PREPARATION PHARMACEUTIQUE CONTENANT UN NANOSOL

PHARMACEUTICAL PREPARATION CONTAINING NANOSOL

Abrégé français

L'invention concerne des préparations pharmaceutiques solides contenant au moins un principe actif chargé partiellement, sous la forme d'un nanosol, dans lequel le principe actif est lié à un dérivé de chitosane de charge opposée. L'invention concerne également des procédés de production desdites préparations et leur utilisation pour fabriquer des produits pharmaceutiques.

Abrégé anglais

The invention relates to solid pharmaceutical preparations
comprising at least one at least partially charged active
substance in the form of a nanosol wherein the active
substance is bonded to an oppositely charged chitosan
derivative, processes for their production, and their use
for the production of medicinal products.

Revendications

7
CLAIMS
1. Solid pharmaceutical preparation comprising at least
one at least partially charged active substance, which
active substance is present in the form of a nanosol in
which the active substance is bonded to an oppositely
charged chitosan derivative, said solid pharmaceutical
preparation being produced by a process, wherein
- a chitosan derivative is selected according to the
type and relative number of its charged groups and in
coordination with the type and relative number of the
charged groups of the active substance such that at a
certain pH value an isoionic state or charge
equalization between active substance and carrier can
be achieved in the preparation,
- an aqueous sol containing the active substance is
prepared from the chitosan derivative,
- the pH value of the aqueous sol is adjusted such that
an isoionic state results, possibly with colloidal or
nano-scale active substance particles precipitating,
and
- the thus-adjusted aqueous sol is dried.
2. Solid pharmaceutical preparation according to Claim 1,
wherein the active substance possesses a
positive charge and is bonded to a zwitterionic, acidic
chitosan derivative.
3. Solid pharmaceutical preparation according to Claim 1,
wherein the active substance possesses a
negative charge and is bonded to a basic chitosan
derivative.
4. Solid pharmaceutical preparation according to any one
of claims 1 to 3, wherein the active

8
substance and the chitosan derivative are present in the
nanosol in isoionic state.
5. Solid pharmaceutical preparation according to any one
of claims 1 to 4, wherein the active
substance is present in the nanosol in colloidal or in
nanoparticulate form.
6. Solid pharmaceutical preparation according to any one
of claims 1 to 5, wherein the active
substance is poorly soluble.
7. Solid pharmaceutical preparation according to any one
of claims 1 to 6, wherein it contains
a further polymeric carrier substance apart from the
chitosan derivative.
8. Use of a pharmaceutical preparation according to any
one of claims 1 to 7 for the production of a
medicinal product.
9. Use of a pharmaceutical preparation according to Claim
8 for the production of a medicinal product for peroral
application.
10. Use of a pharmaceutical preparation according to any
one of Claims 8 or 9 for the production of a medicinal
product that is administered as a powder, granulate, tablet
or capsule.
11. Use of a pharmaceutical preparation according to any
one of Claims 8 to 10 for the production of a medicinal
product which, for the purpose of administration, is
dissolved or redispersed in a liquid.

9
12. Use of a pharmaceutical preparation according to any
one of Claims 8 to 11 for the production of a medicinal
product having controlled active substance release.
13. Use of a pharmaceutical preparation according to any
one of Claims 1 to 7 for the production of a diagnostic
agent.
14. Process for the production of a pharmaceutical
preparation according to any one of Claims 1 to 7,
characterized in that
a) a chitosan derivative is selected according to the
type and relative number of its charged groups and in
coordination with the type and relative number of the
charged groups of the active substance such that at a
certain pH value an isoionic state or charge equalization
between active substance and carrier can be achieved in the
preparation,
b) an aqueous sol containing the active substance is
prepared from the chitosan derivative,
c) the pH value of the aqueous sol is adjusted such that
an isoionic state results, possibly with colloidal or nano-
scale active substance particles precipitating, and
d) the thus-adjusted aqueous sol is dried.

Description

CA 02382359 2007-10-30
i . . =
FfiARMACRVTICAL FRSPARATION CONTAINXNG ATA1+tOSOL
Pharmaceutical preparations wherain an active substance is
precent bound to a carrier are known ir- the gtate of the
art in great tbundance. In the widest sense, the bond to
the carrier can be understood to be purely mechanical; in a
narrovr-senso, however, one makes use of the capacity of
carrier subgta=sceg to enter into speoial chemical or
pryaicochemicai interactions with tho active substance or
substances. One catogory of such interactions are ionic attractive
forces, which of course can only be made use of Lf active
agent and carrier are at least partially proaent in a
charged state. 2n pharmaceutical preparations, ionic bonds
between active oubstances and carriers are used, inter
alia, to preserve sparingly soluble activo substances which
have a low tendency of dissociation in water in their
charged and molecular-disperse state, theraby obtaining a
high dissolution rate. Apart from this, active ag nts are
bonded to oppositely charged oarrier polymers to enable a
high active substance load of the preparationf this
formulation technique ie frequently used, for instance, in
liposomo preparations. A further variant which has been
described are preparations wherein by way of the ionic bozxd
to a charged polymer it is intended to achieve a controlled
reloase of active substance. An example for this is the
cough mixture marketed in Germany under the mark
Codiprout which contains as active substance carrier
complex an active subgtance base, Codeine Poly(styrene,
di.vinyl benzene)sulfonate, bonded to an acidic ion
exchanger.
A special form of active agents bound to opposxtely cksax$e$
cazxiers are the sa-called naAomols with gelatine or

r
CA 02382359 2002-02-25
2
collagen hydrolysates as carriers, which are described by
the firm of Alfatec-Pharma GmbH in various patents and
published applications, e.g., in the documents DE 41 40
195, DE 41 40 178 and DE 41 40 179. Here, one makes use of
the fact that it is easily possible to achieve the desired,
isoionic state with charge equalization between carrier and
active substance if gelatine or gelatine derivatives are
used, thanks to the zwitterionic nature of the same, by
means of a corresponding pH adjustment in the preparation.
It is described that these nanosols can be used to advan-
tage for the production of medicinal preparations both with
rapid and with controlled active substance release.
However, these preparations have the disadvantage that the
population has been uncertain for several years as to the
possible risks of BSE infection and has increasingly been
avoiding products containing gelatine, for example.
Therefore, there is a need for preparations without
gelatine or collagen derivatives which have the same
advantages as, for example, the gelatine-based nanosols
described.
It is thus the object of the present invention to provide a
pharmaceutical preparation without gelatine or the like,
for charged active substances, in which the active
substance is present bonded to an oppositely charged
carrier.
The object is achieved by a pharmaceutical preparation
according to Claim 1.
it was surprisingly found that using chitosans as carriers
it is possible to produce so-called nanosols wherein the
active substance is present stabilized in a state almost
isoionic with the carrier, and that these nanosols are
highly suitable for the production of medicinal products.

~
CA 02382359 2002-02-25
3
The preparation of the present invention contains according
to Claim 1 at least one pharmaceutical active substance,
which is at least partially present in a charged state,
i.e. the active substance is capable of forming an ionic
state and at least part of the active substance molecules
are present in that ionic state.
For a definition of a nanosol, reference is made to
DE 41 40 195.
Considered as chitosan derivatives in the spirit of the
invention are all modified and unmodified deacetylation
products of chitin which still possess a polyglucosamine
base structure. The charge opposite to that of the active
substance, which is demanded according to the present
invention, refers to the net-charge of the carrier used.
Thus there may also be charges in the chitosan derivative
that are like that of the active substance as long as they
are overcompensated by the opposite charges.
in fact, in one of the preferred embodiments there is an
active substance with a positive charge that is bonded in
the nanosol to a chitosan derivative with negative total
charge. Such a chitosan derivative may, for example, be a
zwitterionic, partially sulfated chitosan.
in a further, also preferred, embodiment, the active
substance is present in a negatively charged state and is
bound in the nanosol to a positively charged chitosan
derivative, i.e. in the most simple case to an unmodified
chitosan. Here, too, an active substance may well be
present in a partially undissociated form and may even
possess some charges that are like that of the chitosan
derivative as long as its net-charge is opposite, i.e. in
this case negative.

u
CA 02382359 2002-02-25
4
Preferably, the active substance is present in the nanosol
in a colloidal or nanoparticulate distribution, i.e. with
an average particle size of at maximum about 500-1000 nm,
as far as it is possible to detect a phase boundary between
active substance and carrier phase at all. in particular,
poorly soluble active agents can be incorporated in this
way in pharmaceutical preparations from which they can be
quickly released.
The preparations according to the present invention will as
a rule contain further auxiliary agents which are commonly
used in the pharmaceutics technology and are known to those
skilled in the art. These active auxiliary agents may, for
example, be further polymeric or non-polymeric carrier
substances, but also stabilisers, surfactants, disinte-
gration promoters, antioxidants, dyes, pigments, flavours,
sweeteners or other taste-improving agents, binders,
lubricants etc. in a preferred embodiment, the preparation
contains a further polymeric carrier substance. This can be
required, for example, in order to increase the loadability
of the nanosol with active substance or in order to modify
the release properties of the preparation. Appropriate
formulation techniques are likewise known to those skilled
in the art.
In accordance with the invention, the herein disclosed
pharmaceutical preparations are used for making medicinal
products or diagnostic agents. A preferred use of the
preparation consists in the production of medicinal agents
which are administered as capsules, tablets, powders or
granulates, or, like instant preparations, are first
dissolved or redispersed in water or another suitable
liquid prior to being administered.

~
CA 02382359 2002-02-25
in a further preferred embodiment, the preparations are
used for preparing medicinal products having controlled
active substance release. To this end, they must generally
be further modified, i.e. mixed with further auxiliary
substances or enclosed by these. For instance, capsules or
tablets containing a preparation according to the present
invention can be coated with a polymeric film which
controls the release of the active agent or agents. These
and further techniques for producing medicinal products
with modified or controlled release of active substance are
known to those skilled in the art.
A preparation according to the present invention is
basically produced in a multi-step process which can be
varied if necessary or complemented by further steps.
initially, a chitosan derivative is selected as carrier,
taking into account the relative number and type of the
charged groups of the active agent, which on account of the
type and relative number of its charged groups is matched
with the active substance in such a way that at a certain
pH value an isoionic state or charge equalization can be
achieved between active substance and carrier. This is
generally the case if the net-charges of active substance
and chitosan derivative are opposite and the calculated
isoionic point is in a pH range that is physiologically
acceptable and is not detrimental to the stability of the
active substance.
In a further step, a colloidal aqueous solution is prepared
from the chitosan derivative and the active substance,
which on account of its polymer content and the viscosity
resulting therefrom is a sol. it is of no importance here
whether the active substance is added following or prior to
dissolving the chitosan derivative, or whether a solution
of the chitosan derivative and an independently prepared
solution of the active substance are united.

~
CA 02382359 2002-02-25
6
In a further step, the pH of the aqueous sol is adjusted
such that an isoionic state results. In the course of this
pH shift a precipitation of the active substance may occur.
It has turned out here that the particles do generally not
exceed the colloidal or nanoparticulate size range.
The sol which has been thus prepared and adjusted to an
isoionic state can be dried in a further process step. For
this purpose, conventional drying methods, but preferably
drying methods applying no or only little heat such as
freeze drying, may be used.