Note: Descriptions are shown in the official language in which they were submitted.
2192071
SMB
Putamen va.
The present invention pertains to a method for the preparation
of putamen ovi, putamen ovi having a defined grain size distribu-
tion, and to the use of putamen ovi for the treatment of various
diseases.
Putamen ovi within the meaning of the present invention cotnprises
hygienically processed egg-shell, in particular from Gallus
domesticus.
According to Rbmpp Chemielexikon, 9th edition, 1990, page 1079,
item "Eier" ("eggs"), the egg-shell of chicken eggs has a
thickness of from 0.2 to 0.4 mm and is white or brown in color,
depending on the breed. It is composed of a protein framework
(protein-mucopolysaccharide complex)in which calcium carbonate
as well as a minor amount of Ca and Mg salts are incorporated.
The shell contains pores (7000-17,000 per egg) which are filled
with protein fibers. The eggs of other bird species, such as
goose, duck, pigeon or quail, are much less important than
chicken eggs and are always indicated according to their origins.
The shell has a dry mass content in the order of 98.4% which
consists of 3.3* ofproteins and 95.1* of minerals.
From SU 1 754 104, the use of egg-shells as a dentifrice is
known. The use of this preparation is that of a dentifrice. It
contains an allegedly caries-inhibiting film with reducing
abrasive properties. This dentifrice contains only a very small
and non-activity-determining proportion of egg-shells as an
adjuvant. The egg-shell powder is not present as a monosubstance,
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but is embedded in sodium hydrogencarbonate (35-45g (m/m)) and
is not taken up by the organism.
In CH 193 065 A, a liquid tonic is described which is rich in egg
yolk, and thus particularly rich in cholesterol, and has high
sugar and alcohol contents, but contains little egg-shell
components. This is due to the preparation method. The finished
emulsion contains from 2 to 3t of egg-shell components in the
form of citrates - but only those which are dissolved or
emulsified. This preparation contains only particular fractions
of egg-shell. Due to its high proportion of cholesterol, sugar
and alcohol, this tonic is not acceptable therapeutically in view
of its clear potential of load on physiological feedback control
systems.
According to FR-A-0 649 055, the egg-shells are sterilized with
20k ethylene oxide at 50 C under a pressure of 5 atmospheres.
This method enables a germ reduction rather than a complete
sterilization which would be necessary.
The preparation described in GB 2 218 906 is employed for the
treatment of dermal lesions. Finely ground egg-shells are
processed into a preferably liquid formulation to be used orally
or topically which in particular also includes essences, paraffin
and various waxs and paraffin oils. The use of this preparation
with eczema and.allergic skin conditions is not acceptable by
oral and topical application since egg-shells, due to their
protein base, have a high allergenic potential themselves and may
trigger typical skin irritations and increase existing syndromes
of certain dermal lesions of allergic nature. Heating the egg-
shells for sterilization by means of microwaves over a period of
6 minutes is inadequate for eliminating pathogens.
In EP 0 347 859 A2, a sterilization method for egg-shells is
described. The sterilization method reported is unsuitable for
eliminating the possible presence of pathogenic bacteria, spores,
fungi and protozoans. The sterilization of egg-shell powder with
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dry air at 120 C for about 1 hour is not suitable for effecting
a safe reduction of pathogenic germs and to counteract a loss in
active ingredients due to too high temperatures. An increase in
temperature at > 80 C, especially in the range of x 150 C, for
more than 1 hour destroys the biologically present carriers with
membrane passage ability for an effective transport of minerals
in compact and spongy si.ibstances. Following this thermal ex-
posure, the egg-shell powder.exhibits the biological effects of
calcium carbonate with respect to the 45Ca incorporation rate.
Various formulations comprising egg-shell powder have been
examined in US 3 558 711, especially in rats with topical
application on open wounds. An improved wound healing has been
achieved as compared to the control animals. In this document,
no suitable sterilization method is reported which would not
effect the therapeutic effectiveness of--the egg-shells. An oral
applicationof egg-shell powder isnot intended.
In Chemical Abstracts, vol. 117, 1992, Ref. 33411x, egg-shell
powder is processed into cosmetic preparations under the action
of lactic acid. The calcium lactate products thus generated are
embedded in a protein film. This lactate emulsion is processed
into a cosmetic cream. in much the same way as preparation 1(SU
1754 104), it only contains particular fractions of egg-shell
which are topically applied.
In addition,-there has been many decades of experience in the
preparation of speciaties, in particular in the sterilization
without activity losses, , namely: if a temperature of 80 C is
.exceeded in the sterilization of the egg-shell, then the
biological carrier with membrane passage ability for the minerals
is destroyed, so that the activity of the thermally destroyed
product corresponds to that ofcalcium carbonate with respect to
the 45Ca incorporation rate. On the other hand, this temperature
alone is not sufficient to completely free.the porous, heat-in- -
sulating raw material egg-shell/egg-shell powder from pathogenic
bacteria, spores, fungi and protozoans the presence of which is
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to be expected due to faecal contamination, especially when in
addition the storage conditions are unfavorable.
According to the invention, it has been found that the use of
putamen ovi surprisingly has advantages over the use of pure
calcium carbonate in various conditions of disease. However, a
particular problem in the use of putamen ovi as a medicament is
to provide a standardized sterile medicament having a defined
grain size.
In a first embodiment of the present invention, the above problem
is solved by a method for the preparation of putamen ovi having
a grain size of less than 0.1 mm wherein
a) egg-shells, especially from Gallus domesticus, are washed
with water or an aqueous solution containing disinfectants
and/or tensides with stirring at room temperature or
elevated temperature;
b) the egg-shells having been cleaned from contaminants are
subjected to autoclave treatment;
c) the egg-shells are dried; and
d) the egg-shells are crushed to the desired grain size
following or during the drying.
In the first cleaning step, the cleaning is effected by washing
once or repeatedly with purified water (aqua purificata),
possibly with stirring. Batch sizes of 50 to 100 kg of egg-shells
usually require about 250 1 of water; cleaning agents, especially
surfactants, may optionally be used. The suspended matter formed
in the cleaning is drawn off, and the cleaned egg-shells are
subsequently subjected to a germ count reduction or sterilization
process.
Subsequent to or optionally during the autoclave treatment, the egg-shells are
dried
at elevated temperature. This
especially involves the evaporation of the water contained in the
pores. Particularly preferred drying methods include vacuum
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drying or freeze-drying as well as drying at increased tempera-
tures.
By means of the present invention, it is possible to prepare
putamen ovi having a defined grain size in which a major portion
of the biologically active materials contained in the egg-shell
in addition to calcium carbonate are conserved.
Parti-cularly preferred according to the present invention is hot
air drying at a temperature above the boiling point of water,
especially at a temperature of at least 150 C, for at least 3
hours in which sterilization and drying are conjoined in one
process step.
Then, subsequent to the drying or during the drying, the egg-
shells are crushed to the desired grain size of less than 0.1 mm.
It is particularly preferred according to the present invention
to crush the dried egg-shells with a grinding disk followed by
screening with a mesh size of 0.1 mm x 0.09 mm.
Thus, depending on the grinding aggregate used, it is possible
to provide putamen ovi having a defined grain size while
essent:ially conserving the active companion substances.
Accordingly, a further embodiment of the present invention is
putamen ovi obtainable by a method as defined above and having
a grain size distribution of 35% by weight of > 0.05 mm and 65%
by weight of < 0.01 mm.
2192071
The putamen ovi thus provided can be processed, using per se
known adjuvants and vehicles, into a medicament which may be
employed for various pathologic calcium deficiency conditions.
In particular, it has been found that a natural substance
therapeutic agent thus obtained contains minor amounts of other
essential minerals in addition to calcium, such as iron, fluor-
ine, potassium, silicic acid, magnesium. In addition, it contains
biologically generated active compounds, such as enzymes,
porphyrin, sterols, vitamin D3, along with the biologically
important trace elements copper, molybdenum, selenium and zinc.
The presence of calcium in a biologically bound form so to speak
represents a carrier function for a very effective resorption
from the intestine into the blood. Good resorption of the
minerals, the organic active compounds and the trace elements by
the organism is a precondition for the clear effectiveness of
putamen ovi in bone diseases and concomitant anemia.
The biologically important trace elements promote the development
of a sound bone system and beneficially affect disturbed bone
metabolisms.
With bone fractions, a significant shortening of the healing is
achieved which is caused by a quicker callus and bone formation.
Osteopenia (loss in bone tissue) is not a disease.but the age-
dependent destruction of bone tissue which begins about from the
30th-year of life and may amount up to 1.5!k per year. Thus, until
the 70th year of -life, a loss of about 1/3 of the bone mass
occurs without danger to the bone skeleton.
Upon insufficierit calcium supply, in calcium resorption disorders
or metabolic disorders, however, the organism withdraws calcium
from the bones. Such withdrawal leads to a reduction in the bone
substance. Not all bony organs are equally endangered. The spongy
bones of the vertebral bodies (spinal column) are attacked first,
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the tubular bones of arms and legs only later. Therefore, the
spinal column is particularly in danger with the risk of spine
deformation. The muscles try to counteract such changes in the
spinal column. The additional muscular action sooner or later
results in muscular pain. Therefore, muscular pain is present in
osteoporosis.
Therefore, the putamen ovi to be obtained according to the inven-
tion is especially useful in the treatment of bone marrow
development disorders, bone marrow dysfunctions, dyshemato-
poiesis, o-steopenia, osteoporosis, dental build-up disorders,
spasmophilia, bone fractions, callus formation and calcium
deficiency symptomsduring growth, pregnancy, postmenopause and
nursing period.
The following examples serve to illustrate the invention without
limiting the scope thereof.
Example 1
Preparation of putamen ovi.
Fifty kilograms of egg-shells from Callus domesticus were washed
times with 250 1. of aqua purificata at 60 C, the suspended
matter being drawn off after each washing. The cleaned egg-shells
were dried in a hot-air sterilizer at 165 C for 4 hours for germ
count reduction and sterilization.
The dried egg-shells were 'ground with apin-disk mill and sepa-
rated with a screen having a mesh size of D.1 mm x 0.09 mm.
Putamen ovi was obtained thereby having the following grain size
distribution:
> 0.05 mm 35k by weight; and
< 0.01 mm 65k by weight.
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Using per se known vehicles and citric acid, coated tablets were
prepared which contained 440 mg of micronized putamen ovi,
corresponding to 160 mg of calcium ions. The amount of citric
acid was 1.07 mg.
Clinical tests:
With the coated tablets prepared above, clinical tests were
performed in which the reduced bone density was examined with 41
female patients in the postmenopause.
The coated tablets were administered 3 times a day in the course
of 304 days. An increase in bone density in the total universe
of 9.4% after 304days (as an average) was established. The test
results are derived from repeated osteodensitometric determina-
tions the follow-ups of which were additionally supplemented by
the detection of the biochemical markers of the bone destruction
(osteoclast activity) and activity of bone formation (osteoblast
activity).
The bone mineral density measurements were performed by means of.
quantitative digital radiography (Hologic QDR-1000 TM bone
densitometer) on the lumbar vertebrae 1-4 wherein the result of
the bone mineral dens.ity calculation is expressed as density in
gram of calcium hydroxyapatite/cm3.
In this osteodensitometric procedure, the measuring value for the
absorption in the soft-tissue coat was eliminated so that the
bone mineral content could be determined without soft-tissue
error. The overall bilance on the basis of 41 follow-ups showed
a clear increase in the bone mineral density by 9.4% (from 78.1%
to 85.5%).
In a group A which had been administered putamen ovi for less
than 200 days with the dosage mentioned above, the bone density
already increased by an average of 5.5%. In a group B which had
been administered putamen ovi for less than 300 days with the
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dosage mentioned above, the measuring value increased to 7.2%
while in a group C which had been administered putamen ovi for
more than 300 days with the dosage mentioned above, the measuring
value increased to the 9.4% mentioned. These results showed a
clear dose-effect relationship. While in a first group X, the
value increased by 6.9% upon application of 3 times one coated
tablet of putamen ovi, in another group Y which had been
administered 2 coated tablets of putamen ovi 3 times a day, a
bone-density increase of 10.9% was found.
It has been found that the increase in bone density was less than
5% with 12 of the patients examined, between 5 and 10% with 18
patients, while this value was above 10% (+ 15.5%-) with 11
patients. Thus, the responder rate may be assumed to be about
70%. No patient had a bone density after the end of the therapy
which was below that of the initial examination.
By means of the present invention, it is evidently possible to
generally counteract a bone density reduction of the spinal
column in female patients in the postmenopause, even without a
further substitution with osteoporosis therapeutic agents
currently available commercially.
