BIODEGRADABLE MICROPARTICLES GEL COMPOSITION

FORMULATION PHARMACEUTIQUE

English Abstract

A gel comprises biodegradable microparticles including a wall-forming material
that is relatively insoluble at physiological pH, wherein the liquid phase of
the gel is aqueous, buffered to physiological pH.

French Abstract

Un gel comprend des microparticules biodégradables contenant une matière formant paroi laquelle est relativement insoluble à un pH physiologique, dans laquelle la phase liquide du gel est aqueuse, tamponnée à un pH physiologique.

Claims

5
CLAIMS
1. A gel comprising biodegradable microparticles
including a wall-forming material that is relatively
insoluble at physiological pH, wherein the liquid phase of
the gel is aqueous, buffered to physiological pH.
2. A gel according to claim 1, wherein the microparticles
consist essentially only of a therapeutic agent and the
wall-forming material.
3. A gel according to claim 1 or claim 2, wherein the
microparticles include is a biodegradable natural or
synthetic polymer.
4. A gel according to any preceding claim, wherein the
microparticles include a stabilising or suspending agent
having haemostatic properties.
5. A gel according to any preceding claim, wherein the
microparticles include a protein.
6. A gel according to any preceding claim, wherein the
microparticles include casein.
7. A gel according to any preceding claim, wherein the
microparticles are obtainable by spray-drying from an
aqueous solution having a pH below 4 or above 10.
8. A method for the preparation of a gel according to any
preceding claim, which comprises spray-drying an aqueous
solution as defined in claim 7, and reconstituting the
resultant microparticles in said buffer.

Description

CA 02340177 2001-02-09
WO 00/09084 PCT/GB99/02527
PHARMACEUTICAL FORMU~AmrnN
Field of the Inventio0
This invention relates to a pharmaceutical
formulation. More particularly, it relates to a gel formed
from microparticles.
Backcrround of the Invention
The delivery of therapeutic agents to the site of
action, in an appropriate formulation, is not easily solved
for all drugs. One means of drug delivery comprises
formulating the therapeutic agent and, if necessary, a
wall-forming material as microparticles, and preferably
hollow microcapsules, of defined size, preferably by spray-
drying. Suitable procedures are described in, for example,
WO-A-9218164, WO-A-9408627 and WO-A-9615814.
Microparticles produced by spray-drying may be
soluble, in which case they are particularly adapted for
pulmonary administration. They may also be rendered
insoluble, by chemical cross-linking or heating, in which
case they are particularly adapted for intravascular
administration, so that they reach the liver, a tumour site
or other desired loci.
Solutions or suspensions of therapeutic agent are not
necessarily appropriate for a formulation intended for
subcutaneous injection, in order to provide sustained
release of the drug. A semi-solid consistency would be
desirable.
Summary of the Invention
Surprisingly, it has been discovered that certain
materials that are relatively insoluble in water at
physiological pH can be formulated into microparticles and
provided as a gel. This can be achieved without any
chemical modification of the wall-forming material. More
particularly, a gel according to the present invention
comprises biodegradable microparticles including a wall-
forming material that is relatively insoluble at
physiological pH, and the liquid phase of the gel is
aqueous, buffered to physiological pH.
Without wishing to be bound by theory, it appears that
certain materials, of which casein is one, which can be

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formulated as a solution, albeit not at pH 7, can be spray-
dried to give microparticles or microcapsules that, upon
resuspension in a suitable buffer, provide a gel. This gel
is suitable for subcutaneous injection, and can provide a
therapeutic agent in a sustained release form.
]2escription of the Invention
Typically, the wall-forming material forms an aqueous
solution at a pH below 4 or above 10, i.e. at relatively
acid or alkaline pH. The pH of the solution for spray-
drying will typically be at least 1 or 2, or no more than
13 or 14.
The wall-forming material is relatively insoluble in
water at pH 7. Typically, it will be insoluble at this pH,
to the extent that no sufficiently concentrated solution
could be made of it, that would be worth using, for spray-
drying on a commercial scale. Such materials include
biodegradable natural or synthetic polymers, and other
stabilising and suspending agents, including those with
haemostatic properties. For example, alginates and
oxidised celluloses, pectins and xanthan gums, are soluble
at a pH other than physiological pH, and are known for
their haemostatic properties, upon contact with water.
More particularly, the material may be a protein such as
casein. Casein is a protein derived from milk, having a
molecular weight in the region of 23,000; it is sparingly
soluble in water but is soluble in aqueous alkali.
The wall-forming material may itself be a therapeutic
agent. Alternatively, a therapeutic agent is added, e.g.
in the formulation from which the microparticles are
formed. Suitable agents include insulin, hormones,
cytotoxic agents, antibiotics, antivirals, analgesics and
anti-inflammatory agents; it will be readily apparent to
the skilled person that any suitable agent can be used.
Spray-drying may be conducted by procedures that are
generally known, and are described in more detail in the
Andaris publications given above (the contents of which are
incorporated herein by reference). The hollow or other
microcapsules that can be produced by this technology can
have any desired characteristics, according to the

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conditions that are chosen. The size and size distribution
of the microparticles are not especially critical, for the
purposes of this invention.
In order to prepare the gel, the microparticles are
resuspended in an appropriate buffer, to physiological pH.
Any suitable buffer may be chosen, provided that it is
physiologically-acceptable. For example, if the
therapeutic agent is alkaline, a phosphate-citrate buffer
may be chosen.
The materials etc. that are used in this invention may
have some effect on the ability of the microparticles to
form a gel, upon resuspension in buffer. Based on the
information provided in this specification, one of ordinary
skill in the art can readily determine whether or not a
suitable gel can be formed.
The release characteristics of products of this
invention may be manipulated by controlling the feedstock
formulation prior to spray-drying. Alternatively, or in
addition, the microparticles and/or the gel may be further
stabilised, e.g. by the use of chemical cross-linking
agents or the addition of viscosity enhancers.
The following Example illustrates the invention.
Example
50 g casein (Sigma, Technical grade) was dissolved in
250 ml 0.5 M NaOH; the pH was determined to be 13.4.
Myoglobin (Sigma, Horse heart) was selected for use as a
marker, and as representative of a therapeutic agent to be
released: 1 g was dissolved in 20 ml purified water, and a
1 ml aliquot was removed for the preparation of standards.
The remaining 19 ml was added to the casein solution prior
to spray-drying. The feed solution was continually stirred
during spray-drying, which was conducted under the
following conditions:
Inlet temperature 220°C
Outlet temperature 83°C
Atomisation pressure 5.0 bar
Feed rate 12.5 g/min
Product recovery 51.3%

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The resultant microcapsules were deep red in colour
and appeared to be fairly cohesive.
Resuspension of the microcapsules in low concentration
phosphate buffer (pH 7) proved unsuccessful as the
microcapsules were found to dissolve; the reason is that
the buffer was insufficiently concentrated to overcome the
high pH of the microcapsules. Upon resuspension of 1 g
spray-dried material in 6 ml of phosphate-citrate buffer
(0.15 M, pH 5.0), a gel was formed. The gel was found to
increase in strength over a period of 30 minutes as
determined visually.
Three 1 g aliquots of the spray-dried microcapsules
were placed into universal tubes. 10 ml phosphate-citrate
buffer was added to each tube and the samples vortexed. A
gel was formed immediately in each of the tubes. The tubes
were then centrifuged (3 min @ 3000 rpm) and the whole
supernatants removed. The supernatants were diluted 1:1
before scanning between 500 and 700 nm. A 0.5 mg/ml
standard of the myoglobin was scanned at the same
wavelengths and used to determined the levels of myoglobin
released initially on contact of the microcapsules with
water.
Fresh 5 ml aliquots of the phosphate-citrate buffer
were added to each of the gels and the samples were placed
in a water bath at 37°C. At various timepoints, samples
were removed from the water bath and centrifuged. The
supernatants were diluted 1:1 and scanned as before. 5 ml
aliquots of phosphate-citrate buffer were added to the
centrifuged gels at each timepoint before placement back in
the water bath. The results showed that myoglobin was
retained to some extent.
By way of example, increasing the concentration of
casein in the feedstock, e.g. to 30$ w/v, may increase the
strength of the gel. The same effect may be achieved by
dissolution of casein at different values of pH.