Note: Descriptions are shown in the official language in which they were submitted.
CA 02386027 2002-03-28
Biodegradable carrier systems for therapeutically
active substances and process fcr their production
The invention relates to a suitable formulation of a
biodegradable carrier system for therapeutically active
pharmaceutical substances which on the one hand promote
wound healing or which are able specifically to have
additional pharmacological effects in the organism.
Release of the active ingredient is intended with the
described drug forms to take place in a delayed and
gradual manner, resulting in a prolonged action for
these drug forms in the sense of a depot. The carrier
systems are biodegradable polymers which are
toxicologically acceptable, tolerable and immunogenic
in the human or veterinary organism. Blood plasma
proteins, in particular fibrin glue components
fibrinogen and thrombin are employed according to the
invention. Production takes place by a granulation or
spray agglomeration process in a fluidized bed, which
makes it possible to adjust specific product
properties.
Fibrin glues or tissue glues are employed in human
medicine and in certain cases (e.g. race horses) also
in veterinary medicine usually for example in surgical
operations to promote blood coagulation or hemostasis
and for closing wounds. The principle of fibrin gluing
corresponds to the last stage of the natural hemostasis
system in mammals, a coenzyme/enzyme controlled cascade
reaction in which fibrinogen is converted by thrombin
in the presence of factor XIII and Ca2+ ions into
fibrin. During wound healing, the fibrin is broken down
again by proteolysis and thus absorbed in a natural
way. Technically, the principle of operaticn of the
fibrin glues resembles the principle of two-component
or multicomponent adhesives which are mixed together or
brought into contact usually either only at the place
which is to be bonded or else only shortly before the
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actual time.
Care must be taken on administration and use of fibrin
tissue glue that fibrinogen and thrombin are brought
together only at the immediate site of the bleeding,
because the onset of coagulation is spontaneous.
Adjacent sites must moreover be well covered because of
the very good adhesive effect. A precondition for the
coagulation is free mobility of the individual
molecules involved, for example in water. This is
usually achieved in practice by separating the two
crucial components fibrinogen and thrombin until
applied to the wound, bringing them into contact with
one another only directly on the wound.
The components must each be packaged sterile and stored
in a suitable form and under defined conditions so that
the activity of the individual proteins or enzymes is
not harmed by the storage. This is usually achieved by
the protein concentrates being present in freeze-dried
form in vials. In this form they are stable on storage
under refrigerator conditions (4 to 6 C) for a defined
time, and even under ambient conditions (20 C) for a
shorter time. However, freeze-dried, the concentrate is
in solid, compressed and thus immobile form, but in the
form of a soluble solid. It is therefore necessary for
the protein concentrates to be completely redissolved
before use in order to be able to start the desired
biochemical reaction. As an alternative to this it is
possible for the components also to be stored stably in
a deep-frozen solid form, and they must then be thawed
before use and be applied separately as solution.
The two solutions can then in each case be brought
together by syringes, for example in the same ratio by
volume. In this case, the fibrinogen solution. must be
applied to the wound first and be covered as quickly as
possible with a layer of the thrombin solution. The
parts to be glued must then be immobilized unti.. a
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preliminary uniting has occurred.
In addition, the patent application WO 97/44015
describes the production of microparticles based on
fibrinogen and thrombin, each of which are spray-dried
separately. The removal of water associated with this
reduces the mobility of the protein molecules so far
that the onset of coagulation cannot occur
spontaneously. The microparticles are all smaller than
20 m, preferably smaller than 10 m or 2-5 m, and are
said to be readily soluble. Mixed together, these
fibrinogen- and thrombin-containing microparticles can
be employed for hemostasis. However, one disadvantage
is that much dust is associated with the powder, making
direct application virtually impossible.
Fibrin glues of human, animal or else recombinant
origin are characterized by immediate and comparatively
strong adhesion at the site of applicaticn (e.g. wound,
tissue) of the fibrin formed, the matrix structure
which forms in the crosslinked fibrin, and the
spontaneous biodegradability of the fibrin. The natural
components are additionally distinguished in that these
components are already present in the human or else
animal organism and therefore are toxicologically
acceptable and well tolerated.
Because of these characteristics (adhesion, matrix
structure, tolerability and degradability), fibrir.
glues or components of a fibrin glue may be a suitable
carrier system for additional therapeutically active
substances. Since, however, a fibrin glue can, as
described, be applied only as solution or in two
separate solutions, it is problematic to construct
homogeneous release-controlling matrix structures for
active ingredient-containing fibrin glue formulations.
A number of publications have disclosed fibrin glues as
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carriers of active ingredients. Besides the use of
antibiotics for suppressing local infections, there
have alsc been addition of cytostatics to fibrin glues
for local chemotherapeutic treatment for example of
remaining cancer cells after surgical removal of the
primary tumor. Zinc, for example, has also been
incorporated into fibrin glues in order thus to achieve
a higher content of zinc over a prolonged period
directly in the wound and thus make improved wound
healing possible (US 6,651,982). In addition,
EP 804153A1 also describes the combination of a fibrin
glue with a therapeutic active ingredient which can be
employed, for example, after surgical removal of a
tumor, as radiotherapeutic active ingredient.
It is thus known that fibrin glues can be employed as
carrier system for therapeutic active ingredients. It
is possible by suitable measures to control active
ingredient release in such a way that the release takes
place in a delayed fashion over a defined period. The
release of these active ingredients from the fibrin
glue carrier system varies from 24 hours to a number of
days according to the statements in the scientific
literature; the release of slightly soluble active
ingredients may in fact last for up to 40 days. It is
accordingly possible by combining a fibrin glue with
therapeutically active substances also to achieve a
delayed or extended release of active ingredient with a
slcw, constant uptake of active ingredient into the
blood stream and thus a constant concentration level of
the active ingredient in the blood.
Dosage forms of this type are generally known under the
name depot drug forms and are the aim of numerous
develcpments. Depot drug forms are also used
parenterally, The advantage which emerces in this case
is, for example, that depot drug forms with delayed
release can be administered to patients instead of a
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continuous i.v. infusion, which means considerably
greater independence and mobility for the patient. This
may also make it possible by targeted local
administration and, resulting therefrom, local release
of active ingredient for substances such as highly
active substances such as, for example, cytostatics or
else particular antibiotics to be employed in a more
targeted manner and thus in lower dosage than when they
display a systemic action affecting the whole organism
via the usual route of oral administration. In summary
it can be stated that the scientific literature shows
that fibrin glues have a good potential as carrier
system both for hydrophilic and for lipophilic active
ingredients, with a delayed release profile.
Known parenteral depot drug forms are
- Aqueous suspensions for slightly soluble active
ingredients by subcutaneous or intramuscular
injections. Example: insulin products (duration of
action 12-36 h). The very elaborate aseptic method of
manufacture of parenteral suspensions is
characteristic.
- Oily solutions, suspensions: active ingredient
dissolved or suspended in oil, whereby absortion of
the active ingredient in the aqueous phase of the
tissue (and thus the therapeutic active ingredient
release) is intended or retarded. Products are in
some cases marked by a very long duration of action
(weeks to months).
- Emulsions: after subcutaneous or intramuscular
injection, emulsions are distributed in the tissue
and are absorbed there. Systems of this type are
currently still characterized by a high degree of
incompatibility.
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- Highly viscous solutions, suspensions, hydrocolloids
(polyvidone, cellulose derivatives), in particular
for protein and peptide active ingredients
(simultaneously protective colloid effect and
suspension stabilizers).
Use of particulate vehicles - microparticles,
liposomes, implants. Microparticles and liposomes
appear macroscopically as suspension and dispersion
respectively. Implants are, by contrast, solids and
are used as such. The first products of this type
have been launched in various countries. Besides the
nondegradable silicon implants which, after delivery
of the embedded active ingredient, must be removed
again by a minor surgical operation, the advantage
of particulate vehicles is that they are
biodegradable and thus are removed completely from
the tissue after their hydrolytical cleavage by the
organism itself. It should be noted that the
resulting degradation products must not be either
toxic or immunogenic, or carcinogenic. The polymers
which are mostly used are therefore produced from
tissue-compatible lactic acid and glycolic acid
monomers (PLGA). However, albumin microparticles are
also known in radiodiagnosis and are very suitable
in particular because of their good tolerability and
biodegradability. The like may also apply to
particulate vehicles composed of fibrin glue
components.
It is common to the technical solutions for the
manufacture of parenteral depot drug forms by use of
dissolved, suspended or emulsified active ingredients
in water, solvent or oil that the methods of
manufacture involved are always very elaborate and, in
particular, in some cases the administrations are also
complicated and their pharmacological action can be
displayed only after a number of (bio)chemical/physical
absorption, transport or dissolution processes in the
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organism. A result of this is that the actual
bioavailability can be controlled and monitored to only
a limited extent.
It would therefore be an advantageous development to
find for such carrier systems (which have to date been
administered as liquids) a dosage form which is
characterized by a defined matrix structure which
remains constant or is gradually degraded during the
administration for the duration of the desired release
of active ingredient. These are properties which have
already been realized for example for certain solid
pharmaceutical dosage forms (such as tablets) which
have a defined, delayed release behavior for example in
the gastrointestinal tract. This cannot be realized
with liquid administrations as are at present usual for
fibrin glue components. Such novel dosage forms ought
to be improved depot drug forms.
On the other hand, it appears advantageous to use
particulate vehicles which can in some circumstances be
employed directly at the site of action as long as they
can be immobilized there in a suitable way. The release
of active ingredient then takes place for example by
diffusion-controlled absorption in the tissue or at the
site of action. Administration might in this case
advantageously take place directly for example as dry
powder without the microparticles being suspended in a
carrier liquid. Direct dry administration by injection
of the dry particles can take place for example with
the aid of PowderJect technology ("needle-free
injection") . Suitable particle sizes fcr this method
are between 50 and 200 m. It is also possible to
inject smaller particles as suspension or to implant
large shaped articles with a larger needle suitable
fcr this purpose.
The microparticles are produced either by phase
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separation methods or by spray drying a polymer/active
ingredient solution or suspension. It is likewise
required that the production conditions are sterile or
at least aseptic, which is very demanding. This
requirement is usually avoided by sterilizing the
microparticles after the spray drying. However, this
procedure can be applied for example only to synthetic
polymers which do not undergo unwanted changes in the
sterilization process. Thermally labile biological
polymers with protein-based specific activity, such as,
for example, fibrin glues and fibrinogen, may in some
circumstances be denatured by such a treatment, and
thus this method is unsuitable for polymers of this
type. =n addition, spray-dried particles are also in
particular characterized in that the particle sizes are
very small (usually < 20 m) and thus are very prone to
dusting and are not free-flowing in practice, which
greatly restricts accurate metering and direct
application of the solid powder.
In the scientific literature there is a description by
Senderoff et al. of the use of fibrin glues as carrier
system for therapeutically active components based on
microparticles, and in this case the proposed systems
are fibrin glues as microparticles, fibrin glue
particles with sugar coating and fibrin glue strips
with dispersed active ingredient particles.
Microparticles can be obtained after preceding
emulsification of the active ingredient, extraction
with an organic solvent and subsequent evaporation of
the solvent, Especially when these production steps
must be carried under aseptic conditions on the
industrial scale, the process is made very elaborate
thereby and is to be regarded as very problematic from
3' the industrial viewpoint.
A feature of a preferred embodiment of the present
invention thus is to produce solid particles in a suitable
manner that they can be employed as carrier
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systems for therapeutically active substances, and can also at
the same time be administered as solid. The components forming
the carrier system are essentially biodegradable blood plasma
proteins which may comprise, for example, at least one fibrin
glue component. However, other human or animal proteins may
also be suitable, such as, for example, albumin, which is
distinguished in that albumin already has an important
biochemical transport function in the organism and is therefore
both well tolerated and degradable.
In accordance with an embodiment of the present invention there
is provided a biodegradable depot medicament formulation
consisting of a carrier system in the form of microporous
granules with a particle size of from 20 to 50 pm composed of
biodegradable blood plasma proteins where the blood plasma
protein is selected from thrombin and fibrinogen, albumin or
mixtures thereof which have been dried by fluidized bed drying
with retention of their properties, and an active ingredient
which is to be administered as depot or an active ingredient
combination which is selected from the group consisting of
antibiotics, corticosteroids, antimycotics, neuroleptics,
antiepileptics, steroid hormones, anticancer hormones,
substances which promote wound healing, cytostatics,
immunomodulators, anesthetics, analgesics, peptide hormones
(replacement therapy), antirheumatics, vaccines, antibodies,
monoclonal antibodies, amino acid sequences (DNA, peptides,
proteins), gene therapy, biological cells, biotechnologically
produced growth factor and cells.
In the invention particles which comprise, for example, the
components fibrinogen and thrombin are produced in a granulation
process in a fluidized bed. The procedure for this is analogous
to the process, described in DE 198 49 589.7 Cl, in which either
mixed granules comprising at least fibrinogen and thrombin or
else granule mixtures which represent a mixture of fibrinogen-
and thrombin-containing granules, are produced in a fluidized
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bed process. Besides the fibrin glue components, it is also
possible to apply one or else a plurality of additional
therapeutic pharmacological active ingredient component(s) to
the particle or the granules so that they are sufficiently
immobilized there in order to make administration together with
the fibrin glue components possible. This can usually take
place in fluidized bed applications by spraying the additional
active ingredient together with at least one of the fibrin glue
components, preferably with fibrinogen or else with thrombin,
simultaneously from a polymer/active ingredient solution or
suspension onto the granules which comprise both fibrinogen and
thrombin. In the first variant, the active ingredient can, for
example, be integrated directly into the interior of the
granules into the solid fibrin glue matrix, while in the second
variant the active ingredient or the active ingredients can be
bound to the surface of the particles or granules. Moreover the
additional process options known for fluidized bed processes,
such as application of a (protective) coating consisting of a
coating material or else of a colloid (polyvidone or cellulose
derivatives), are possible. These coatings can be applied for
example inside the granule as separating layers or only as pure
external coating on the surface. The purpose of these coatings
may be to achieve a protection for example of the active
ingredient (for example for coating with antioxidants in the
case of oxidation-sensitive active ingredients) or else to alter
(extend) the delayed release of active ingredient. However, it
must be noted in this connection that possible external coatings
may presumably also reduce or, in some circumstances, also
enhance the adhesive effect of the fibrin glue. A coating
composed of molecules with a particular affinity for particular
tissues is also conceivable. Besides the fibrin glue components
as carrier polymer, it is also possible in an analogous
procedure to produce granules or powders composed of albumin or
of the biodegradable proteins mentioned.
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In this connection too it is necessary to observe very strict
manufacturing instructions for products employed parenterally,
in particular concerning rigorous conformance of all process and
technical measures with maximum microbiological cleanliness.
Both sterile (aseptic) filling, especially of temperature-
sensitive preparations which cannot be sterilized in the final
container, and the requirement for lower initial microbe counts
make it obligatory to employ optimal cleanliness and
appropriately developed (aseptic) production lines.
Reference will now be made to the accompanying drawings,
wherein:
Figure 1 shows principal production steps;
Figure 2 presents the requirement for the area of production of
granules, powders or pellets, where the production area and the
technical area are clearly separated; and
Figure 3 shows the filling of the granules or pellets in a
dedicated area.
It is proposed, as shown in fig. 1, that the principal
35
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production steps for isolating and obtaining the
polymers (e.g. the blood plasma protein fractions
fibrinogen and throtrbin) and the active ingredients,
and the production of the powder or of the granules or
of the micropellets and the filling of the granules
into the final packaging be separated. In this
connection it is possible, depending on requirements,
to comply appropriately with the particular room
classes (clean room zone A and room zone C/D) required
by national and international guidelines (for example
GMP guidelines).
The requirement for the area of production of the
granules or powders or pellets (fig. 2) is - as usual
in pharmaceutical production - that the production area
and technical area are clearly spatially separate from
one another, e.g. through constructional measures 38.
Located in the technical area are the necessary
additional technical facilities needed to operate the
installation. These may comprise in the area of intake
of fresh air 1, the process air treatment, including
various filter stages, heating and cooling, 2, an
additional sterilizing filter 3, a sterilizable double
flap system 4 and in the area of outgoing air once
again a sterilizable double flap system 17, a
sterilizing filter 16 and the ventilator 15. Also
disposed in the technical area are a circulation
cleaning station 5 for CIP (cleaning in place) of the
installation and various installation components, and
ar. extra pure steam generator 6 for providing sterile
steam for sterilizing the installation, the cleaning
installation and other components yet to be specified
in detail. The installation can be cleaned by the
cleaning station 5 in accordance with a cleaning
program which is to be specified (parameters are the
nature of the cleaning composition(s), cleaning times,
temperatures and quantity of the cleaning compositions
and of the water used for rinsing and after-rinsing).
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Various cleaning nozzles on the installation and in a
piping system are actuated via the piping system. The
same applies to the sterilization operation, in which
saturated steam is admitted both to the installation
and to various positions in the piping system. The
sterilization takes place in accordance with a formula
which is to be set under appropriate autoclaving
conditions: after heating the installation to the
desired sterilization temperature (e.g. 121 C and 3 bar
pressure of saturated steam), a defined holding time is
observed for the complete installation and the
peripherals to be sterilized, e.g. 20 minutes. After
the installation has cooled to, for example, room
temperature or a higher process temperature, the then
sterilized installation is available for a new process,
but it should be noted that the installation must not
be opened. The installation tower 9 has special CIP-
able metal filters 20 as well as other specific CIP-
able design details such as, for example, special
aseptic 0 rings, which are not depicted, and suitable
contamination-free port systems 18, 19 for any feed
tanks 13 and product collection tanks 11, which are in
turn for example steam-sterilizable on their own. The
installation tank wall is designed as jacket 7 for
heating and cooling and, in some circumstances, with an
additional insulation S. The active ingredient- and
polymer-containing solution or suspension is sprayed
into the installation via a pump 12, for example a
peristaltic pump, from a closed feed tank 10 which
derives from the production of active ingredient and
polymer. It is also conceivable for the feed tank 10 to
remain in the area of polymer and active ingredient
production and be connected via a suitable tubing or
piping system to the spray pump 12. The installation
and the peripheral facilities are operated via an
operating terminal 14 which can be installed both in
the production area and outside the production area. A
possible alternative to the 'described open production
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mode, in which fresh air is drawn via a plurality of filter
stages through the installation and, after appropriate treatment
of the outgoing air, is returned to the environment, is a closed
operating mode in which the incoming and outgoing air sides are
connected together by a circulation.
Filling of the granules or pellets once again takes place in a
dedicated area. This area can be designed, for example, by
isolator technology (fig. 3), so that the product collection
tank 11 is connected to a suitable isolator filling unit 21 in
the closed state after granule production has taken place.
After the contamination-free flap 39 has been opened, the
product is screened 22 and, in some circumstances, mixed 23 in a
special area. Before it is then metered in the actual unit 24
through a tunnel 25 into the individual containers 32, samples
are taken and analyzed 28 within the scope of the described in-
process controls. After the individual containers 32 are
filled, the containers are closed 26 and leave the filling unit
in this state and are then passed to the subsequent production
units such as in-process controls within the scope of quality
assurance and control and finally to packaging and finishing 27.
In a similar way, the empty primary packaging 29 is passed,
after it has passed through a washing and rinsing device 30 and
been sterilized in a sterilization tunnel 31, to the filling
unit 24. Clean room conditions (i.e. above-ambient pressure,
particle class 100 and laminar flow conditions) prevail inside
the isolator filling unit in each of the treatment steps with
open handling of product 33, 34, 35, 36 and 37. Furthermore,
there is a defined pressure gradient between these zones 33, 34,
35, 36 and 37 so that no cross-contamination can occur. With an
appropriate constructional design it is also possible to
dispense with transfer of the product using the collection tank
11. This takes the form of a multi-story vertical arrangement
with the filling unit
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installed directly below the granule production
installation tower. However, in this case, it is also
necessary for granule production to be separated from
the filling unit by constructional measures.
Possible formulations may be:
- Mixing of particles or granules which (lacuna) fibrin
glue components and active ingredients which may have
either hydrophilic, amphiphilic or else lipophilic
properties. Release of active ingredient can in these
cases also be influenced by formulation additives
known from the prior art. It is additionally possible
to admix excipients such as, for example, lecithins
(egg or soybean lecithin) or else Tween to the
particles or granules to improve the wettability. The
range of sizes of such powder and granule mixtures
can be in a range from 50 to 500 m or preferably in
a range from 50 to 200 pm or else from 200 to 500 m.
- Mixtures of particles or granules which comprise
integrated for example polymer microparticles with
additional active ingredients. The polymer may also
be polymers not containing fibrinogen or thrombin and
of synthetic origin but likewise biodegradable. It is
possible to mention as example polymers of lactic
acid/glycolic acid (PLGA) or polyanhydrides or
polyorthoesters or other suitable polymers known in
the prior art. However, protein-based polymers are
also possible, such as, for example, albumin. Also
suitable are synthetic polymers which are employed as
synthetic fibrin glues, such as, for example,
poly(octyl cyanoacrylate). The range of sizes of such
powder or granule mixtures can be in a range from 50
tc 5CC pm or preferably in a range frcm 50 to 200 W
or else from 200 tc 500 m.
- Mixtures of particles or granules which are each
composed of an internal core and an external layer.
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The external layer comprises fibrin glue components
in order to ensure adequate immobilization of the
particles or granules in the tissue. The internal
core may, on the other hand, also be formed of inert
conventional excipients such as, for example,
carbohydrates (lactose, mannitol, etc.). It is
possible by appropriate choice of the excipients and
by appropriate pharmaceutical formulation to
influence the solubility of the core in such a way
that it is, for example, only slightly soluble and
thus brings about a delayed or extended release of
active ingredients. The additional active ingredient
or active ingredients can be integrated both into the
external layer and into the internal core. Suitable
examples thereof are crosslinked polymers, for
example cellulose derivatives, which are used for
example in matrix tablets. The range of sizes of such
powder or granule mixtures can be in a range from 50
to 500 m or preferably in a range from 50 to 200 m
or else from 200 to 500 }un.
Solids which can be produced by compressing the
particle or granule mixture to tablets or else by
compaction to compacts (for example roll compaction
with subsequent screening (= sizing) to adjust to
defined sizes or else briquetting). This results in
further degrees of freedom for the pharmaceutical
formulation, thus making it additionally possible to
alter the release or else making novel administration
forms possible. Examples of conceivable modifications
according to the prior art are the following: coated
tablets, matrix tablets, Oros tablets, components
which control release, tablet size and shape. On the
other hand, it is possible with compactors to produce
from the powder or granules for example lencthy thin
strips which could in turn be placed flat directly
into a body orifice or an incision after surgical
operations. Defined and specific matrix structures of
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the fibrin glue components and of the active
ingredient components can be constructed both by
means of tablets and by means of extrudates. Other
conceivable examples are additional stabilizing
reticulate fabric structures which can be applied
either additionally together with the tablets or with
the compacts, thereby making use possible for healing
of wounds associated with chronic disease. This makes
applications for tissue replacement, for example
skin, possible.
- Compact homogeneous micropellets with an average
particle diameter of about 50 n. These may be
biodegradable micropellets which do not contain
fibrinogen or thrombin (for example albumin, PLGA)
and which are coated on the outer surface with a
fibrin glue component layer. This exploits the we"l-
known good adhesive properties of the fibrin glue. In
addition, at least one therapeutically active
substance, or else more than one, is incorporated
into the internal biodegradable polymer core. The
advantage is that this makes better local
administration of the micropellets possible, and they
can also be immobilized. It is also possible for the
time course of the biodegradability to differ between
the layers.
- Compact homogeneous micropellets with an average
particle diameter of about 50 Am which comprise a
core of fibrin glue components and into which
slightly soluble active ingredients are integrated.
- Porous ceramic granules or granules made of materials
for bone replacement, such as, for example, calcium
phosphates, which are coated with blood plasma
proteins, and these coated granules being compressed
to a solid. This solid can then be employed as bone
replacement. It is also possible in this case to mix
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the granules with active ingredients such as
antibiotics or growth factors such as, for example,
BMP or TGF-0 types. One example of BMP is collagen.
This can be carried out in such a way that, in a
first step, the ceramic granules are coated with a
1st fibrinogen-containing layer. In a 2nd step,
thrombin with, for example, growth factors is then
applied in a fluidized bed. This can take place as
described in DE 198 49 569 C1. The disclosure content
is incorporated by reference.
Possible applications of the fibrin glue as carrier
system are:
- Topical administration in the same way as
conventional fibrin glues for hemostasis in
connection with wounds, surgical operations, open
body cavities or via mrucosal membranes, e.g. mouth,
nose, colon or vagina, For local or systemic
administration.
- Use as parenteral depot drug form in conjuction with
the properties of tolerability, adhesiveness,
biodegradability in the form as powder or as granule
mixture or else micropellets, without these being
dissolved or suspended before administration (for
example using special Ject(D injection, i.e. needle-
free injection of solids).
- Use as parenteral depot drug form in conjunction with
the properties of tolerability, adhesiveness,
biodegradability as micropellet suspension or of a
carrier liquid as dispersion. Suitable examples
thereof are oily suspensions (triglycerides, sesame
oil) . In order to prevent premature coagulation of
the suspended micropellets before or during
injection, it is possible to add anticoagulants (e.g.
trisodium citrate) to the suspension. With polymers
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based on fibrin glue components it is necessary in
particular to take account of the problems usual with
currently available systems for fibrin glues (=
spontaneous coagulation through premature contact of
the active components fibrinogen and thrombin must be
prevented => elaborate preparation etc., see also
DE 198 49 569.7 Cl).
- Use as carrier system for therapeutic active
ingredients by nonparenteral administration (e.g.
oral, topical, rectal or vaginal administration).
- Transdermal administration (plaster).
- Use as implant, e.g. as bone replacement or as
tissue.
The process for producing powders or granules can
preferably be carried out in such a way that the
fluidization gas is passed upward through the fluidized
bed chamber, and the liquid (solution or suspension) to
be dried is sprayed in from the top (top spray) , from
the bottom. (bottom spray) or else from the side (rotor
fluidized bed) via a spray system. The fluidization gas
has at the same time the task of fluidizing the product
present in the fluidizing chamber, introducing the heat
necessary to evaporate the spray liquid (water or
organic solvent) into the spray stream or the moist
product and at the same time taking up and transporting
away the evaporated amount of liquid. Discharge of the
dried product is prevented on the one hand by choosing
a suitable fluidization rate (less than the so-called
product discharge rate which can be determined by
calculation and experiment), and on the other hand by
the product retaining filter which is present in the
upper region of the fluidizing chamber and is regularly
cleaned, or else by another product separator known
from the prior art (such as, for example, a cyclone
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separator).
The liquid droplets in a fine mist in the spray cone
impinge on the fluidized powdered carrier material and
are dried there because of the heat- and matter-
transfer conditions which are ideal for fluidized bed
processes and which are essentially a consequence of
the very large specific surface areas of the particles
of the fluidized product. During the spraying there is,
for example because of the slow increase in the
moisture in the product particle, formation of
agglomerates or granules and thus an increase in the
particle size.
In the choice of process conditions for thermally
labile products (polymers or active ingredients), it
must primarily be ensured that they are not harmed by
high temperatures. This applies in particular when
natural protein-based polymers are processed,
especially for natural fibrin glue components
(especially for fibrinogen). Suitable incoming air
temperatures are,-for example, between 15 and 100 C for
the product temperature but preferably below 37 C (this
particularly applies to fibrinogen). With albumin on
the other hand, product temperatures for example of up
to 50 C may also be possible without denaturation of
the albumin occurring. It must be taken into account in
this connection that possible inactivation must always
be considered in connection with a particular moisture
content, i.e. the thermal stability increases with a
decrease in moisture content in the solid product, so
that higher temperatures may also acceptable toward the
end of the drying.
Another important parameter for assessment of a process
is the so-called yield or else recovery of the
substance which has beer. sprayed onto the carrier
material. The aim is, of course, to recover virtually
CA 02386027 2002-03-28
-20-
1000 of the substance which has been introduced with
the spray liquid on the carrier or in the fluidizing
chamber. It is true in this connection too that the
parameters (e.g. fluidization rate, amount of product
precharged, position of the spray nozzle, size and
geometries of the apparatus) must and can be selected
as suitable, and adapted by experiments, in accordance
with the known prior art of fluidized bed technology.
The drying must be carried out to a residual moisture
content which is so low that, depending on the chosen
storage conditions, no unwanted molecular changes are
observed in the polymers or that there is even a marked
loss of active ingredient. The residual moisture
content for the polymer matrix based on fibrin glue
components must be so low that the coagulation reaction
does not take place spontaneously. Suitable storage
conditions may be: cold storage at 4 to 83C or ambient
conditions (20 C). The granules may additionally be
enclosed in a protective atmosphere (e.g. nitrogen or
carbon dioxide) and, for example, with exclusion of
light. Possible residual moisture contents may then be,
for example, between 0.1-5% water content.
Homogeneous active ingredient-containing micropellets
of polymers are formed by fibrin glue components or
other biodegradable protein or else by biodegradable
polymers such as, for example, lactic acid/glycolic
acid polymers can, on the other hand, preferably also
be produced by direct spraying of a polymer/active
ingredient solution or suspension into an empty
installation. In this case, the granule nuclei or
finely divided particles are produced in situ in the
installation and can serve as starter nuclei for
further granulation. The installation to be used for
this purpose may be, for example, a spray tower or else
a fluidized bed installation with a sufficiently free
fl=ght path fcr the sprayed liquid droplets. If
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suitable process conditions are complied with, the
sprayed liquid droplets can be dried in accordance with
the conditions in a spray dryer (but with reduced
drying temperatures) in a fluidized bed installation
before they, for example, make. contact with the
container wall in the still moist state and remain
stuck there. These fine particles produced in this way
are kept in motion and suspension by the fluidizing gas
and thus come into contact with the spray mist of the
liquid which is subsequently sprayed in and then begin
to granulate. It is possible in this way, especially by
proceeding very cautiously when starting up the
process, to generate a defined granule growth in the
originally empty installation. This can be assisted for
example by adding known binders. Combination with a
classifying discharge of the granules (e.g. through a
zigzag classifier and classifying air stream) makes it
possible to produce granules with a defined particle
size in the installation and to operate the process
even in a continuous or quasi continuous manner. The
process described herein is essentially based on
European patent EP 85103501.4.
It is thus possible to achieve the following physical
product properties:
- Particle density: 250-2 000 g/ml, preferably 500-
1500 g/ml
- Particle sizes: 20-1 000 m, preferably 50-500 m or
30-350 m
- Particle size distribution: e.g. over- and undersize
+/- 50% of the average particle size, preferably
+/-25% of the average particle size
- Active ingredient content: 0.1-100%
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- Product properties: dust-free, round, cup-shaped
particle structure, ccrr.paratively high density, no
inert cores, no attrition.
The therapeutic active ingredients used can be assigned
to the following classes of active ingredients:
Human uses:
- antibiotics
- corticosteroids
- antimycotics
- neuroleptics
- antiepileptics
- steroid hormones
- anticancer hormones
- substances which promote wound healing
- cytostatics
- immunomodulators
- anesthetics, analgesics
- peptide hormones (replacement therapy)
- antirheumatics
- vaccines, antibodies
- monoclonal antibodies
- amino acid sequences (DNA, peptides, proteins)
=> gene therapy
- biological cells (gene therapy)
- biotechnologically produced growth factors, cells
(tissue growth factors)
Veterinary medicine:
- hormones
- antibiotics
- insecticides, anthelmintics
vaccines, antibodies
