U.S. patent application number 11/298887 was filed with the patent office on 2006-12-07 for polymer complexes of glucuronoglucanes.
This patent application is currently assigned to Alpenstock Holdings Limited. Invention is credited to Jiri Briestensky, Frantisek Kiss, Ivan Santar.
Application Number | 20060275251 11/298887 |
Document ID | / |
Family ID | 27547368 |
Filed Date | 2006-12-07 |
United States Patent
Application |
20060275251 |
Kind Code |
A1 |
Santar; Ivan ; et
al. |
December 7, 2006 |
Polymer complexes of glucuronoglucanes
Abstract
A biocompatible intermolecular polymer complex comprises an
anionic component and a non protein cationic component. The anionic
component comprises a linear or branched polysaccharide chain
wherein at least 5% of the basic structural units are glucuronic
acid. The cationic component comprises a linear or branched
natural, semi-synthetic or synthetic oligomer or polymer.
Inventors: |
Santar; Ivan; (Predklasteri,
CZ) ; Kiss; Frantisek; (Brno, CZ) ;
Briestensky; Jiri; (Cernilov, CZ) |
Correspondence
Address: |
JACOBSON HOLMAN PLLC
400 SEVENTH STREET N.W.
SUITE 600
WASHINGTON
DC
20004
US
|
Assignee: |
Alpenstock Holdings Limited
|
Family ID: |
27547368 |
Appl. No.: |
11/298887 |
Filed: |
December 12, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10463875 |
Jun 18, 2003 |
|
|
|
11298887 |
Dec 12, 2005 |
|
|
|
09764346 |
Jan 19, 2001 |
6596791 |
|
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10463875 |
Jun 18, 2003 |
|
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PCT/IE99/00067 |
Jul 21, 1999 |
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09764346 |
Jan 19, 2001 |
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Current U.S.
Class: |
424/78.27 ;
424/443; 424/464; 424/49; 514/13.6; 514/21.92; 514/54 |
Current CPC
Class: |
A61K 2800/5426 20130101;
A61K 31/715 20130101; A61K 8/73 20130101; A61P 3/06 20180101; A61K
2800/5424 20130101; A61K 9/0034 20130101; A61K 31/785 20130101;
A61K 8/731 20130101; A61K 9/2027 20130101; A61K 9/2054 20130101;
A61P 7/04 20180101; A61P 17/00 20180101; A61P 31/12 20180101; A61K
8/737 20130101; A61P 35/00 20180101; A61P 1/04 20180101; A61K
8/8158 20130101; A61K 47/38 20130101; A61K 8/736 20130101; A61K
9/16 20130101; A61K 9/1617 20130101; A61P 31/04 20180101; A61K 9/02
20130101; A61Q 19/00 20130101; A61K 9/12 20130101; A61K 9/1635
20130101; A61K 8/65 20130101; A61P 11/00 20180101 |
Class at
Publication: |
424/078.27 ;
514/002; 514/054; 424/443; 424/049; 424/464 |
International
Class: |
A61K 31/785 20060101
A61K031/785; A61K 31/715 20060101 A61K031/715; A61K 9/70 20060101
A61K009/70; A61K 9/20 20060101 A61K009/20; A61K 8/81 20060101
A61K008/81 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 21, 1998 |
IE |
S980594 |
Jul 21, 1998 |
IE |
S980595 |
Jul 21, 1998 |
IE |
S980596 |
Jul 21, 1998 |
IE |
S980597 |
Jul 21, 1998 |
IE |
S980598 |
Jul 21, 1998 |
IE |
S980599 |
Claims
1-33. (canceled)
34. A pharmaceutical or cosmetic composition including at least one
biocompatible intermolecular polymer complex of: an anionic
component comprising a linear or branched polysaccharide chain
wherein at least 5% of the basic structural units are glucuronic
acid; and a non protein cationic component comprising a linear or
branched natural, semi-synthetic or synthetic oligomer or
polymer.
35. The composition as claimed in claim 34 wherein the cationic
component contains nitrogen that either carries a positive charge
or wherein the positive charge is induced by contact with the
polysaccharidic anionic component.
36. The composition as claimed in claim 35 wherein the cationic
component is selected from derivatives of acrylamide,
methacrylamide and copolymers thereof.
37. The composition as claimed in claim 34 wherein the cationic
component is a cationised natural polysaccharide.
38. The composition as claimed in claim 37 wherein the
polysaccharide is a starch, cellulose or gum.
39. The composition as claimed in claim 34 wherein the cationic
component is a synthetic or semi-synthetic polyamino acid.
40. The composition as claimed in claim 34 wherein the cationic
component is a synthetic anti-fibrinolytic.
41. The composition as claimed in claim 34 wherein the cationic
component is a natural or semi-synthetic peptide.
42. The composition as claimed in claim 34 wherein the cationic
component is an aminoglucane or derivatives thereof.
43. The composition as claimed in claim 34 wherein the anionic
component is polyanhydroglucuronic acid.
44. The composition as claimed in claim 43 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
group, at most 5 per cent by weight of carbonyl groups, and at most
0.5 per cent by weight of bound nitrogen.
45. The composition as claimed in claim 44 wherein the
polyanhydroglucuronic acid and salts thereof contain in their
polymeric chain at most 0.2 per cent by weight of bound
nitrogen.
46. The composition as claimed in claim 44 wherein the molecular
mass of the polymeric chain of the anionic component is from
1.times.10.sup.3 to 3.times.10.sup.5 Daltons.
47. The composition as claimed in claim 44 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
group.
48. The composition as claimed in claim 44 wherein the anionic
component contains at most 1 per cent by weight of carbonyl
groups.
49. The composition as claimed in claim 44 wherein the carbonyl
groups are intra- and intermolecular 2,6 and 3,6 hemiacetals,
2,4-hemialdals and C2-C3 aldehydes.
50. The composition as claimed in claim 34 wherein the cationic
component is gelatine.
51. The composition as claimed in claim 34 wherein the cationic
component is chitosan.
52. The composition as claimed in claim 34 including at least one
biocompatible biologically active substance.
53. The composition as claimed in claim 34 including at least one
biologically acceptable adjuvant.
54. The composition as claimed in claim 34 wherein the composition
is a slow release formulation.
55. The composition as claimed in claim 34 wherein the composition
is a suppository formulation.
56. The composition as claimed in claim 34 wherein the composition
is in the form of a tablet.
57. The composition as claimed in claim 34 wherein the composition
is in the form of a pellet.
58. The composition as claimed in claim 34 wherein the composition
is in the form of a granule.
59. The composition as claimed in claim 34 wherein the composition
is in the form of a microsphere.
60. The composition as claimed in claim 34 wherein the composition
is in the form of a flat flexible material.
61. The composition as claimed in claim 35 wherein the cationic
component is selected from polyacrylamide, copolymer of
hydroxyethylmethacrylate and hydroxypropylmethacrylamide,
copolymers of acrylamide, butylacrylate, maleinanhydride and/or
methylmetacrylate.
62. The composition as claimed in claim 38 wherein the gum is
guargumhydroxypropyl-triammonium chloride.
63. The composition as claimed in claim 34 wherein the cationic
component is polylysin, polyarginin, or
.alpha.,.beta.-poly-(N-(2-hydroxyethyl)-DL-aspartamide).
64. The composition as claimed in claim 40 wherein the
anti-fibrinolytic is a hexadimethrindibromide (polybren).
65. The composition as claimed in claim 41 wherein the peptide is a
protamine, gelatine, fibrinopeptide, or derivatives thereof.
66. The composition as claimed in claim 42 wherein the aminoglucane
is fractionated chitin or its de-acetylated derivative
chitosan.
67. The composition as claimed in claim 42 wherein the aminoglucane
is of microbial origin or is isolated from the shells of
arthropods.
68. The composition as claimed in claim 44 wherein the molecular
mass of the polymeric chain of the anionic component ranges from
5.times.10.sup.3 to 1.5.times.10.sup.5 Daltons.
69. A textile-like fabric comprising at least one biocompatible
intermolecular polymer complex of: an anionic component comprising
a linear or branched polysaccharide chain wherein at least 5% of
the basic structural units are glucuronic acid; and a non protein
cationic component comprising a linear or branched natural,
semi-synthetic or synthetic oligomer or polymer.
70. A foam comprising at least one biocompatible intermolecular
polymer complex of: an anionic component comprising a linear or
branched polysaccharide chain wherein at least 5% of the basic
structural units are glucuronic acid; and a non protein cationic
component comprising a linear or branched natural, semi-synthetic
or synthetic oligomer or polymer.
71. A dental pin comprising at least one biocompatible
intermolecular polymer complex of: an anionic component comprising
a linear or branched polysaccharide chain wherein at least 5% of
the basic structural units are glucuronic acid; and a non protein
cationic component comprising a linear or branched natural,
semi-synthetic or synthetic oligomer or polymer.
Description
[0001] This is a continuation application of Ser. No. 10/463875
filed Jun. 18, 2003, which in turn is a continuation of Ser. No.
09/764346 filed Jan. 19, 2001, now U.S. Pat. No. 6,596,791.
INTRODUCTION
[0002] Oxidised cellulose and its derivatives have been widely used
in medicine and pharmacy since the first preparation by Chair and
Kenyon [Shorygin P P., Chait E. V.: Zh. obshch. chim. 7, 188
(1937); Yackel E. C., Kenyon W. O.: J Am. Chem. Soc. 64, 121
(1942)].
[0003] 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; U.S. Pat. No.
4,100,341, or salts thereof prepared according to more recent
patents, such as.: CS AO 242920;. EP 0659440A1 and PCT IE
98/00004.
[0004] 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.
[0005] Within the last two decades, during investigations of
various types of polysaccharides, it was established that during
their biodegradation in the living organism, certain functions of
various types of cells are influenced. [Berger J., 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; Burchard W.: Polysacharide,
Eigenschaften und Nutzung, Springer-Verlag, Berlin, Heidelberg, New
York, Tokyo, p. 144 (1985); U.S. Pat. No. 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 .beta. bond have
immunomodulative properties while 1,4 .beta. 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.
[0006] 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
polyelectrolyte 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.
[0007] 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.
[0008] Co-pending patent application PCT IE98/00004 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.
STATEMENT OF INVENTION
[0009] According to the invention there is provided a biocompatible
intermolecular polymer complex of: [0010] an anionic component
comprising a linear or branched polysaccharide chain wherein at
least 5% of the basic structural units are glucuronic acid; and
[0011] a non protein cationic component comprising a linear or
branched natural, semi-synthetic or synthetic oligomer or
polymer.
[0012] In a preferred embodiment of the invention the cationic
component contains nitrogen that either carries a positive charge
or wherein the positive charge is induced by contact with the
polysaccharidic anionic component.
[0013] In one case the cationic component is selected 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.
[0014] In another case the cationic component is a cationised
natural polysaccharide. Preferably the polysaccharide is a starch,
cellulose or gum. The gum may be guargumhydroxypropyltriammonium
chloride.
[0015] In another case the cationic component is a synthetic or
semi-synthetic polyamino add. Preferably the cationic component is
polylysin, polyarginin, or
.alpha.,.beta.-poly-[N-(2-hydroxyethyl)-DL-aspartamide].
[0016] In a further embodiment the cationic component is a
synthetic anti-fibrinolytic. The anti-fibrinolytic may be a
hexadimethrindibromide (polybren).
[0017] In a still further embodiment the cationic component is a
natural or semi-synthetic peptide. Preferably the peptide is a
protamine, gelatine, fibrinopeptide, or derivatives thereof.
[0018] In a further case the cationic component is an aminoglucane
or derivatives thereof. 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.
[0019] In a preferred embodiment of the invention the anionic
component is polyanhydroglucuronic acid and/or bicompatible salts
thereof.
[0020] 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.
[0021] In a preferred embodiment the molecular mass of the
polymeric chain of the anionic component is from 1.times.10.sup.3
to 3.times.10.sup.5 Daltons, ideally, the molecular mass of the
polymeric chain of the anionic component ranges from
5.times.10.sup.3 to 1.5.times.10.sup.5 Daltons.
[0022] 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 the uronic type.
[0023] In a preferred embodiment of the invention the anionic
component contains at most 1 per cent by weight of carbonyl
groups.
[0024] The carbonyl groups are preferably intra- and intermolecular
2,6 and 3,6 hemiacetals, 2,4-hemialdals and C2-C3 aldehydes.
[0025] The cationic component may be gelatine.
[0026] Alternatively the cationic component is chitosan.
[0027] The invention also provides a pharmaceutical or cosmetic
composition including at least one biocompatible complex of the
invention.
[0028] Preferably the composition includes at least one
biocompatible biologically active substance.
[0029] The composition may alternatively or additionally include at
least one biologically acceptable adjuvant.
DETAILED DESCRIPTION
[0030] 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.
[0031] 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.
[0032] 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.
[0033] Polymeric cations suitable to form IMCs with
glucuronoglucanes prepared for example according to PCT IE 98/00004
may roughly be subdivided into the following groups: [0034] 1.
Synthetic biocompatible nitrogen-containing oligomers and polymers.
[0035] a) Derivatives of acrylamide and methacrylamide and their
copolymers [such as polyacrylamide, copolymer of
hydroxyethylmethacrylate 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. [0036] 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. [0037] 2. Natural or semi-synthetic
peptides such as gelatine, protamines, or fibrinopeptides, and
their derivatives. [0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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).
[0044] 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. 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] The invention will be more clearly understood from the
following examples of polymer complexes of glucuronoglucanes.
EXAMPLE 1
[0051] Material: long-fibre cotton--medicinal cotton wool oxidised
by N.sub.xO.sub.y (proprietary) TABLE-US-00001 C.sub.6OOH 18.8% b/w
ash content <0.1% b/w .SIGMA. C.dbd.O 0.6% b/w
[0052] 20% solution Na.sub.2CO.sub.3 (Lachema, a.s. Neratovice)
[0053] CaCl.sub.2.6H.sub.2O anal.grade (Lachema, a.s. Neratovice)
[0054] demineralised water 2 .mu.S [0055] ethanol, synthetic
rectified conc. 98% (Chemopetrol Litvinov, a.s.) [0056] acid acetic
anal.grade (Lachema, a.s. Neratovice) [0057] H.sub.2O.sub.2
anal.grade 30% (Lachema, a.s. Neratovice) [0058] N-HANCE 3000
guargumhydroxypropyltriammonium chloride (Aqualon-Hercules) [0059]
Equipment: mixer: bottom stirring, 150 litre (duplicator),
stainless steel EXTRA S [0060] vibrating screen: stainless steel,
150 mesh [0061] rotary air pump: rotor diameter 150 mm [0062]
turbostirrer: ULTRA TURAX (Janke-Kunkel) [0063] beaker: 5 litre
[0064] pH meter PICCOLO [0065] thermocouple thermometer
[0066] Procedure:
[0067] 30 g of N-HANCE 3000 were placed into a 5 l beaker and 3 l
of demineralised water 2 .mu.S 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.
[0068] 60 l of demineralised water 2 .mu.S were introduced into a
mixer. 3 kg of CaCl.sub.2.6H.sub.2O anal.grade were added and the
contents heated up to a temperature of 50.degree. 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 Na.sub.2CO.sub.3 to 6-6.5 and 13 kg of H.sub.2O.sub.2
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. 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 l of demineralised water 2
.mu.S. The fibre suspension was filtered again on the vibrating
screen.
[0069] The isolated material thus prepared may further serve to
prepare final products of the nonwoven type via a wet or dry
process.
[0070] Analysis: TABLE-US-00002 Ca content 4.0% b/w Na content 1.8%
b/w .SIGMA. C.dbd.O content 0.0% b/w COOH content 20.7% b/w
EXAMPLE 2
[0071] Material: oxidised short-fibre cotton (Linters-Temming)
(proprietary) TABLE-US-00003 C.sub.6OOH 16.8% b/w ash content
<0.15% b/w .SIGMA. C.dbd.O 2.6% b/w
[0072] 20% solution Na.sub.2CO.sub.3 (Lachema, a.s. Neratovice)
[0073] CaCl.sub.2.6H.sub.2O anal.grade (Lachema, a.s. Neratovice)
[0074] redistilled water (PhBs 1997) [0075] ethanol, synthetic
rectified conc. 98% (Chemopetrol Litvinov, a.s.) [0076] isopropanol
99.9% (Neuberg Bretang) [0077] H.sub.2O.sub.2 anal.grade 30%
(Lachema, a.s. Neratovice) [0078] gelatine (PhBs 1997) [0079]
Equipment: turbostirrer: ULTRA TURAX (Janke-Kunkel) [0080]
sulphonation flask 1 litre [0081] heater 1.5 kW [0082] laboratory
centrifuge: 4000 rpm [0083] thermostated water bath [0084] pH meter
PICCOLO [0085] glass thermometer [0086] rotary vacuum dryer or
hot-air dryer
[0087] Procedure:
[0088] Into a 1 litre sulphonation flask equipped with a
turbostirrer and a heater, 400 ml of redistilled H.sub.2O were
placed, 15.73 g of CaCl.sub.2.6H.sub.2O were added and on
dissolution, 40.0 g of 20% Na.sub.2CO.sub.3 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.degree. C. with the stirring intensity set to a
maximum. After 10 minutes, 30 g of 30% H.sub.2O.sub.2 were. added
into the flask and the hydrolysis continued for another 10 minutes.
The contents were then cooled down to 60.degree. 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 Na.sub.2CO.sub.3. A gelatine solution
(10 g of gelatine in 70 g of redistilled H.sub.2O) warmed to
50.degree. C. was added and left to react for another 20 minutes.
The flask contents were then cooled to 30.degree. 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.degree. C. The gel formed was centrifuged and the product was
dried in a rotary vacuum dryer or a hot-air dryer.
[0089] 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.
[0090] Analysis: TABLE-US-00004 content Ca 4.4% b/w content Na 2.7%
b/w content .SIGMA. C.dbd.O 0.0% b/w content COOH 20.5% b/w content
N 1.8% b/w
EXAMPLE 3
[0091] Material: oxidised short-fibre cotton (Linters-Temming)
(proprietary) TABLE-US-00005 C.sub.6OOH 16.8% b/w ash content
<0.15% b/w .SIGMA. C.dbd.O 2.6% b/w
[0092] NaOH anal.grade (Lachema, a.s. Neratovice) [0093]
redistilled water (PhBs 1997) [0094] ethanol, synthetic rectified
conc. 98% (Chemopetrol Litviiiov, a.s.) [0095] isopropanol 99.9%
(Neuberg Bretang) [0096] H.sub.2O, anal.grade 30% (Lachema, a.s.
Neratovice) [0097] gelatine (PhBs 1997) [0098] Equipment:
turbostirrer: ULTRA TURAX (Janke-Kunkel) [0099] sulphonation flask
1 litre [0100] heater 1.5 kW [0101] laboratory centrifuge: 4000 rpm
[0102] thermostated water bath [0103] pH meter PICCOLO [0104] glass
thermometer [0105] rotary vacuum dryer or hot-air dryer
[0106] Procedure:
[0107] Into a 1 litre sulphonation flask equipped with a
turbostirrer and a heater, 400 ml of redistilled H.sub.2O 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.degree. C. and the stirring intensity set to a maximum. After 20
minutes, 40 g of 30% H.sub.2O.sub.2 were added into the flask, the
temperature was increased to 85.degree. C., and maintained for
another 10 minutes. The contents were then cooled to 50.degree. C.
on a water bath and gelatine solution (10 g of gelatine in 70 g of
redistilled H.sub.2O) warmed 50.degree. C. was added to the
hydrolysate. The temperature was decreased to 25-30.degree. 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.degree. C. The gel formed was centrifuged and the product was
dried in a rotary vacuum dryer or a hot-air dryer.
[0108] 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.
[0109] Analysis: TABLE-US-00006 Na content 3.8% b/w .SIGMA. C.dbd.O
content 0.0% b/w COOH content 21.5% b/w N content 2.7% b/w
EXAMPLE 4
[0110] Material: oxidised short-fibre cotton (Linters-Temming)
(proprietary) TABLE-US-00007 C.sub.6OOH 16.8% b/w ash content
<0.15% b/w .SIGMA. C.dbd.O 2.6% b/w
[0111] 20% solution Na.sub.2CO.sub.3 (Lachema, a.s. Neratovice)
[0112] CaCl.sub.2.6H.sub.2O anal.grade (Lachema, a.s. Neratovice)
[0113] redistilled water (PhBs 1997) [0114] ethanol, synthetic
rectified conc. 98% (Chemopetrol Litvinov, a.s.) [0115] isopropanol
99.9% (Neuberg Bretang) [0116] H.sub.2O.sub.2 anal.grade 30%
(Lachema, a.s. Neratovice) [0117] chitosan, degree of deacetylation
92% (Henkel) [0118] Equipment: turbostirrer: ULTRA TURAX
(Janke-Kunkel) [0119] sulphonation flask 1 litre [0120] heater 1.5
kW [0121] laboratory centrifuge: 4000 rpm [0122] thermostated water
bath [0123] pH meter PICCOLO [0124] glass thermometer [0125] rotary
vacuum dryer or hot-air dryer
[0126] Procedure:
[0127] Into a sulphonation flask, 250 ml redistilled H.sub.2O 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.degree. C. and the stirring intensity set to a
maximum. After hydrolysing for 15 minutes, 35 g of 30%
H.sub.2O.sub.2 were gradually added to the system and the
temperature was maintained at 50.degree. C. for another 20 minutes.
The contents were cooled to 30.degree. 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.degree. C.
The gel formed was centrifuged and the product was dried in a
rotary vacuum dryer or a hot-air dryer.
[0128] 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.
[0129] Analysis: TABLE-US-00008 Na content 1.8% b/w .SIGMA. C.dbd.O
content 0.0% b/w COOH content 10.4% b/w N content 2.8% b/w
EXAMPLE 5
[0130] Material: oxidised short-fibre cotton (Linters-Temming)
(proprietary) TABLE-US-00009 C.sub.6OOH 16.8% b/w ash content
<0.15% b/w .SIGMA. C.dbd.O 2.6% b/w
[0131] NaOH anal.grade (Lachema, a.s. Neratovice) [0132] HCl 39%
anal.grade (Lachema, a.s. Neratovice) [0133] redistilled water
(PhBs 1997) [0134] ethanol, synthetic rectified conc. 98%
(Chemopetrol Litvinov, a.s.) [0135] isopropanol 99.9% (Neuber
Bretang) [0136] H.sub.2O.sub.2 anal.grade 30% (Lachema, a.s.
Neratovice) [0137] gelatine (PhBs 1997) [0138] Ambroxol (H. Mack,
Germany) [0139] Equipment: turbostirrer: ULTRA TURAX (Janke-Kunkel)
[0140] sulphonation flask 21 [0141] heater 1.5 kW [0142] laboratory
centrifuge: 4000 rpm [0143] laboratory pin mill ALPINE (35 000 rpm)
[0144] thermostated water bath [0145] pH meter PICCOLO [0146] glass
thermometer [0147] rotary vacuum dryer or hot-air dryer
[0148] Procedure:
[0149] Into a sulphonation flask, 400 ml redistilled H.sub.2O 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.degree. C. and the stirring intensity was set to a
maximum. After hydrolysing for 20 minutes, 40 g of 30%
H.sub.2O.sub.2 were gradually added to the system and the
temperature was increased to, and maintained at, 85.degree. C. for
another 10 minutes. The content were cooled down to 50.degree. C.
in a water bath, and gelatine solution (2 g of gelatine in 70 g of
redistilled H.sub.2O) warmed up to 50.degree. C. was added to the
hydrolysate. The temperature was decreased to 25-30.degree. 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 stiring, a solution of
Amnbroxol (25 g of ambroxolium hydrochloride in 500 ml of
redistilled H.sub.2O) 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.degree. 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.
[0150] The product serves for the preparation of a mucoregulatory
drug with a prolonged action.
[0151] Analysis: TABLE-US-00010 Na content 4.6% b/w .SIGMA. C.dbd.O
content 0.0% b/w COOH content 14.8% b/w N content 1.9% b/w
EXAMPLE 6
[0152] Material: oxidised short-fibre cotton (Linters-Temming)
(proprietary) TABLE-US-00011 C.sub.6OOH 16.8% b/w ash content
<0.15% b/w .SIGMA. C.dbd.O 2.6% b/w
[0153] 20% solution Na.sub.2CO.sub.3 (Lachema, a.s. Neratovice)
[0154] CaCl.sub.2.6H.sub.2O anal.grade (Lachema, a.s. Neratovice)
[0155] redistilled water (PhBs 1997) [0156] ethanol, synthetic
rectified conc. 98% (Chemopetrol Litvinov, a.s.) [0157] isopropanol
99.9% (Neuberg Bretang) [0158] H.sub.2O, anal.grade 30% (Lachema,
a.s. Neratovice) [0159] gelatine (PhBs 1997) [0160] gentamycin
sulphate (MERCK) [0161] Equipment: turbostirrer: ULTRA TURAX
(Janke-Kunkel) [0162] sulphonation flask 2 litre [0163] heater 1.5
kW [0164] laboratory centrifuge: 4000 rpm [0165] laboratory pin
mill ALPINE (35 000 rpm) [0166] thermostated water bath [0167] pH
meter PICCOLO [0168] glass thermometer [0169] hot-air dryer [0170]
lyophiliser (Leibold Heraus, Germany)
[0171] Procedure:
[0172] Into a 2 litre sulphonation flask equipped with a
turbostirrer and a heater, 400 ml of redistilled H.sub.2O were
placed, 15.73 g of CaCl.sub.2.6H.sub.2O were added and on
dissolution, 40.0 g of 20% Na.sub.2CO.sub.3 solution were
introduced under stirng. Subsequently, 50 g of oxidised Linters
were added to the white emulsion formed and the contents were
heated up to 95.degree. C. and the stirring intensity set to a
maximum. After 10 minutes, 30 g of 30% H.sub.2O.sub.2 were added
into the flask and the hydrolysis was continued for another 10
minutes. The contents were then cooled down to 60.degree. 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.sub.2CO.sub.3. A gelatine
solution (10 g of gelatine in 70 g of redistilled H.sub.2O) warmed
up to 50.degree. C. was added and let to react for another 20
minutes. The flask contents were then cooled down to 30.degree. C.
in a water bath and 40 g of gentamycin sulphate in 600 ml of
redistilled H.sub.2O 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
centrifiged and after the separation of the supernatant liquid, the
LAC was redispersed into 250 ml of synthetic rectified ethanol
conc. 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.degree. C. The gel formed was centrifuged and the
product was dried in a rotary vacuum dryer or a hot-air dryer.
[0173] The product can be used, for instance, for the manufacture
of a dusting powder or a powder spray for the treatment of infected
wounds.
[0174] Analysis: TABLE-US-00012 Ca content 2.4% b/w Na content 1.6%
b/w .SIGMA. C.dbd.O content 0.0% b/w COOH content 9.6% b/w N
content 2.7% b/w
EXAMPLE 7
[0175] Material: long-fibre cotton--medicinal cotton wool oxidised
by N.sub.xO.sub.y (proprietary) TABLE-US-00013 C.sub.6OOH 18.8% b/w
ash content <0.1% b/w .SIGMA. C.dbd.O 0.6% b/w
[0176] 20% solution Na.sub.2CO.sub.3 (Lachema, a.s. Neratovice)
[0177] CaCl.sub.2.6H.sub.2O anal.grade (Lachema, a.s. Neratovice)
[0178] demineralised water 2 .mu.S [0179] ethanol, synthetic
rectified conc. 98% (Chemopetrol Litvinov, a.s.) [0180] isopropanol
99.9% (Neuberg Bretang) [0181] acid acetic anal.grade (Lachema,
a.s. Neratovice) [0182] H.sub.2O.sub.2 anal.grade 30% (Lachema,
a.s. Neratovice) [0183] N-HANCE 3000
guargumhydroxypropyltriammonium chloride (Aqualon-Hercules) [0184]
polybren (hexadimethrindibromide) (FLUKA) [0185]
chlorhexidindigluconate [0186] Equipment: mixer: bottom stirring,
150 l (duplicator), stainless steel EXTRA S [0187] vibrating
screen: stainless steel, 150 mesh [0188] rotary air pump: rotor
diameter 150 mm [0189] turbostirrer: ULTRA TURAX (Janke-Kunkel)
[0190] beaker: 5 litre [0191] pH meter PICCOLO [0192] thermocouple
thermometer
[0193] Procedure:
[0194] 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 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.
[0195] 60 l of demineralised water 2 .mu.S were introduced into a
mixer. Then 3 kg of CaCl.sub.2.6H.sub.2O anal.grade were added and
the contents heated up to a temperature of 50.degree. 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 Na.sub.2CO.sub.3 to 6-6.5 and 13 kg
of H.sub.2O.sub.2 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 2 .mu.S 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 2
.mu.S 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 60 l of a mixture
of 18 l of synthetic rectified ethanol conc. 98% and 42 l of
dernineralised water 2 .mu.S. The fibre suspension was filtered
again on the vibrating screen.
[0196] 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.
[0197] Analysis: TABLE-US-00014 Ca content 3.6% b/w Na content 1.9%
b/w .SIGMA. C.dbd.O content 0.0% b/w COOH content 18.1% b/w N
content 0.35% b/w
EXAMPLE 8
[0198] Material: oxidised short-fibre cotton (Linters-Temming)
(proprietary) TABLE-US-00015 C.sub.6OOH 16.8% b/w ash content
<0.15% b/w .SIGMA. C.dbd.O 2.6% b/w
[0199] 20% solution Na.sub.2CO.sub.3 (Lachema, a.s. Neratovice)
[0200] CaCl.sub.2.6H.sub.2O anal.grade (Lachema, a.s. Neratovice)
[0201] redistilled water (PhBs 1997) [0202] ethanol, synthetic
rectified conc. 98% (Chemopetrol Litvinov, a.s.) [0203] isopropanol
99.9% (Neuberg Bretang) [0204] H.sub.2O.sub.2 anal.grade 30%
(Lachema, a.s. Neratovice) [0205] Chitosan, degree of deacetylation
92% (Henkel) [0206] Clarithromycin lactobionan (Abbott
Laboratories, Italy) [0207] Equipment: turbostirrer: ULTRA TURAX
(Janke-Kunkel) [0208] sulphonation flask 1 litre [0209] heater 1.5
kW [0210] laboratory centrifuge: 4000 rpm [0211] thermostated water
bath [0212] pH meter PICCOLO [0213] glass thermometer [0214] rotary
vacuum dryer or hot-air dryer [0215] dialysing bag (regenerated
cellulose) [0216] lyophiliser (Leybold Heraus, Germany) [0217]
laboratory pin mill ALPINE (35 000 rpm)
[0218] Procedure:
[0219] Into a sulphonation flask 250 ml redistilled H.sub.2O 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.degree. C. and the stirring intensity set to a maximum. After
hydrolysing for 15 minutes, 35 g of 30% H.sub.2O.sub.2 were
gradually added to the system and the temperature was maintained at
50.degree. C. for another 20 minutes. The content were cooled down
to 30.degree. 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 H.sub.2O) was introduced
and the pH of the system was adjusted to a value of 7.0-7.5.
[0220] 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.
[0221] The product can be used, for instance, to prepare tablets or
granules efficient against Helicobacter pylori occurring in the
gastrointestinal tract.
[0222] Analysis: TABLE-US-00016 Na content 4.8% b/w .SIGMA. C.dbd.O
content 0.0% b/w COOH content 18.8% b/w N content 0.7% b/w
EXAMPLE 9
[0223] Material: oxidised short-fibre cotton (Linters-Temming)
(proprietary) TABLE-US-00017 C.sub.6OOH 16.8% b/w ash content
<0.15% b/w .SIGMA. C.dbd.O 2.6% b/w
[0224] NaOH anal.grade (Lachema, a.s. Neratovice) [0225]
redistilled water (PhBs 1997) [0226] ethanol, synthetic rectified
conc. 98% (Chemopetrol Litvinov, a.s.) [0227] isopropanol 99.9%
(Neuberg Bretang) [0228] H.sub.2O.sub.2 anal.grade 30% (Lachema,
a.s. Neratovice) [0229] gelatine (PhBs 1997) [0230]
Bi(NO.sub.3).5H.sub.2O (MERCK) [0231] Equipment: turbostirrer:
ULTRA TURAX (Janke-Kunkel) [0232] sulphonation flask 2 litre [0233]
heater 1.5 kW [0234] laboratory centrifuge: 4000 rpm [0235]
thermostated water bath [0236] pH meter PICCOLO [0237] glass
thermometer [0238] rotary vacuum dryer or hot-air dryer
[0239] Procedure:
[0240] Into a sulphonation flask 400 ml redistilled H.sub.2O 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.degree. C. and the stirring intensity was set to a maximum.
After hydrolysing for 20 minutes, 40 g of 30% H.sub.2O.sub.2 were
gradually added to the system and the temperature was increased to,
and maintained at, 85.degree. C. for another 10 minutes. The
contents were cooled down to 50.degree. C. in a water bath, and a
gelatine solution (0.5 g of gelatine in 50 ml of redistilled
H.sub.2O) warmed up to 50.degree. C. was added to the hydrolysate.
The temperature was decreased to 25-30.degree. C. and the pH of the
system was checked and adjusted to a value of 1.6-1.8 by addition
of 39% HCl. A freshly prepared solution of BiNO.sub.3 (54 g of
BiNO.sub.3.5H.sub.2O in 746 ml of H.sub.2O) was introduced and the
temperature maintained for another 15 minutes. The temperature was
decreased to 25-30.degree. 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 BiO.sup.+ 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.degree. C.
The suspension formed was then centrifuged again and the product
was dried in a rotary vacuum dryer or a hot-air dryer.
[0241] The product can be used, for instance, to prepare dusting
powders for wound treatment or tablets for treatment of
gastrointestinal tract malfunctions.
[0242] Analysis: TABLE-US-00018 Na content 1.9% b/w .SIGMA. C.dbd.O
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
[0243] Material: oxidised short-fibre cotton (Linters-Temming)
(proprietary) TABLE-US-00019 C.sub.6OOH 16.8% b/w ash content
<0.15% b/w .SIGMA. C.dbd.O 2.6% b/w
[0244] 20% solution Na.sub.2CO.sub.3 (Lachema, a.s. Neratovice)
[0245] CaCl.sub.2.6H.sub.2O anal.grade (Lachema, a.s. Neratovice)
[0246] redistilled water (PhBs 1997) [0247] ethanol, synthetic
rectified conc. 98% (Chemopetrol Litvinov, a.s.) [0248] isopropanol
99.9% (Neuberg Bretang) [0249] H.sub.2O.sub.2 anal.grade 30%
(Lachema, a.s. Neratovice) [0250] gelatine (PhBs 1997) [0251]
cimetidine hydrochloride (SPOFA) [0252] Equipment: turbostirrer:
ULTRA TURAX (Janke-Kunkel) [0253] sulphonation flask 2 litre [0254]
heater 1.5 kW [0255] laboratory centrifuge: 4000 rpm [0256]
thermostated water bath [0257] pH meter PICCOLO [0258] glass
thermometer [0259] rotary vacuum dryer or hot-air dryer
[0260] Procedure:
[0261] Into a 1 l sulphonation flask equipped with a turbostirrer
and a heater, 400 ml of redistilled H.sub.2O were placed. 15.73 g
of CaCl.sub.2.6H.sub.2O were added and on dissolution 40.0 g of 20%
Na.sub.2CO.sub.3 solution were introduced with stirring. 50 g of
oxidised Linters were added to the white emulsion formed and the
contents were heated up to 95.degree. C. and the stirring intensity
set to a maximum. After 10 minutes, 30 g of 30% H.sub.2O.sub.2 were
added into the flask and the hydrolysis was continued for another
10 minutes. The contents were then cooled down to 60.degree. 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.sub.2CO.sub.3. A gelatine
solution (10 g of gelatine in 70 g of redistilled H.sub.2O) warmed
up to 50.degree. C. was added and allowed react for another 20
minutes. The flask contents were then cooled down to 30.degree. C.
in a water bath and a solution of cimetidine (36 g of cimetidine
hydrochloride in 400 ml of redistilled H.sub.2O) 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 supematant
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.degree. C. The gel formed was centrifuged again
and the product was dried in a rotary vacuum dryer or a hot-air
dryer.
[0262] The product can be used, for instance, to manufacture
tablets or granulates for the treatment of the gastrointestinal
tract or other non-malignant ulcerations.
[0263] Analysis: TABLE-US-00020 Ca content 4.4% b/w Na content 2.7%
b/w .SIGMA. C.dbd.O content 0.0% b/w COOH content 20.5% b/w N
content 2.1% b/w
EXAMPLE 11
[0264] Material: IMC-microdispersed oxidised cellulose (MDOC)
complex (as per above Example 2) [0265]
[(2S;2R)-3-amino-2-hydroxy-4-phenylbutenoyl]-L-leucin (Bestatin)
(Boehringer Mannheim, Germany) [0266] redistilled water (PhBs 1997)
[0267] methanol, conc. anal.grade (Chemopetrol Litvinov, a.s.)
[0268] diethylether (Lachema, a.s. Neratovice) [0269] Equipment:
turbostirrer: ULTRA TURAX (Janke-Kunkel) [0270] sulphonation flask
2 l [0271] laboratory centrifuge: 4000 rpm [0272] hot-air dryer
[0273] Procedure:
[0274] 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.
[0275] 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.
[0276] 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
[0277] MDOC=Microdispersed Oxidised cellulose [0278] Material:
IMC-MDOC complex--see Example 2 [0279] magnesium stearate (SIGMA)
[0280] ascorbic acid (MERCK) [0281] .alpha.-tocoferol acetate
(Slovakofarma Hlohovec) [0282] ethanol synthetic rectified
(Chemopetrol Litvinov, a.s.) [0283] Equipment: tabletting machine
(KORSCH EK 0, Berlin) [0284] blender (Nautamix 300) [0285]
counter-flow drier BINDER
[0286] Procedure:
[0287] 10 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 .alpha.-tocoferol acetate emulgated in
2500 ml of ethanol, and 1000 g of magnesium stearate were added.
The mixture was homogenized for 3 hours. It was then dried in a
counter-flow drier at a temperature of 50.degree. C. until ethanol
was removed.
[0288] 100 g of the resulting dry powder were introduced into the
tabletting machine, and the tabletting force was set at a value of
7 kN.
[0289] Result:
[0290] 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.degree. C., and 8 minutes at 37.degree.
C.
APPLICATION EXAMPLE
[0291] 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.
TABLE-US-00021 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/l 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
[0292] Material: IMC-MDOC complex--see Example 8 [0293] MDOC,
particle size 0.1-2.0 .mu.m, specific surface area 86 m.sup.2, COOH
group content 22.2% b/w, Ca content 4.2% b/w, Na content 3.8% b/w
[0294] IMC-MDOC complex containing BiO.sup.+--see Example 9 [0295]
Equipment: laboratory mixer, bottom agitated, 4000 rpm [0296]
tabletting machine (KORSCH EK 0, Berlin)
[0297] Procedure:
[0298] 9.5 g of IMC-MDOC containing clarithromycin were placed into
the mixer, and 12.0 g of BiO.sup.+ 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.
[0299] Result:
[0300] 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 12 minutes at 20.degree. C., and 5 minutes at 37.degree.
C.
[0301] Indication:
[0302] 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.sup.+ 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
[0303] Material: MDOC, particle size 0.1-2.0 .mu.m, specific
surface area 86 m.sup.2, COOH group content 22.2% b/w, Ca content
4.2% b/w, Na content 3.8% b/w [0304] IMC-MDOC complex containing
Ambroxol--see Example 5 [0305] microcrystalline cellulose (SIGMA)
[0306] hydroxypropylcellulose (Natrosol HHR 250) [0307] magnesium
stearate (SIGMA) [0308] Macrogol 400 (SIGMA) [0309] Equipment:
laboratory mixer, bottom agitated, 4000 rpm [0310] tabletting
machine (KORSCH EK 0, Berlin)
[0311] Procedure:
[0312] 43.0 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 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.
[0313] Result:
[0314] 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.degree. C., and 6 minutes at 37.degree.
C.
[0315] Indication:
[0316] 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
[0317] Material: MDOC, particle size 0.1-2.0 .mu.m, specific
surface area 86 m.sup.2, COOH group content 22.2% b/w, Ca content
4.2% b/w, Na content 3.8% b/w [0318] IMC-MDOC complex containing
cinetidine--see Example 10 [0319] Macrogol 400 (SIGMA) [0320]
Equipment: laboratory mixer, bottom agitated, 4000 rpm [0321]
tabletting machine (KORSCH EK 0, Berlin)
[0322] Procedure:
[0323] 63.0 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.
[0324] Result:
[0325] 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.degree. C., and 6 minutes at 37.degree.
C.
[0326] Indication:
[0327] 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. Bide 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 BiO.sup.+ Complex
containing Aminophenazon and Allobarbital
[0328] Material: Adeps neutralis (WERBA) [0329] Oleum cacao (WERBA)
[0330] IMC-MDOC complex containing BiO.sup.+--see Example 9 [0331]
Aminophenazonum (SPOFA) [0332] Allobarbitalum (SPOFA) [0333]
Equipment: stainless melting tank, agitated, volume 1000 ml, input
power 600 W [0334] movable support carrying a shaped blister
foil
[0335] Procedure:
[0336] 282.6 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.degree. C. On melting, 16 g of Allobarbitalum,
117.3 g of Aminophenozonum and 61.33 g of IMC-MDOC complex
containing BiO.sup.+ 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.
[0337] Result:
[0338] Suppository of 8 mm diameter, 20 mm length, conical shape,
weight 2.25 g.
[0339] Indication: [0340] Combined suppositories having
antihaemorroidal and analgetic/antipyretic effects.
EXAMPLE F
Preparation of Vaginal Suppositories from IMC-MDOC Complex
containing Gelatine, Nitrofurantoin and Chlorohexidine
[0340] [0341] Material: IMC-MDOC complex--see Example 2 [0342]
gelatina animalis (SIGMA) [0343] 1,2-monopropylenglykol (SIGMA)
[0344] glycerol, medicinal MERCK) [0345] nitrofurantoinum (SPOFA)
broad spectrum anti-microbial and anti-inflammatory [0346]
chlorohexidine digluconate (FEROSAN)--local bacteriocide [0347]
redistilled H.sub.2O [0348] Equipment: stainless melting tank,
agitated, volume 1000 ml, input power 600 W movable support
carrying a shaped blister foil
[0349] Procedure:
[0350] 78 g of redistilled H.sub.2O, 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.degree. 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.
[0351] Result:
[0352] Suppository of 8 mm diameter, 17 mm length, cylindrical
shape, weight 2.0 g.
[0353] Indication:
[0354] 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
[0355] Material: IMC-MDOC complex--see Example 2 [0356]
chlorohexidine digluconate (FEROSAN) [0357] ethanol synthetic
rectified 98% [0358] Equipment: laboratory mixer 4000 rpm [0359]
tabletting machine (KORSCH EK 0, Berlin)
[0360] Procedure:
[0361] 100 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.
[0362] Result:
[0363] 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.
[0364] Indication:
[0365] 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
[0366] Material: IMC-MDOC complex containing chitosan--see Example
4 [0367] MDOC, particle size 0.1-2.0 .mu.m, specific surface area
86 m.sup.2/g, COOH group content 22.2% b/w, Ca content 4.2% b/w, Na
content 3.8% b/w [0368] polyvinylpyrrolidone-iodine complex PVP-I
micronised (ISP-USA) [0369] Equipment: laboratory mixer 4000 rpm
[0370] tabletting machine (KORSCH EK 0, Berlin)
[0371] Procedure:
[0372] 50 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.
[0373] Result:
[0374] 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.
[0375] Indication:
[0376] Treatment of massive postextractional bleeding with
simulataneous administration of an antimicrobial agent.
EXAMPLE I
Preparation of Granules from IMC-MDOC Complex containing
Clarithromycin
[0377] Material: IMC-MDOC complex--see Example 8 [0378] MDOC,
particle size 0.1-2.0 .mu.m, specific surface area 86 m.sup.2/g,
COOH group content 22.2% b/w, Ca content 4.2% b/w, Na content 3.8%
b/w [0379] IMC-MDOC complex containing BiO.sup.+--see Example 9
[0380] ethanol synthetic rectified 98% [0381] redistilled H.sub.2O
[0382] Equipment: set of vibrating screens with mesh size 100, 150,
200, 250, 350, 500 .mu.m [0383] mixer, bottom agitated, vessel size
1000 ml, 8000 rpm, equipped with a nozzle for inlet of the
granulation medium counter-flow drier BINDER
[0384] Procedure:
[0385] 100 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.degree. 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
.gamma. irradiation with a dose of 25 kGy.
[0386] Indication:
[0387] 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.sup.+ acts as a mild astringens.
Clarithromycin depresses the growth of Helicobacter pylori beyond
pathologic limits.
EXAMPLE J
Preparation of Granules from IMC-MDOC Complex
[0388] Material: IMC-MDOC complex--see Example 2 [0389] Equipment:
set of vibrating screens with mesh size 100, 150, 200, 250, 350,
500 .mu.m [0390] mixer, bottom agitated, vessel size 1000 ml, 8000
rpm, equipped with a nozzle for inlet of the granulation medium
counter-flow drier BINDER
[0391] Procedure:
[0392] 100 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 10 g/45 seconds. The
granulate formed was transferred to the counter-flow drier and
dried at a temperature of 45.degree. 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 .gamma. irradiation with a dose
of 25 kGy.
[0393] Indication:
[0394] 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
[0395] Material: IMC-MDOC complex--see Example 2 [0396]
polyvinylpyrrolidone-iodine PVP-I complex-micronised (ISP-USA)
[0397] 1,2-monopropyleneglycol (MERCK) [0398] redistilled H.sub.2O
[0399] ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)
[0400] Equipment: set of vibrating screens with mesh size 100, 150,
200, 250, 350, 500 .mu.m [0401] mixer, bottom agitated, vessel size
1000 ml, 8000 rpm, equipped with a nozzle for inlet of the
granulation medium counter-flow drier BINDER
[0402] Procedure:
[0403] 90 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 10 g/50 seconds.
The granulate formed was transferred to the counter-flow drier and
dried at a temperature of 45.degree. 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 .mu.m
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 e
required.
[0404] Indication:
[0405] Haemostatic preparation with antimicrobial and antiviral
effect (powder spray, dusting powder).
EXAMPLE L
Preparation of Microspheres from IMC-MDOC Complex containing
Mitoxanthron
[0406] Material: IMC-MDOC complex--see Example 3 [0407]
1,4-bis-2-(-2-hydroxyethylamino-ethylamino-)5,8-dihydroxyantrachinon
(mitoxanthron) (Aliachem a.s.) [0408] ethanol synthetic rectified
98% (Chemopetrol Lirvinov, a.s.) [0409] redistilled H.sub.2O [0410]
Equipment: turbostirrer ULTRA TURAX (Janke-Kunkel) [0411]
sulphonation flask 1 l [0412] beaker 250 ml [0413] set of vibrating
screens with mesh size 100, 150, 200, 250, 350, 500 .mu. [0414]
counter-flow drier BINDER [0415] vial 10 ml [0416] injection
syringe 25 ml
[0417] Procedure:
[0418] 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.
[0419] 495 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.
[0420] 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.degree. 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.
[0421] Indication:
[0422] Intraarterial (regional) chemotherapy of malignant tmours
where mitoxanthron is indicated.
EXAMPLE M
Preparation of Microspheres from IMC-MDOC Complex containing
Mitoxanthron
[0423] Material: MDOC (Ca/Na salt of PAGA), particle size 0.1-2.0
.mu.m, specific surface area 86 m/g, COOH group content 22.2% b/w,
Ca content 4.2% b/w, Na content 3.8% b/w [0424] ethanol synthetic
rectified 98% (Chemopetrol Litvinov, a.s.) [0425] redistilled
H.sub.2O [0426] 1,2-monopropyleneglycol (Sigma) [0427] sorbitol
(Sigma) [0428] isopropanol (Sigma) [0429] Equipment: propeller
stirrer, 50 rpm [0430] sulphonation flask 1 l [0431] beaker 250 ml
[0432] set of vibrating screens with mesh size 100, 150, 200, 250,
350, 500 .mu.m [0433] counter-flow drier BINDER [0434] injection
syringe 25 ml
[0435] Procedure:
[0436] 10 g of MDOC Ca/Na salt and 90 g of redistilled H.sub.2O
were introduced into the beaker, and dispersed using the propeller
stirrer to obtain a colloidal solution.
[0437] 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.
[0438] 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.degree. 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.
[0439] Indication:
[0440] 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
[0441] Material: IMC-MDOC complex--see Example 3 [0442]
1,2-dihydroxypropane (Sigma) [0443] gelatine, hydrolysed (Infusia,
a.s.) [0444] glycerol, medicinal (PhBs 1997) [0445] redistilled
H.sub.2O [0446] Equipment: turbostirrer ULTRA TURAX (Janke-Kunkel)
[0447] sulphonation flask 1 l [0448] beaker 250 ml [0449]
lyophiliser
[0450] Procedure:
[0451] 400 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 task. The mixture
was heated up to 70.degree. 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.
[0452] Indication:
[0453] Suitable for use as biocompatible and fully resorbable nasal
tampons.
EXAMPLE O
Preparation of Rigid Foams from IMC-MDOC Complex containing
Chitosan
[0454] Material: IMC-MDOC complex--see Example 3 [0455]
1,2-dihydroxypropane (Sigma) [0456] gelatine, hydrolysed (Infusia,
a.s.) [0457] glutaraldehyde (Sigma) [0458] chitosan, degree of
deacetylation 92% (Henkel) [0459] glycerol, medicinal (PhBs 1997)
[0460] redistilled H.sub.2O [0461] Equipment: turbostirrer ULTRA
TURAX (Janke-Kunkel) [0462] sulphonation flask 1 l [0463] beaker
250 ml [0464] lyophiliser
[0465] Procedure:
[0466] 400 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.degree. 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.degree.
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.
[0467] Indication:
[0468] 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
[0469] Material: MDOC (Ca/Na salt of PAGA), particle size 0.1-2.0
.mu.m, specific surface area 86 m.sup.2/g, COOH group content 22.2%
b/w, Ca content 4.2% b/w, Na content 3.8% b/w [0470] ethanol
synthetic rectified 98% (Chemoperrol Litvinov, a.s.) [0471]
redistilled H.sub.2O [0472] 1,2-dihydroxypropane (Sigma) [0473]
polyacrylamide, 50% aqueous solution (Aldrich) [0474] glycerol,
medicinal (PhBs 1997) [0475] Equipment: laboratory miner, bottom
agitated, 4000 rpm [0476] sulphonation flask 1 l [0477] injection
syringe 25 ml
[0478] Procedure:
[0479] 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 (NH.sub.3) ligands. The
microspheres formed, contained (NH.sub.3).sub.2Pt(II) groups, were
isolated from the coagulating bath by decantation, washed with
concentrated ethanol, and vacuum dried at 25.degree. C.
[0480] Indication:
[0481] Intraarterial (regional) chemotherapy of malignant tumours
where diamoplatinum(II) complexes are indicated.
EXAMPLE Q
Preparation of Rigid Foams from IMC-MDOC Complex containing
Chitosan and Bestatin
[0482] Material: IMC-MDOC bestatin complex--see Example 11 [0483]
chitosan, degree of deacetylation 92% (Henkel) [0484]
polyacrylamide, 50% aqueous solution (Aldrich) [0485] glycerol,
medicinal (PhBs 1997) [0486] redistilled H.sub.2O [0487] Equipment:
turbostirrer ULTRA TURAX (Janke-Kunkel) [0488] sulphonation flask 1
l [0489] laboratory heater [0490] counter-flow drier BINDER
[0491] Procedure:
[0492] 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.
[0493] Indication:
[0494] Suitable for use in preparation of embolisation agents,
plasters and similar products.
EXAMPLE R
Preparation of Flat Textile-Like Stores containing MDOC and
IMC-MDOC Complex with Bestatin
[0495] Material: cotton dressing pad [0496] MDOC (Ca/Na salt of
PAGA), particle size 0.1-2.0 .mu.m, specific surface area 86
m.sup.2/g, COOH group content 22.2% b/w, Ca content 4.2% b/w, Na
content 3.8% b/w [0497] IMC-MDOC bestatin complex--see Example 11
[0498] ethanol synthetic rectified 98% (Chemopetrol Litvinov, a.s.)
[0499] demineralised water 2 .mu.S [0500] Equipment: continuous
spray-coating equipment
[0501] Procedure:
[0502] 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/m.sup.2. An impregnated flat
textile-like structure was obtained on evaporating the aqueous
ethanol.
[0503] Indication:
[0504] Suitable for use in preparation of dressing materials for
e.g. covering skin lesions after surgical removal of skin
neoplasies.
[0505] The invention is not limited to the embodiments hereinbefore
described which may be varied in detail.
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