U.S. patent application number 12/453460 was filed with the patent office on 2009-09-03 for shaped body and method for production of said body.
Invention is credited to Friedrich Fisseler, Rainer Rogasch, Marc Schmieding.
Application Number | 20090218731 12/453460 |
Document ID | / |
Family ID | 7925862 |
Filed Date | 2009-09-03 |
United States Patent
Application |
20090218731 |
Kind Code |
A1 |
Rogasch; Rainer ; et
al. |
September 3, 2009 |
Shaped body and method for production of said body
Abstract
Water-dispersible or water-soluble polymers, particularly those
of the family of compounds comprising the poloxamers or the
polyesters or amphiphilic agents (emulsifiers), and also lipophilic
materials are dispersed by melting the components at suitable
temperatures with admixture of pharmaceutically active substances
by mechanical procedures, i.e. a lipophilic disperse phase is
distributed in a hydrophilic continuous polymer phase to form a
stable dispersion. By controlled cooling, curing, and storage
followed by high-pressure molding at defined temperatures and
operating pressures there are produced, in addition to other types
of shaped bodies, dispersed polymeric fatty sticks distinguished by
particularly good fracture strength, flexibility, and variable
time-specific dimensional stability.
Inventors: |
Rogasch; Rainer; (Waldeck,
DE) ; Fisseler; Friedrich; (Vohl, DE) ;
Schmieding; Marc; (Korbach, DE) |
Correspondence
Address: |
CLARK & BRODY
1090 VERMONT AVENUE, NW, SUITE 250
WASHINGTON
DC
20005
US
|
Family ID: |
7925862 |
Appl. No.: |
12/453460 |
Filed: |
May 12, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11143609 |
Jun 3, 2005 |
7541047 |
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12453460 |
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10110431 |
Aug 26, 2002 |
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11143609 |
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Current U.S.
Class: |
264/319 |
Current CPC
Class: |
B29C 48/05 20190201;
B29C 48/0022 20190201; A61K 9/0014 20130101; A61K 9/02 20130101;
A61P 17/02 20180101; A61K 47/10 20130101 |
Class at
Publication: |
264/319 |
International
Class: |
B29C 47/36 20060101
B29C047/36 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 15, 1999 |
DE |
DE 19949897.0 |
Claims
1-17. (canceled)
18. Process for the production of a shaped body for medical
administration in body cavities and/or wound cavities in humans or
animals, wherein a) at least one hydrophilic continuous phase is
melted together with at least one lipophilic component as disperse
phase to form a melt, to which at least one active substance or
combination of active substances is added and the whole is
mechanically dispersed under constant temperature conditions to
produce a composition, b) said composition is poured into a
receptacle, where it is cooled and stored for a definable period of
time at a constant temperature and c) the composition thus obtained
is heated to a temperature which is not far below its softening
point, is rendered flowable by the application of pressure or shear
forces and is compressed to a predefined shaped body, during which
operation the operating pressure does not fall below 50 bar, and
the operating temperature is below the softening point of the
composition.
19. Process as defined in claim 18, wherein the active substance or
active substances or combination of active substances is added to a
low-molecular molten polymer, which premix is dispersed and added
to the melt.
20. Process as defined in claim 18, wherein the composition is
compressed at constant temperature and under a specific operating
pressure to form a dispersed solid shaped body.
21. Process as defined in claim 18, wherein the composition is
compressed in an extruder to form extrudates of from 2 to 19 mm and
is cut up into lengths of from 40 to 100 mm.
22. Process for the production of compressed shaped bodies having a
composition, as defined in claim 18, wherein d) beads derived from
a cooled melt of the composition are compressed into a compressed
shaped body, or e) spherules of the predefined shaped body are
formed, and are pulverized and compressed into the compressed
shaped body, or f) a cooled powder obtained form the predefined
shaped body is filled into capsules.
23. The method of claim 18, wherein at least one hydrophilic
continuous phase is a water-soluble or water-dispersible
polymer.
24. The method of claim 21, wherein the composition is compressed
in the extruder to form extrudates of from 2 to 10 mm in diameter.
Description
[0001] The invention relates to a shaped body for medicinal use in
body cavities and/or wound cavities in humans or animals according
to the generic clauses of claims 1, 4, 7, 9, and 10 and also to a
method of producing said shaped bodies according to the generic
clauses of claims 23 and 28 and to a method of using the same as
defined in claim 29 and claim 30.
[0002] Pharmaceutical or medical sticks (shaped bodies) are an old
pharmaceutical dosage form, usually obtained by casting and curing
suitable pharmaceutical auxiliary materials in appropriate casting
molds. A frequently used special form of medical sticks comprises
suppositories for anal or rectal administration, these usually
being produced on the basis of triglycerides. Since triglycerides
(fats) tend to become brittle, it is hardly possible to use these
materials for making sticks of lasting non-breakability having a
diameter of less than 4 mm and lengths of more than 20 mm.
[0003] In order to counteract this, it might be possibly to use
pure blends of plastics material and active agent and to extrude
them to produce sticks of any diameter. Such sticks would indeed
have adequate fracture strength and high elasticity and would thus
have the desired material characteristics, but they would suffer
from serious drawbacks with regard to their compatibility in
physiological compartments, since plastics materials are degradable
only to a small extent or not at all. If on the other hand the
carrier degrades too quickly, the desired compartment will not, in
most cases, be supplied with the necessary medicinal substance to
an adequate extent, which may spoil the wound healing effect.
[0004] These handicaps are counteracted in Patent Application EP-A
1,064,514 by adding polyethylene glycols acting as amphiphilic
agents. Despite the resulting increased elasticity of the shaped
body formed, it is not possible to dispersely stabilize large
concentrations, by weight, of lipids or fatty acids in the shaped
body and thus to vary the release rate of various polar
pharmaceutically active substances over a wide range.
[0005] It is an object of the present invention to avoid these and
other prior art drawbacks and to provide shaped bodies for medical
administration in body cavities and/or wound cavities in humans or
animals, which shaped bodies show high elasticity and a high
fracture strength and release the active substances or combinations
of active substances present therein at a constant rate over a
quite long period of time.
[0006] The main features of the invention are declared in the
characterizing clauses of claims 1, 4, 7, 9, and 10 and in the
characterizing clauses of claims 23 and 28, and in claims 29 and
30. Embodiments are the subject of claims 2 to 3, from 5 to 6, 8,
from 11 to 22, and from 24 to 27.
[0007] A shaped body for medical administration in body cavities
and/or wound cavities in humans or animals, comprising at least one
amphiphilic continuous phase, for example, a water-dispersible
polymer, and at least one lipophilic component as disperse phase
and also comprising at least one pharmaceutically effective
water-soluble or fat-soluble material, is characterized, as defined
in claim 1 according to the present invention, in that the
continuous phase is a biologically neutral oligomer, for example, a
copolymer, of a polyether. By this means the shaped body is
imparted with exceptionally high elasticity and fracture strength,
which is particularly important for its introduction into a body
cavity or wound cavity. This also ensures stabilization of
relatively high concentrations, by weight, of the lipophilic
disperse phase. The shaped body is capable of residing in the
desired compartment for many hours and of releasing its content of
(pharmaceutically) active substances (in retarded manner) to the
environment over a long period of time. The curative action is
exceptional good. The use of a biologically neutral oligopolyether
ensures that no undesirable reciprocal effects occur with the
environment.
[0008] According to claim 2, the continuous phase is an ether-like
block oligopolymer having at least two consecutively linked sets of
blocks of various alkoxyl groups, for example, a block copolymer.
This class of substances having the general empirical formula
R.sup.1O--{[(CHR.sup.3).sub.a--O].sub.k--[(CHR.sup.3).sub.b--O].sub.l--[-
(CHR.sup.3).sub.c--O].sub.m}n--OR.sup.2,
in which k, m.gtoreq.50 and L.gtoreq.20 and also a, b, and c=1 to
6, where a, c.noteq.b and in which R.sup.1, R.sup.2.dbd.H, alkyl,
aryl and R.sup.3.dbd.H, methyl, and having the polaxamer-typical
formula
HO--(CH.sub.2--CH.sub.2--O).sub.a--(CH.sub.3--CH--CH.sub.2--O).sub.b--(C-
H.sub.2--CH.sub.2--O).sub.a--H,
in which a=2 to 130 and b=15 to 67, is distinguished by the fact
that lipophilic contents such as beeswax or triglycerides can be
mixed therewith in high concentrations of up to 52 wt % to give
homogeneous dispersions without the shaped body losing the
elasticity or fracture strength necessary for its introduction into
the cavity, which is of particular significance for the present
invention. The block copolymer can, as defined in claim 3, be a
poloxamer, for example, poloxamer 124, poloxamer 188, poloxamer
237, poloxamer 338, or poloxamer 407.
[0009] In the embodiment defined in claim 4, for which independent
protection is claimed, the invention provides that the continuous
phase is a biologically neutral polyester. The latter, depending on
its structure, is more or less readily hydrolytically cleavable,
which also applies to polyanhydrides and polyamide ester to various
extents. It is preferred to use biodegradable copolymeric or
oligopolymeric structures, and use may also be made of block
copolymers and block oligopolymeric forms. These molecules are on
account of their heterogeneous periodic structure particularly
suitable for the production of shaped bodies containing active
substance, since specific selection of these polymers can precisely
adjust the rate of degradation thereof and thus that of the shaped
body in the tissue compartment. In this way it is easy to achieve
uniform release of active substance into the organism over a
specific period of time. Another advantage consists in that the
monomers forming in the tissue compartment as a result of
degradation can be metabolized by the body.
[0010] According to claim 5, the continuous phase is a
thermoplastic polyester, for example, a polyortho ester, a
polylactic acid in the D, L or D/L form, a polyglycolide, a
poly(.epsilon.-caprolactone), a polydioxanone, a polytrimethylene
carbonate, a polyhydroxybutyrate, or a polyhydroxyvalerate. Claim 6
provides, on the other hand, the use of an oligopolymer or a block
oligopolymer composed of at least two different monomers, for
example, a copolymer or a block copolymer.
[0011] In another independent embodiment of the invention as
defined in claim 7, the continuous phase comprises at least one
biologically neutral, non-ionic or neutrally charged emulsifier.
Here again, there are obtained shaped bodies which despite large
lipophilic contents have a high degree of elasticity and fracture
strength. Biologically acceptable, neutrally charged or non-ionic
emulsifiers, i.e. detergents, such as CHAPS, Tween.RTM., or
Span.RTM. can be used in the continuous phase as amphiphilic
components, which is particularly advantageous when the shaped body
is not an oral administration form. They form association colloids
in which otherwise very difficultly stabilizable pharmaceutically
active species can be very easily introduced.
[0012] It is expedient to use emulsifiers having a high CMC, e.g.,
octyl glucoside or dodecyl maltoside, since such surfactants avoid
excessive foam formation and, in particular, avoid cell lysis at
the site of action. According to claim 8, the CMC should be, say,
greater than 6.
[0013] If very long residence times of the shaped body in the
desired compartment are required or if the pharmaceutically active
substance is required to be released extremely slowly from the
shaped body, the continuous phase comprises, according to the
invention as defined in the independent claim 9, a biologically
neutral polyanhydride, polyester amide, or polyamide or comprises
an oligopolymer or copolymer containing oligomeric or polymeric
D-amino acid regions. The decisive factor here is the use of
chemically and mechanically more stable amphiphilic polymers in the
formulation. Particularly suitable are polyamides or polypeptides
and polyester amides comprising D-amino acids. Oligopolymeric or
block oligopolymeric structures of the aforementioned molecule
families are likewise admirably suitable, but in such cases the
amide-binding portion must be increased.
[0014] In the case of the preparation of shaped bodies in the form
of tablets or sticks, claim 10 provides that the continuous phase
is a macrogol (homopolyether), for example, PEG 1000, PEG 1500, PEG
2000, or PEG 4000, which in one embodiment is associated with
low-molecular macrogols, for example, PEG 400 or PEG 200. This
makes it possible to achieve very homogeneous distribution of the
pharmaceutically active substance during dispersion, and it has
been found to be particularly practical to dissolve the
pharmaceutically active substance in low-molecular macrogols before
adding it to the dispersion.
[0015] In an advantageous development of the invention, as defined
in claim 11, the continuous phase is composed of copolymers of said
polymer types or emulsifier/polymer mixtures. This is particularly
useful when, on the one hand, an active species is required to be
introduced into the shaped body in a finely dispersed form in the
interior of micelles only and, on the other hand, a slow release
thereof to the environment is required. Furthermore, numerous other
possible variations are feasible, particularly regarding the
residence times of the shaped body in the cavity and also with
reference to the release of the active substances or combinations
of active substances to the environment.
[0016] The feature defined in claim 12 also serves this end, in
which the proportion of lipophilic component is between 25 and 50
wt % and preferably between 40 and 50 wt %, and the proportion of
the continuous phase is from 40 to 70 wt % and preferably between
48 and 52 wt %. Thus the proportion of lipophilic phase, which
usually contains the pharmaceutically active substances, is
relatively large compared with the continuous phase. Wound healing
is optimally assisted by the retarded release of active substance.
Nevertheless the shaped body possesses adequate dimensional
stability, for which reason it does not break when introduced into
the cavity.
[0017] In the embodiment defined in claim 13, the lipophilic
component used is a wax, particularly an ester of a long-chain
fatty acid with a long-chain fatty alcohol, for example, officinal
beeswax EuAB 98 or bleached beeswax EuAB 98, or the lipophilic
component used is a fatty alcohol or a mixture of fatty alcohols,
for example, stearyl alcohol or cetyl/stearyl alcohol.
[0018] According to claim 14 the lipophilic component can be a
triglyceride mixture, for example, a high-melting suppository
composition having a melting point above 40.degree. C.
Alternatively, as defined in claim 15, the lipophilic component
used is a long-chain hydrocarbon mixture, for example, a
higher-melting paraffin composition having a melting point above
40.degree. C. Also suitable are ozocerites (hard paraffins) or
mixtures of pharmaceutically useful fatty alcohols (cetyl/stearyl
alcohols) as the retarding disperse matrix, which serve for delayed
release of the active substances added to the shaped body at the
site of action. In order to fix very non-polar active substances,
use is made of mixtures of long-chain hydrocarbons, to great
advantage.
[0019] The group of possible active substances and/or combinations
of active substances, for example, pharmaceutical materials having
anti-infective, antimicrobial, fungistatic or fungicidal,
virustatic or virucidal action alone or together with steroidal
antiphlogistics, local anesthetic agents, or anesthetic agents,
from which a selection may be made, is disclosed in claims 16 to
20. The concentration of active substances or combination of active
substances should not exceed 10 wt %. The active substance present
can be an antibiotic agent, e.g., benzyl penicillin procaine or
gentamicin, an antiseptic agent, an antimycotic agent, and/or a
virustatic agent, e.g., Aciclovir.RTM.. Alternatively, use can be
made of a glucocorticoid, e.g., a hydrocortisol, its esters, a
betamethason, its esters or a triamcinolone acctonide. A
particularly good curative action is achieved when PVP iodine is
incorporated as an active substance. Depending on the field of
application, use may also be made of metronidazol. In addition,
higher doses are conceivable in individual cases.
[0020] The geometry of the shaped bodies of the invention can,
according to claim 21, be characterized in that the stick has a
cylindrical conical or barrel-like shape. For example, the shaped
body can have a cylindrical corpus of from 2 to 10 mm in diameter
and from 40 to 100 mm in length in order to be suitable for
administration in wound cavities and body cavities in humans and
animals. Furthermore the shaped body as defined in claim 22 can
have the shape of a suppository or torpedo or be in the form of a
tablet. Another possibility is the production thereof in
suppository form (suppository or torpedo form or the like) or
vaginal globulin form (vaginal tablets). Other shapes are
realizable, depending alone on their end use.
[0021] The patent also relates to a process for the production of
the shaped bodies of the invention according to the independent
claim 23. This is characterized in that at least one hydrophilic
continuous phase, for example, a water-soluble or water-dispersible
polymer (e.g., polyethers or polyesters of various molecular
weights and compositions or emulsifiers of various molecular
weights), is melted with at least one lipophilic component (e.g.,
waxes, triglycerides, or the like) acting as disperse phase, to
form a melt, to which at least one active substance or a
combination of active substances is added and the whole is
mechanically dispersed under constant temperature conditions to
form a composition. This is poured into a receptacle, vessel or the
like, where it is cooled and stored for a specific period of time
at constant temperature. The composition thus obtained is then
heated to just below its softening point, plasticized by pressure
or shearing, and compressed to a predefined shaped body, during
which operation the operating pressure is not less than 50 bar,
i.e. is for example at least 100 bar and the operating temperature
is below the softening point of the composition.
[0022] According to claim 24 there is added to a molten,
low-molecular polymer the active substance or active substances or
a combination of active substances, to which end this premix is
dispersed and added to the melt, this having a favorable effect on
the overall procedure.
[0023] It is important that the composition is cooled at a constant
temperature gradient of at least 5.degree. C./h, as defined in
claim 25. This prevents flocculation or crystallization of the
individual components, which would make the shaped body
brittle.
[0024] Expediently, the composition as defined in claim 26 is
compressed at a constant temperature and under a specific operating
pressure to form dispersed solid shaped bodies, for which purpose
preferably an extruder is used, by means of which the composition
is compressed, as defined in claim 27, to produce extrudates of
from 2 to 10 mm in diameter, which are then cut into lengths of
from 40 to 100 mm.
[0025] The cylindrical shaped bodies produced by the process of the
invention (sticks, styli medicinalis) have, compared with those
produced by simple melting and subsequent pouring into casting
molds, exceptionally high elasticity and fracture strength.
[0026] A significant development of the invention is defined in
claim 28, for which independent protection is claimed. According to
said claim, a process for the production of compressed shaped
bodies having a high content of low-melting hydrophobic components,
or a process for the production of flowable or pourable
pelletizable mixtures exhibiting a high content of low-melting
hydrophobic components, is characterized in that small beads of a
cooled melt are compressed, small spherules are pulverized and
compressed, or a cooled powder is filled into capsules.
[0027] A pharmaceutical preparation is characterized, as defined in
claim 29, by a solid dispersed fat in a polymer dispersion or a fat
in a detergent dispersion.
[0028] Yet another object of the present invention is, finally, the
use of dispersed solid shaped bodies containing active substances
as pharmaceuticals in the teats of agricultural working animals,
for example, milk-producing cows.
[0029] Other features, details, and advantages of the invention may
be gathered from the wording of the claims and from the following
description of working examples.
[0030] A shaped body of the invention possesses an amphiphilic
continuous phase, for example, a biologically neutral oligomer of a
polyether, a lipophilic component as the dispers phase, for
example, an officinal beeswax EuAB 98 or bleached beeswax EuAB 98,
and a water-soluble or fat-soluble active substance such as PVP
iodine. The continuous phase and the lipophilic disperse phase
dispersed therein form a dispersed "fat-in-polymer system", which
can release the medically active substances dissolved therein to
the environment at a retarded rate.
[0031] The shaped bodies are preferably sticks having diameters of
from 2 to 19 mm, preferably from 2 to 10 mm, and lengths of from 40
to 100 mm, these sticks being characterized by high elasticity and
bending strength by reason of their novel composition. They are
used as pharmaceuticals for the treatment of diseases and injuries.
In particular, they can be readily introduced into wound cavities,
where the dissolved active substances are released.
[0032] The rate at which the active substance is released depends
on the amount of lipophilic phase in the shaped body. It decreases
as the amount of usable lipophilic phase increases. Heteropolymers
and block heteropolymers (eg, copolymers) in a concentration of up
to 70 wt % (advantageously from 48 to 52 wt %) as the continuous
phase allow the introduction of lipophilic disperse phase in
concentrations of up to 50 wt %. Under specific conditions, still
higher percentages of the lipophilic phase are suitable to be used.
Important representatives of these heteropolymeric alkoxamers are
the polyethers poloxamer 124, poloxamer 188, poloxamer 237,
poloxamer 338, and poloxamer 407. It is generally also possible to
use ether-like polymers having a molecular weight of from 300 g/mol
to 30,000 g/mol for the formulation.
[0033] Moreover, the release rate of the active substance is
governed by the dwell time of the shaped body and the decomposition
thereof in the destinated compartment, i.e. by the polymer selected
for the continuous phase and its mechanical and chemical stability.
Polymers which are labile in a physiological environment are
degraded either by surface erosion or by hydrolytic cleavage over a
period of time dependent on the polymer composition to form
monomers which can be metabolized by the organism. The use of
hydrolytically cleavable polymers allows for the control of the
release rate of the pharmaceutically active substance to be
governed not only by the dwell time of the shaped body in the
organism or by the concentration of the disperse phase, but also by
the stability of the shaped body. Degradable biologically
acceptable polyesters, polyanhydrides, or polycarbonates in
multifarious forms, as, for example, the combination of D-lactides
and L-lactides, offer manifold possibilities of controlling the
release kinetics of active species. Furthermore the biodegradable
polyesters poly(dioxanone-co-.epsilon.-caprolactone),
poly(lactide-co-glycolide), poly(glycolide-co-trimethylene
carbonate), poly(hydroxybutyrate-co-hydroxyvalerate),
poly(trimethylene carbonate-co-.epsilon.-caprolactone),
poly(D/L-lactide-co-.epsilon.-caprolactone), and
poly(glycolide-co-.epsilon.-caprolactone), or the terpolymer
poly(glycolide-co-trimethylene carbonate-co-p-dioxanone) are, for
example, very suitable for this field of activity.
[0034] If a very slow release of the pharmaceutical is desired
and/or if it is desired that only very slow or no degradation of
the shaped body takes place in the organism due to fusion or
decomposition, the concentration of the disperse phase must be very
high and the polymer used should be relatively resistant to
hydrolysis. In addition to polyethers, use is preferably made of
polyamides and polymeric structures in which D-amino acid regions
linked by peptide bonds are present.
[0035] If it is desired to make a shaped body from aggregating
active substances or poorly solubilizable and emulsifiable
pharmaceutical substances, in finely divided form, it is convenient
to use, as the continuous phase, neutrally charged or non-ionic,
biologically harmless detergents. It is advantageous to select
representatives having a CMC greater than 6, as otherwise excessive
foaming in the tissue compartment and lysis of cells may occur. For
example, N-octylglucoside, dodecyl maltoside, or CHAPS may be
used.
[0036] Especially when producing tablets and sticks, it is
particularly advantageous to use polyethylene glycols. If PEG 1000,
PEG 1500, PEG 2000, and PEG 4000 and furthermore PEG 200 or PEG 400
are used to form the continuous phase, the resulting dispersions
can, after maturing, be processed, not only directly to compression
moldings but also to small spherules or a powder. The powder can be
placed in capsules or compressed to tablets. The beads can also be
used to form a tablet having, however, a different type of fine
distribution. PEG 200 and PEG 400, moreover, have the advantage
that they can be used as low-molecular polyethylene glycols for
wetting or dissolving the active species. This is carried out,
where necessary, prior to the actual dispersing process.
[0037] The medical action of the shaped body of the invention may
be described as follows:
[0038] Topical administration (for example, for wound disinfection,
care of bite wounds, administration in the teats of milk-providing
working animals and the like) of anti-infective agents,
chemotherapeutants, antimicrobial, fungicidal, or virucidal
pharmaceutically active substances by way of the shaped body,
achieves a bacteriostatic or bacteriocidal, virucidal or fungicidal
action at or in the desired compartment, i.e. the body cavity or
wound cavity, which action is characterized by a high, uniform
local concentration of active substance over a defined period of
time (retarded liberation of active substance) and at the same time
low systemic absorption of active substances.
[0039] The addition of steroidal antiphlogistic active substances
(antiphlogistics) has a decongesting and anti-adhesive action. The
addition of suitable analgesics or local anesthetics relieves wound
pain.
[0040] The shaped body retarded, inter alia, by the lipophilic
disperse phase remains at the site of action for hours and thus
keeps the lumen of the compartment concerned open, which is of
considerable advantage particularly when administering to teats.
Adhesion of the tissue concerned is reliably avoided. There is a
reduction of the secondary swelling occurring with an injury. The
water-soluble or water-dispersible polymers used in the shaped body
(predominantly polyethers and polyesters, alternatively emulsifiers
and polyamides) are also secretion-absorbing and thus unfold an
adjuvant antimicrobial action. In addition, they assist
proliferation and thus accelerate wound healing.
Possible compositions of the shaped body are as follows:
(BW=beeswax; HC=cortisol):
TABLE-US-00001 Example 1: PVP iodine 5.0 g HC 1.0 g poloxamer 188
79.0 g BW 5.0 g ethyl alcohol 96% 10.0 g Example 2: PVP iodine 5.0
g HC 1.0 g poloxamer 407 79.0 g BW 5.0 g propylene glycol 10.0 g
Example 3: PVP iodine 5.0 g HC 1.0 g macrogol 1500 89.0 g BW 5.0 g
Example 4: PVP iodine 5.0 g HC 1.0 g poloxamer 188 46.0 g Witepsol
40 40.0 g ethyl alcohol 96% 10.0 g Example 5: PVP iodine 5.0 g HC
1.0 g poloxamer 188 79.0 g BW 5.0 g macrogol 400 10.0 g Example 6:
PVP iodine 5.0 g HC 1.0 g poloxamer 188 77.5 g BW 7.5 g macrogol
400 10.0 g Example 7: PVP iodine 5.0 g HC 1.0 g poloxamer 407 79.0
g BW 5.0 g macrogol 400 10.0 g Example 8: PVP iodine 5.0 g HC 1.0 g
poloxamer 407 77.5 g BW 7.5 g macrogol 400 10.0 g Example 9: PVP
iodine 5.0 g HC 1.0 g poloxamer 407 46.0 g Witepsol 40 40.0 g ethyl
alcohol 96% 10.0 g
[0041] The individual steps of the manufacturing process of the
invention can be described as follows:
1. The selected water-soluble or water-dispersible polymers or
surfactants are melted together with the lipophilic component (eg,
official beeswaxes, fatty alcohols, triglycerides), the processing
temperature being governed by the melting points of the components
used. 2. The pharmaceutically active substance(s) can be optionally
dissolved or dispersed in a low-molecular macrogol (eg, PEG
200/400) or in alcohols conventionally used for pharmaceutical
purposes, and then added to the melt or directly dispersed in the
melt.
[0042] The pharmaceutically active substances used can be any of
the pharmaceutically active substances which are suitable for
administration in body cavities or wound cavities. Preference is
given to the following groups of active agents: antibiotics,
antiseptics, antimycotics, virustatics (anti-infective agents,
chemotherapeutants), antiphlogistics, particularly glucocorticoids
and anesthetic agents or local anesthetics, which can be added
individually or in combination with each other in amounts or
concentrations known to the person skilled in the art.
[0043] Particularly preferred antibiotics are penicillins,
particularly benzyl penicillin procaine and gentamycin and their
chemical derivatives, the preferred antiseptic agent being PVP
iodine. The preferred glucocorticoids employed are hydrocortisol
and its esters, betamethason and its esters, dexamethason and its
esters, and triamcinolone (triamcinolone acctonide) and its esters.
The preferred anti-infectious and antiprotozoal agent used is
metronidazol, and the preferred virustatic agent used is
Aciclovir.RTM..
3. The mixtures of 1. and 2. are, if necessary, combined and
mechanically dispersed, during which process the temperature should
not fall below the melting temperature of the polymers used. 4. The
dispersion melt is poured into a temperature-controlled vessel
(e.g., a cylinder) and cooled to 15.degree. C. under time control
and then left to mature or cure for at least 4 hours at 15.degree.
C. 5. Following this period of cool storage, the dispersed solid
composition thus obtained and containing active substance, is
hydraulically extruded (extended) by means of a
temperature-controlled high-pressure extruder at operating
temperatures which must be from ca 5.degree. to 10.degree. C. below
the softening point of the mixture used, to form shaped bodies via
various nozzles or attached molds, the operating pressure being 100
bar.
[0044] In one embodiment, the manufacturing process is modified for
the production of tablets and capsules. To this end, the
pressure-loaded dispersion is converted by compression molding at a
temperature below its softening point through a breaker plate to
form small spherules. These are sifted and then compressed to
tablets or ground to a powder with cooling. The latter is
compressed to tablets or filled into capsules
[0045] By combining physiologically acceptable polymers or
emulsifiers with various conventional pharmaceutically acceptable
fats, waxes, and fatty alcohols in a dispersed solid system, the
drawbacks of the prior art, particularly the limits imposed by use
of only polymers or fats or waxes may be overcome. Hitherto
possible maximum concentrations of the lipophilic component are
pushed up to higher values by the use of copolymers and block
copolymers or their oligomeric variants, and this considerably
influences the release rate of the active species. The solid
fat-in-polymer dispersions or polymer-in-fat dispersions of the
invention exhibit the material characteristics necessary for
handling and administration and are at the same time a retarded
pharmaceutical dosage form for administration in wound cavities and
body cavities. The sticks show good physiological compatibly and
degradability.
[0046] The process steps of the invention and their order of
execution guarantee high and stable dispersity of the medical
sticks, i.e. the degree of interdispersion of the materials and the
interfacial affinity of the materials used toward each other is
exceptionally high compared with conventional shaped bodies. The
medical sticks form a homogeneous solid dispersion exhibiting all
of the required properties.
[0047] The invention is not restricted to any of the embodiments
described above but can be modified in diverse ways. For example,
instead of a fat-in-polymer system, use may be made of a reverse
system, ie a polymer-in-fat system. Furthermore non-lamellar phases
and inverted systems comprising lipids, surfactants, or
phospholipids can be used.
[0048] It is seen that water-soluble or water-dispersible polymers,
particularly those of the family of compounds comprising the
polyethers, polyesters, polyamides and/or detergents, and also
lipophilic materials can readily form a dispersion by melting the
components at suitable temperatures and admixing pharmaceutically
active substances by mechanical procedures, i.e. a lipophilic
disperse phase is distributed in a hydrophilic polymer phase as the
continuous phase, to form a stable dispersion. By controlled
cooling, curing, and storage followed by high-pressure molding or
worm extrusion at defined temperatures and operating pressures, it
is possible to produce, in addition to other types of shaped
bodies, dispersed polymeric fatty sticks distinguished by
particularly good fracture strength and flexibility. When used for
medicinal purposes, such sticks have the advantage that the
polymers and hydrophobic materials used for production (waxes,
fatty alcohols, triglycerides etc.) are physiologically and
toxicologically acceptable and any desired pharmaceutically active
substances are suitable to be incorporated.
[0049] The combination of water-dispersible polymers with
hydrophobic substances has the great advantage of delayed
degradation of the dimensionally stable sticks in the desired
physiological compartment, due to the lipophilic disperse matrix,
which can only be slowly dissolved by endogenic liquids and
secretions. This is accompanied by delayed but uniform release of
active substance in the desired compartment, which ensures that
there is an adequate therapeutic active level of pharmaceutically
active substances over prolonged periods of time. Furthermore the
slowly degrading stick corpus (shaped body) can maintain an injured
body lumen, which is thus protected from undesirable adhesion.
[0050] All of the features and advantages, including structural
details, spatial arrangements, and process steps, disclosed in the
claims and description can be essential to the invention both
independently and in a great variety of combinations.
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