving 25 g of sorbitol and 25 g of
monopropyleneglycol in 450 ml of 98% ethanol placed in the sulphonation flask. 1.0
g of mitoxanthron hydrochloride was placed into the 10 ml vial and dissolved in 5 g
of redistilled water. The solution was then transferred into the sulphonation flask
with ethanol under stirring.
The colloidal solution of MDOC was then gradually introduced into the sulphonation
flask by being dropped, via the injection syringe, at a rate of 10 drops per minute.
The microspheres were isolated from the coagulating bath by decantation, 250 ml of
isopropanol were added and the microspheres were allowed to stay for 8 hours. The
isopropanol was then removed by filtration and the microspheres were dried in the
counter—flow drier at a temperature of 40°C until the humidity content was reduced
below 3 % b/w. The dry microspheres were sieve—screened using the set of vibrating
screens, and packaged into glass vials in amounts of 0.5 g each.
Indication:
Microembolisation agent to achieve tissue necrotisation, e.g. in gynecological
treatment of non-malignant tumours.
Example N: Preparation of rigid foams from IMC-MDOC complex containing
gelatine
Material: lMC—MDOC complex — see Example 3
l,2—dihydroxypropane (Sigma)
gelatine, hydrolysed (Infusia, a.s.)
glycerol, medicinal (PhBs 1997)
redistilled H20
E i m n 2 turbostirrer ULTRA TURAX (Janke—Kunkel)
sulphonation flask l l
beaker 250 ml
lyophiliser
Procedure:
g IMC-MDOC complex, 100 g of gelatine, 100 g of 1,2-dihydroxypropane, 500
ml of redistilled water and 100 g of glycerol were introduced into the sulphonation
flask. The mixture was heated up to 70°C and homogenised using the propeller
stirrer. Thereafter, the mixture was injected into suitably shaped moulds. After
cooling down to room temperature, the moulds have been placed into the lyophiliser
and the mass lyophilised. Tampons of the required shape were obtained in the form
of a rigid flexible foam.
Indication:
Suitable for use as biocompatible and fully resorbable nasal tampons.
Example 0: Preparation of rigid foams from IMC-MDOC complex containing
chitosan
Material: IMC-MDOC complex — see Example 3
1,2—dihydroxypropane (Sigma)
gelatine, hydrolysed (Infusia, a.s.)
glutaraldehyde (Sigma)
chitosan, degree of deacetylation 92 % (Henkel)
_ 45 _
glycerol, medicinal (PhBs 1997)
redistilled H20
E i m n : turbostirrer ULTRA TURAX (Janke—Kunkel)
sulphonation flask l l
beaker 250 ml
lyophiliser
Procedure:
g IMC-MDOC complex, 100 g of gelatine, 100 g of 1,2—dihydroxypropane, 500
ml of redistillcd water and 100 g of glycerol were introduced into the sulphonation
flask. The mixture was heated up to 70°C and homogenised using the propeller
stirrer. Subsequently, 20 g of chitosan were added, and the mixture was homogenised
for another 5 minutes, Thereafter, 200 g of glutaraldehyde were added and the
mixture was maintained 70°C until the viscosity attained the value of 500 mPas. The
mixture was then injected into suitably shaped moulds. After cooling down to room
temperature, the moulds have been placed into the lyophiliser and the mass was
lyophilised. Foamed sheets of the required shape consisting of an insoluble, highly
absorbing, crosslinked foam were obtained.
Indication:
Suitable for use as inner absorbing layers of biocompatible pads and plasters.
Example P: Preparation of microspheres from IMC-MDOC complex containing
platinum (II) compounds
Material: MDOC (Ca/Na salt of PAGA), particle size 0.1 - 2.0 um, specific
surface area 86 m2/g, COOH group content 22.2 % b/w, Ca content
4.2 % b/w, Na content 3.8 % b/w
ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)
redistilled H20
,2-dihydroxypropane (Sigma)
polyacrylamide, 50 % aqueous solution (Aldrich)
glycerol, medicinal (PhBs 1997)
Equipment: laboratory mixer, bottom agitated, 4000 rpm
sulphonation flask 1 1
injection syringe 25 ml
Pro r 2
A colloidal aqueous solution of an MDOC—chitosan—polyacrylamide complex
containing 30% b/w of MDOC Ca/Na salt was dropped, via the injection syringe at a
rate of 10 drops per minute, into a ethanol/glycerol/water system containing salts of
bivalent platinum with two ammonia (NH3) ligands. The microspheres formed,
contained (NH3)2Pt(II) groups, were isolated from the coagulating bath by
decantation, washed with concentrated ethanol, and Vacuum dried at 25°C.
Indication:
Intraarterial (regional) chemotherapy of malignant tumours where diamoplatinum(Il)
complexes are indicated.
Example Q: Preparation of rigid foams from IMC-MDOC complex containing
chitosan and bestatin
Material; IMC-MDOC bestatin complex ~ see Example 11
chitosan, degree of deacetylation 92 % (Henkel)
polyacrylamide, 50 % aqueous solution (Aldrich)
_ 43 _
glycerol, medicinal (PhBs 1997)
redistilled H20
Equipment: turbostirrer ULTRA TURAX (J anke—Kunl
sulphonation flask l l
laboratory heater
counter—flow drier BINDER (RTM)
Pro r :
Bestatin containing IMC-MDOC complex as prepared according to Example 11,
glycerol, 25% aqueous solution of polyacrylamide, 3% solution of chitosan in acetic
acid solution, and redistilled water were placed into the sulphonation flask in
amounts such that the glycerol content in the system attains 30% b/w and that of the
IMC-MDOC complex attains 0.1% b/w. The mixture was toroughly homogenised
for 5 minutes using the turbostirrer, and n—pentane in an amount of 3%, calculated on
the total volume basis, was added and dispersed into the system. Thereafter, the
mixture was injected into suitably shaped moulds and dried to obtain flexible foamed
sheets.
Indieation;
Suitable for use in preparation of embolisation agents, plasters and similar products.
Example R: Preparation of flat textile-like structures containing MDOC and
IMC-MDOC complex with bestatin
cotton dressing pad
MDOC (Ca/Na salt of PAGA), particle size 0.1 — 2.0 um, specific
Material;
surface area 86 m2/g, COOH group content 22.2 % b/w, Ca content
4.2 % b/W, Na content 3.8 % b/w
‘
IMC—MDOC bestatin complex — see Example 11
ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)
demineralised water 2uS
E i m n: continuous spray—coating equipment
Procedure:
A dispersion of MDOC Ca/Na containing 10 % b/w IMC—MDOC bestatin complex
prepared by the procedure according to Example 11 in 88.5% aqueous solution of
ethanol was prepared within the storage tank of the spray coater. The dispersion was
spray coated onto a cotton knitted pad to achieve an add—on within a range of area
weights between 10 to 500 g/mz. An impregnated flat textile—like structure was
obtained on evaporating the aqueous ethanol.
Indication:
Suitable for use in preparation of dressing materials for e.g. covering skin lesions
after surgical removal of skin neoplasies.
The invention is not limited to the embodiments hereinbefore described which may
be varied in detail.
Claims (1)
- CLAIMS Biocompatible intermolecular polymer complex of: an anionic component comprising polyanhydroglucuronic acid [PAGA] wherein at least 5% of the basic structural units are glucuronic acid, said PAGA being prepared by partially or completely hydrolysing and neutralising in an oxidative environment a polyanhydroglucuronic acid- containing material; and a non protein cationic component comprising a linear or branched natural, semi-synthetic or synthetic oligomer or polymer. A complex as claimed in claim 1 wherein the cationic component is a synthetic bio—compatible nitrogen-containing oligomer or polymer that either carries a positive charge or wherein the positive charge is induced by contact with the polysaccharidic anionic component. A complex as claimed in claim 2 wherein the cationic component is selected from derivatives of acrylamide, methacrylamide and copolymers thereof. A complex as claimed in claim 3 wherein the cationic component is selected from polyacrylamide, copolymer of hydroxyethylmethacrylate and hydroxypropylmetacrylamide, copolymers of acrylamide, butylacrylate, maleinanhydride and/or methylmetacrylate. A complex as claimed in claim 2 wherein the cationic component is a cationised natural polysaccharide. A complex as claimed in claim 5 wherein the polysaccharide is a starch, cellulose or gum. A complex as claimed in claim 6 wherein the gum is guargumhydroxypropyltriammonium chloride. A complex as claimed in claim 1 wherein the cationic component is a synthetic or semi—synthetic polyamino acid. A complex as claimed in claim 8 wherein the cationic component is polylysin, polyarginin, or Ot, [3—poly—[N-(2-hydroxyethyl)—DL—aspartamide]. A complex as claimed in claim 1 wherein the cationic component is a synthetic anti-fibrinolytic. A complex as claimed in claim 10 wherein the anti-fibrinolytic is a hexadimethrindibromide (polybren). A complex as claimed in claim 1 wherein the cationic component is a natural or semi—synthetic peptide. A complex as claimed in claim 12 wherein the peptide is a protamine, gelatine, fibrinopeptide, or derivatives thereof. A complex as claimed in claim 1 wherein the cationic component is an aminoglucane or derivatives thereof. A complex as claimed in claim 14 wherein the aminoglucane is fractionated chitin or its de—acetylated derivative chitosan. A complex as claimed in claim 14 or 15 wherein the aminoglucane is of microbial origin or is isolated from the shells of arthropods such as crabs. A complex as claimed in claim 1 wherein the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain from 8 to 30 per cent by weight of carboxyl groups, at least 80 per cent by weight of these groups being of the uronic type, at most 5 per cent by weight of carbonyl groups, and at most 0.5 per cent by weight of bound nitrogen. A complex as claimed in claim 17 wherein the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain at most 0.2 per cent by weight of bound nitrogen. A complex as claimed in claim 17 or 18 wherein the molecular mass of the polymeric chain of the anionic component is from 1x103 to 3x105 Daltons. A complex as claimed in claim 19 wherein the molecular mass of the polymeric chain of the anionic component ranges from 5x103 to 1.5xl05 Daltons A complex as claimed in any of the claims 17 to 20 wherein the content of carboxyl groups is in the range of from 12 to 26 per cent by weight, at least 95 per cent of these groups being of the uronic type. A complex as claimed in any of claims 17 to 21 wherein the anionic component contains at most 1 per cent by weight of carbonyl groups. A complex as claimed in any of claims 17 to 22 wherein the carbonyl groups are intra- and intennolecular 2,6 and 3,6 hemiacetals, 2,4— hemialdals and C2- C3 aldehydes. A complex as claimed in any of claims 1 to 2, 11, 12 or 17 to 23 wherein the cationic component is gelatine. A complex as claimed in any of claims 1, or 13 to 23 wherein the cationic component is chitosan. A biocompatible intermolecular polymer complex substantially as hereinbefore described with reference to the examples. A pharmaceutical or cosmetic composition including at least one biocompatible complex as claimed in any preceding claim. A composition as claimed in claim 27 including at least one biocompatible biologically active substance. A composition as claimed in claims 27 or 28 including at least one biologically acceptable adjuvant. A composition substantially as hereinbefore described with reference to the examples. A composition as claimed in any of claims 24 to 26 in the form of a biocompatible dressing material. A composition as claimed in any of claims 24 to 26 for use as haemostatic agents. A pharmaceutical composition for the prophylaxis or treatment of peptic ulcers including a complex as claimed in any of claims 1 to 26. A slow release formulation including a complex as claimed in any of claims 1 to 26. An antilipemic composition including a complex as claimed in any of claims 1 to 26. A suppository formulation including a complex as claimed in any of claims 1 to 26. A tablet including a complex as claimed in any of claims 1 to 26. A pellet including a complex as claimed in any of claims 1 to 26. A granule including a complex as claimed in any of claims 1 to 26. A microsphere including a complex as claimed in any of claims 1 to 26. A flat flexible material including a complex as claimed in any of claims 1 to 26. A textile—like fabric including a complex as claimed in any of claims 1 to 26. A foam including a complex as claimed in any of claims 1 to 26. A dental pin including a complex as claimed in any of claims 1 to 26.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE1999/0613A IE83675B1 (en) | 1999-07-21 | Polymer complexes with polysaccharide comprising glucuronic acid residues |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IEIRELAND21/07/1998S1998/0594 | |||
IE980597 | 1998-07-21 | ||
IE980596 | 1998-07-21 | ||
IE980599 | 1998-07-21 | ||
IE980594 | 1998-07-21 | ||
IE980595 | 1998-07-21 | ||
IE980598 | 1998-07-21 | ||
IE1999/0613A IE83675B1 (en) | 1999-07-21 | Polymer complexes with polysaccharide comprising glucuronic acid residues |
Publications (2)
Publication Number | Publication Date |
---|---|
IE990613A1 IE990613A1 (en) | 2000-05-03 |
IE83675B1 true IE83675B1 (en) | 2004-11-17 |
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