Note: Descriptions are shown in the official language in which they were submitted.
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a
Pharmaceutical form for delivery of active substances to
wounds
D E S C R I P T I O N
In the treatment of wounds it is necessary for active
substances which are intended or need to come into direct
contact with the surface of the wound or the floor of the
wound to be administered by means of pharmaceutical forms
which, by reason of their consistency, can be applied
without gaps even to very uneven surfaces. This normally
takes place,with the aid of solutions, powders, dusting
powders, sprays, semisolid preparations such as ointments,
creams and gels. The disadvantages of these pharmaceutical
forms become clear in particular when it is necessary to
give doses of highly active substances in a small amount
accurately and reproducibly, or when controlled release from
the pharmaceutical form is desirable for the therapy to
maintain a uniform concentration of active substance in the
wound throughout a particular period.
Wound dressings which, by reason of their composition and
their structure, are loaded with active substances and
release the latter in a delayed or controlled manner are
described, for example, in US 5,098,417, in EP 49 177 or in
DE-B 11 90 608. These wound dressings have the disadvantage
that, especially in the case of deep wounds, they do not
come into contact with the floor of the wound. The ability
of such wound dressings to function is moreover greatly
dependent on the interaction with wound fluid since release
can take place only by diffusion of the active substance at
the interface between wound dressing and wound fluid or by
erosion of the active substance from the wound dressing
after uptake of fluid and swelling of the carrier material.
Since the fluid conditions in wounds vary greatly between
individuals and depending on the type.of wound and phase of
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wound healing, it is not possible to achieve comparable and
reproducible kinetics of release with such wound dressings
in vivo.
The present object is based on the object of indicating a
pharmaceutical form which, on the one hand, permits an
accurate and reproducible dose of active substance to be
given and the release of active substance to be controlled
reliably and which, on the other hand, corresponding to the
traditional pharmaceutical forms mentioned at the outset,
can be adapted to uneven wound surfaces even with deep
wounds and can be brought into contact therewith. It has
surprisingly been found that this is achieved by a
deformable, sheet-like pharmaceutical form which delivers
active substance, is coherent and is designed to be in its
sheet-like extent equal to or smaller than the wound area to
be managed and which contains the active substance in
defined amounts in homogeneously dispersed form.
Further embodiments of the pharmaceutical form are provided
in accordance with the features of the dependent claims.
Conventional deformable pharmaceutical forms which deliver
active substance and which, after application into the
wound, form sheet-like structures such as, for example,
gels, ointments, creams or else liquid multicomponent
systems which, after mixing in the wound, react together
with solidification, belong, according to the specialist
terminology, to the so-called multiple dose pharmaceutical
forms. This means that the amount of the pharmaceutical form
present in one container is intended for a plurality of uses
with appropriate dosing procedures. The dosage itself is
performed by the individual user. The user is able to make
statements about the amount of active substance in the dose
only if he weighs the particular dose before use. On
repeated use, reproducible application of a constant amount
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of active substance would be possible only with the aid of a
weighing procedure beforehand. This individually variable
dosage is possible only because of the low coherence and
easy divisibility of these pharmaceutical forms. On the
other hand, the low coherence has the advantage that the
pharmaceutical form can be, as mentioned, deformed as
required and can be adapted to uneven surfaces.
By contrast, the pharmaceutical form according to the
invention is a single dose pharmaceutical form which,
similar to tablets or capsules, is coherent and preshaped
and contains a defined dose of active substance for one use
in homogeneously dispersed form. This has the advantage that
a predetermined amount of active substance can be
administered as often as required and reproducibly.
Coherence means in this connection a firmness and an
internal cohesion of the pharmaceutical form which, in
contrast to the conventional pharmaceutical forms described,
permits manipulation by the user such that the preset amount
of pharmaceutical form and thus the given amount of active
substance is not automatically determined, altered or
influenced by the manipulation itself.
The pharmaceutical form according to the invention differs
from other single dose pharmaceutical forms, such as, for
example, tablets or capsules, in that although, on the one
hand, it has the coherence necessary for manipulation, on
the other hand it is flexible and deformable so that it can,
after introduction into the wound, be adapted to the
irregularities of the floor of the wound and can be brought
into contact with the latter. The precondition for this is
that the sheet-like extent of the pharmaceutical form is
less than or not more than equal to the wound area to be
managed. Similar to the solid pharmaceutical forms
mentioned, the homogeneity of dispersion of the active
substance is achieved by initially preparing a complete
composition of the ancillary components in which the active
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substance is homogeneously dispersed. Normally, during the
course of the process of making the pharmaceutical form, a
plurality of divided pharmaceutical forms of the same shape
and same weight, all of which accordingly have the same
content of active substance, is produced from such a
composition. Typically, a consolidation which confers
coherence on the divided individual pharmaceutical form
takes place during the making of the pharmaceutical form by
physical means, for example exertion of pressure, or
chemical reactions.
To produce a pharmaceutical form according to the invention,
first a low-viscosity, free-flowing composition is prepared,
for example a solution, a dispersion or a melt, which
contains active substance in homogeneously dispersed form.
This composition is then coated onto a flat substrate by
processes known to the skilled person. In contrast to the
solid pharmaceutical forms mentioned, in the production of a
pharmaceutical form according to the invention the
consolidation procedure which confers the coherence on the
individual divided pharmaceutical form takes place not
during the procedure of making and dividing the
pharmaceutical forms but beforehand. The consolidation takes
place after the coating onto a flat substrate by removing
the dissolving or dispersing medium by drying or by cooling
if a melt has been used for coating. The buildup of cohesive
forces which takes place during this depends in nature and
strength on the composition of the ancillary substances. The
result is a wide, sheet-like continuous belt with a
thickness which is predetermined by the coating. The
limiting factor for the thickness of the band is, for a
given formulation, the requirement for flexibility and
deformability of the individual divided.pharmaceutical form
for adaptation to the floor of the wound after introduction
into a wound. Individual pharmaceutical forms with a
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predetermined area are divided out of the endless belt by
known processes, such as, for example, punching and cutting.
Since the coating is carried out with a composition which
contains active substance in homogeneously dispersed form
and maintenance of a constant coating weight, all the
individually divided pharmaceutical forms contain the same
amount of active substance in homogeneous dispersion. This
makes accurate and reproducible dosage by the user possible.
Since the content of active substance per unit area and area
itself can be varied continuously over a wide range by the
production process, the pharmaceutical form according to the
invention provides the possibility of accurate and reliable
dosage of even very small amounts of active substance.
Furthermore, the user is able to dose the active substance
based on the particular problem and the therapeutic
requirements. Thus, the user is able, for example, to
introduce a plurality of pharmaceutical forms simultaneously
into the wound and apply them side by side to the floor of
the wound. However, the user is also able to divide off
small pieces from a pharmaceutical form of given area if,
for example, the wound area to be treated is smaller than
the extent in terms of area of the pharmaceutical form, or
if the dose of active substance in the pharmaceutical form
given by the area is too high for a specific treatment.
Thus, the pharmaceutical form according to the invention
can, for example, be provided to the user in conjunction
with an inert sheet-like substrate from which the
pharmaceutical form can easily be detached, such as, for
example, a siliconized sheet, the latter possibly having
divisions on the cm scale. Since the surface loading of the
pharmaceutical form with active substance is known, the user
is able to cut the area, and thus the amount of active
substance which he regards as necessary from the therapeutic
viewpoint, out of or off from the pharmaceutical form which
is in the form of a sheet or rolled-up strip.
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In each case the result is that the sheet-like extent of the
pharmaceutical form is less than or not more than equal to
the wound area to be managed. This makes application to the
floor of the wound possible and ensures that the amount of
active substance administered is released in the wound. On
application overlapping the edges of the wound, only the
part of the pharmaceutical form extending into the wound
would release active substance, which would cancel out the
advantage of accurate dosage.
Active substances which are used in the pharmaceutical forms
according to the invention in wounds are preferably
haemostatic active substances, wound-cleansing active
substances such as, for example, enzymes, antiseptics,
disinfectants and antibiotics, and active substances which
promote wound healing and which stimulate granulation,
induce neoangiogenesis or promote epithelization.
Increasingly important active substances which promote wound
healing are biologically active peptides and proteins which
even in very low concentration display high activities and
most of which are produced by recombinant technologies. The
pharmaceutical form according to the invention represents a
particularly suitable carrier and delivery system for these
substances, which include so-called growth factors such as
platelet derived growth factor (PDGF), epidermal growth
factor (EDF), platelet derived endothelial cell growth
factor (PD-ECGF), acidic fibroblast growth factor (aFGF),
basic fibroblast growth factor (bFGF), transforming growth
factor a(TGFa) , transforming growth factor P (TGFP),
keratinocyte growth factor (KGF), insulin-like growth
factors 1 and 2(IGF1 IGF2) and tumour necrosis factor
(TNF).
Another advantage of the pharmaceutical form according to
the invention is that controlled release of active substance
therefrom is possible. Since the pharmaceutical form always
comes into contact with wound or tissue fluid after
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application, the interaction with fluid has a crucial effect
on the release of active substance, which can in turn be
utilized to control the release. Thus, the formula of the
pharmaceutical form according to the invention can, in order
to achieve relatively rapid release of active substance, be
designed so that the pharmaceutical form is soluble or able
to disintegrate in wound fluid. The kinetics of release_of
active substance depend in this case on the rate of
dissolution or disintegration of the pharmaceutical form.
After the application time has elapsed, the dissolved or
disintegrated pharmaceutical form must, similar to ointments
or creams, be washed out of the wound, unless the formula is
designed so that the pharmaceutical form can be completely
broken down and absorbed in wound fluid as far as the
molecular range of the individual components. Release of
active substance can be delayed and prolonged by choosing
the composition so that the pharmaceutical form merely
swells on uptake of wound fluid. The wound fluid in
particular dissolves the active substance out of the
pharmaceutical form, which leads to slow erosion of the
latter. In this case, the release of active substance
depends on the swelling capacity and the rate of erosion of
the pharmaceutical form.
Release of active substance is delayed and prolonged even
further by choosing the composition of the pharmaceutical
forms so that it is inert to wound fluid and does not
interact therewith. The kinetics of release of active
substance then depend only on the rate of diffusion of
active substance within the pharmaceutical form and at the
interface between pharmaceutical form and floor of the wound
or wound fluid.
In the cases mentioned, in which the pharmaceutical form is
not soluble or able to disintegrate, the user has the
advantage that he can remove it completely from the wound at
any time without washing out or similar manipulations.
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In another preferred embodiment, the pharmaceutical form
according to the invention has a multilayer structure. Thus,
for example, a layer which is soluble or able to
disintegrate in wound fluid and which serves for rapid
release of active substance for the minimum necessary
concentration of active substance to be reached as quickly
as possible can be combined in laminate form with a
swellable or an inert layer which serves for slow and
uniform release of active substance to maintain the
necessary concentration of active substance over a lengthy
period. Multilayer pharmaceutical forms of this type can
also be used if, for example, the release of different
active substances is to take place at different times or
with different rates of release.
In a preferred embodiment of a multilayer pharmaceutical
form, this comprises a barrier and/or control element which
contains no active substance such as, for example, a
flexible sheet of polyurethane, polyester or polypropylene.
The intention of such a barrier or control element is to
direct delivery of active substance in a particular
direction. If, for example, a deformable layer which
delivers active substance is applied to the floor of the
wound, a barrier layer laminated thereon is able to prevent,
for example in a wound with heavy exudation, active
substance being delivered to the surrounding wound fluid,
which might possibly lead to an undesirably great dilution
effect. A pharmaceutical form according to the invention
with barrier element proves to be particularly advantageous,
for example, when bacterial colonies located in mixtures in
the floor of the wound in cases of infection are to be
controlled rapidly and in high concentration with
antiseptics or antibiotics.
In another preferred embodiment of the pharmaceutical form
according to the invention for wound treatment, the latter
is porous, for example foam- or sponge-like. The size of the
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pores and the structure of the pharmaceutical form is
designed so that cells such as, for example, fibroblasts are
able to migrate into it and, at the same time, a structural
orientation is given to the cells, which is attributable in
particular to the degree of order, which is preferably
similar to natural connective tissue, of the sponge
structure in the pharmaceutical form. Ingrowth of cells may,
for example, be necessary for breakdown of the preparation
or for the delivery or deposit of substances which, for
example, are needed for new tissue formation or for
vascularization of a tissue which is to replace the
pharmaceutical form according to the invention after
breakdown thereof. The preconditions for porosity of the
pharmaceutical form would in this case be produced during
production by, for example, introducing air into the
composition which is to be coated and which has a
homogeneous dispersion of active substance, or by holes or
pores being left in the coated web by the evaporating
solvent or dispersing medium due to external drying
conditions after coating from the solution or dispersion.
The selection of materials and ancillary substances for
producing the pharmaceutical form according to the invention
is primarily determined by the requirement of its coherence,
flexibility and deformability and by requirements for the
required kinetics of release of active substance. Another
restricting factor is that the range of materials and
ancillary substances which can be used is reduced to those
which display excellent tolerability on contact with wound
tissue. The pharmaceutical form produced from a combination
of materials and ancillary substances ought, after
application into the wound, not impede the function and
activity of cells such as, for example, keratinocytes,
fibroblasts or endothelial cells.
The minimum necessary for producing a pharmaceutical form
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according to the invention are ancillary substances from the
group of polymers and ancillary substances from the group of
plasticizers. Polymers ensure the internal cohesion and the
coherence of the pharmaceutical form because, after coating
and drying or cooling, they form, through, for example,
covalent bonds, hydrogen bonds or ionic interactions,
networks which serve for consolidation and thus provide the
necessary coherence to the pharmaceutical form. Plasticizers
adjust the consistency of the pharmaceutical form so that it
is flexible and deformable and thus can be adapted to the
floor of the wound. Suitable plasticizers with physiological
suitability for wound treatment are preferably low molecular
weight polyhydric alcohols such as, for example, glycerol,
sorbitol,.low molecular weight polyethylene glycol or low
molecular weight polypropylene glycol.
Polymers suitable for a rapid-release device which is
soluble, or at least disintegrates, in wound fluid are, in
particular, water-soluble polymers. These preferably include
collagen and gelatin, vegetable polysaccharides such as
alginates, pectins, carrageenans or xanthan, cellulose
derivatives such as methylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose, hydroxypropylmethylcellulose or
sodium carboxymethylcellulose, starch and starch
derivatives, galactomannan and galactomannan derivatives,
chitosan and chitosan derivatives, glycoproteins,
proteoglycans, glucosaminoglycans, polyvinyl alcohol,
polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate
copolymers, high molecular weight polyethylene glycols and
high molecular weight polypropylene glycols.
Polymers suitable for a pharmaceutical form with delayed
release over a lengthy period, which swells in wound fluid
or does not interact with wound fluid, are, in particular,
polymers which are swellable in water or. insoluble in water.
These preferably include cellulose derivatives such as
ethylcellulose, cellulose acetate phthalate, hydroxypropyl-
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methylcellulose phthalate, cellulose acetate succinate or
ethylcellulose succinate, polyoxyethylene/polyoxypropylene
copolymers, polyvinyl alcohol, polyacrylates and
polymethacrylates, polylactides, polyglycolides and
polyamino acids.
The pharmaceutical may contain the following as further
ancillary substances:
= preservatives such as, for example p-C1-m-cresol,
phenylethyl alcohol, phenoxyethyl alcohol, chloro-
butanol, methyl 4-hydroxybenzoate, propyl 4-hydroxy-
benzoate, benzalkonium chloride, cetylpyridinium
chloride, chlorhexidine diacetate or digluconate,
ethanol or propylene glycol
= pH regulators such as, for example, glycine buffer,
citrate buffer, borate buffer, phosphate buffer or
citric acid/phosphate buffer
= antioxidants such as, for example, ascorbic acid,
ascorbyl palmitate, tocopherol acetate, propyl gallate,
butylhydroxyanisole or butylhydroxytoluene,
= ancillary substances to stabilize the biological
activity of active substances such as mannitol, glucose,
lactose, fructose, sucrose, cyclodextrin or dextran,
= emulsifiable ancillary substances such as oils, fats and
waxes,
= emulsion stabilizers such as, for example, nonionic
emulsifiers, amphoteric emulsifiers, cationic
emulsifiers and anionic emulsifiers,
= bulking agents such as, for example, microcrystalline
cellulose, aluminium oxide, zinc oxide, titanium
dioxide, talc, silicon dioxide, magnesium silicate,
magnesium aluminium silicate, kaolin, hydrophobic
starch, calcium stearate or calcium phosphate,
= foaming agents such as saponins, alginic esters, amine
oxides or fatty amine oxides.
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Example 1:
34 g of acetone, 6 g of polyethylene glycol 400 and 16 g of
ethyl acetate are introduced into a stirring vessel which
can be closed. While stirring at a constant speed, 33.6 g of
a polyvinylpyrrolidone/polyvinyl acetate copolymer, 2 g of a
polyoxyethylene/polyoxypropylene copolymer and 3.3 g of
hydroxypropylcellulose are successively dissolved in the
solvent mixture.
Example 2:
3.3 g of lidocaine are dissolved in the stock solution of
Example 1 while stirring at a constant speed. The solution
is coated with a coat thickness of 300 m on siliconized
paper and dried convectively in a drying channel at 50 C
with an air speed of about 5 m/sec. Drying results in a
soft, slightly cloudy, flexible film which has a weight per
unit area of 130 g/m2 and accordingly has an active substance
content of 0.8 mg of lidocaine/cm2.
Circular pharmaceutical forms with an area of 5 cm2 and,
accordingly, an active substance content of 4 mg of
lidocaine are punched out of the film. The pharmaceutical
forms are each placed in a paddle-over-disc apparatus and
stirred in 500 ml of demineralized water at 50 rpm and 32 C.
ml portions of the released medium are removed after
30 minutes, 1, 2, 4 and 24 hours. The amount of active
substance released is determined by HPLC. Result:
Removal time Amount of active substance
released (in mg; cumulative)
30 min 3.1865
1 hour 3.4828
2 hours 3.7978
4 hours 3.8807
24 hours 4.1102
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The pharmaceutical form has disintegrated into several small
pieces after 30 min; the release of active substance from
the pharmaceutical form at this time is already almost 80 %
and is 97 % after 4 hours. The desired requirements for this
type of pharmaceutical form, rapid release of active
substance to achieve rapid alleviation of pain and maximal
utilization of the active substance administered, are met.
Example 3:
5.2 g of chlorhexidine hydrochloride are dissolved in the
stock solution of Example 1 while stirring at a constant
speed. The solution is coated on siliconized paper and dried
under the same conditions as in Example 2. The resulting
soft, deformable film has a weight per unit area of 130 g/mZ
and, accordingly, an active substance content of 1.2 mg of
chlorhexidine hydrochloride/cmZ. Circular pharmaceutical
forms with an area of 5 cm2 and, accordingly, an active
substance content of 6 mg of chlor.hexidine hydrochloride are
punched out of the film. The pharmaceutical forms are each
placed in a paddle-over-disc apparatus and stirred in 500 ml
of demineralized water at 50 rpm and 32 C. 10 ml portions of
the release medium are removed after 30 minutes and
one hour. The amount of active substance released is
determined by HPLC. Result:
Removal time Amount of active substance
released (in mg; cumulative)
30 min 6.1400
1 hour 6.1963
The pharmaceutical form has completely disintegrated after
30 minutes, and 100 % of the amount of active substance
administered is released. On use, the antiseptic effect of
the chlorhexidine hydrochloride would have a very rapid and
highly concentrated onset, which is also necessary for
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infections. Utilization of the active substance introduced
is optimal.
Example 4-
34 g of acetone, 16 g of ethyl acetate and 6 g of poly-
ethylene glycol 400 are introduced into a stirred apparatus
which can be closed. While stirring at a constant speed, 6 g
of ethylcellulose, 11 g of a polyvinylpyrrolidone/polyvinyl
acetate copolymer, 5.5 g of hydroxypropylcellulose, 1 g of
polyoxyethylene/polyoxypropylene copolymer and 0.9 g of
oestradiol are successively dissolved in the solvent
mixture.
The solution is coated with a coat thickness of 400 m on
siliconized paper and dried convectively in a drying channel
at 50 C with an air speed of about 5 m/sec. Drying results
in a soft, deformable film which has a weight per unit area
of 130 g/m2 and, accordingly, an active substance content of
0.385 mg of oestradiol/cm2. This film differs from those
described in Examples 2 and 3 in that it is necessary, in
order to achieve an effect promoting wound healing by
administration of oestradiol, for release of an initial dose
of this active substance optimally to be followed by
continuous and controlled release over a lengthy period of a
low-dose maintenance dose.
To investigate the kinetics of release, circular
pharmaceutical forms with an area of 5 cm2 and an active
substance content of 1.924 mg of oestradiol are punched out
of the film. The devices are each placed in a paddle-over-
disc apparatus and stirred in 500 ml of demineralized water
at 50 rpm and 32 C. 10 ml portions of the release medium are
removed after 30 minutes and 2, 6 and 24 hours. The amount
of active substance released is determined by HPLC.
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Result:
Removal time Amount of active substance
released (in mg; cumulative)
30 minutes 0.9957
2 hours 1.0943
6 hours 1.1814
24 hours 1.3079
After 30 minutes, the pharmaceutical form shows moderate
swelling; about half the amount of active substance
administered has been released. The results show that the
release of active substance is subsequently distinctly
reduced and about 10 - 20 g of oestradiol per hour are
delivered as maintenance dose. 68 % of the amount of active
substance administered are released after 24 hours. The
active substance reservoir in the pharmaceutical form, which
also disintegrates after several hours, is sufficient for
continuous, low-dose oestradiol release to be possible even
on use for several days.
