Title: Spray-drying process for the preparation of
United States Patent: 6,451,349
Issued: September 17, 2002
Inventors: Robinson; Stuart (Melton Mowbray, GB); Smith;
Susan Stewart (Leicestershire, GB)
Assignee: Quadrant Healthcare (UK) Limited (Nottingham, GB)
Appl. No.: 342356
Filed: June 29, 1999
Microparticles, obtainable by spray-drying a substantially pure solution
of a therapeutic agent, consist essentially of the agent having its
therapeutic activity when administered to the lung. In a preferred
embodiment the agent is insulin.
DESCRIPTION OF THE INVENTION
Microparticles of the invention "consist essentially" of the therapeutic
agent. This term is used herein to indicate that they are substantially
free of polysaccharide, or buffer salt, e g citrate, since none is
necessary. In general, there will be no polysaccharide present at all,
although an amount of up to, say 10% by weight may be tolerated. The
absence of polysaccharide has the advantage that a given unit dosage, e.g.
a particle, contains essentially only the intended active component. This
is an important consideration, for a drug that may be required in large
amounts. Another advantage is the avoidance of delivering unnecessary
material to a subject. A further advantage is that consistent dosing of
the therapeutic agent is facilitated, this is especially important where
there is a narrow therapeutic window.
The absence of buffer salt is desirable as it allows a more concentrated
feedstock solution of the active agent to be spray-dried resulting in
significant cost savings and providing a more commercial-scale process to
The term "substantially pure" is used herein to indicate that the
feedstock solution to be spray-dried comprises primarily only therapeutic
agent and solvent. Again, as described above, there may be minor amount of
solids other than the active agent, but this has no significant effect on
the eventual stability of the product.
Insulin microparticles of the invention may include components that are
produced during the successive addition of acid and alkali, in preparation
of the feedstock, e.g. a salt. For example, NaCl is formed if the acid and
alkali are respectively HCl and NaOH. It has been found that the presence
of NaCl apparently has no stabilising effect. Indeed, stability may be
greater with reduced amounts of salt, again allowing a more concentrated
feedstock to be used.
Typically, the solution for spray-drying may contain less than 4% by
weight of salt, by weight of total solids. The salt content is based on
theoretical considerations, by titration to pH 7. More particularly, this
value is calculated by consideration of the molar quantities of the ions
added during dissolution. The solution may contain any desired amount of
the therapeutic agent, e.g. more than 20, 30 or 50 mg/ml, often up to 100
or 200 mg/ml.
As indicated above, successive addition of acid and alkali apparently
destroys the crystalline form of Zn insulin. Zn may dissociate from the
hexameric complex but need not be removed. Accordingly, Zn may be present
in the microparticles. If desired, this or any other component, other than
the therapeutic agent, may be removed, using any suitable technique known
to those of skill in the art. In a preferred embodiment for insulin, the
Zn is removed from solution prior to spray-drying. This may be achieved by
diafiltering the solution according to methods known in the art. The
Zn-free insulin may have greater stability than the Zn-containing product.
Moisture may also be present.
As disclosed in more detail in WO-A-9218164, WO-A-9408627 and other
Andaris publications, the conditions of spray-drying can be controlled so
that microparticles having a defined size range, e.g. 0.1 to 50 .mu.m, can
be obtained. The mass median particle size is preferably 1 to 10 .mu.m,
when the product is intended for administration by inhalation.
The microparticles (microcapsules) obtained by spray-drying may be solid
or hollow Further, the surface may be smooth or "dimpled"; a dimpled
surface may be beneficial for inhalation.
The microparticles have good stability and may be maintained as such, i.e.
as a dry powder, in a container. During storage or in formulation, they
may be mixed with any suitable pharmaceutical agents, carriers, bulking
agents etc, and they may be processed by any technique desired to give a
product having the properties intended for the ultimate therapeutic use.
In particular, the formulation of particles for formulations that can be
delivered to the lung, e.g. using a metered dose or dry powder inhaler,
are known to those skilled in the art.
The nature of the container is not critical. For example, it may be a
glass jar or plastics box. It merely defines a storage environment within
which, unlike the prior art and as evidenced below, there is no need to
remove moisture or otherwise to control the conditions.
The therapeutic agent may be any protein or peptide having a desired
therapeutic effect. Included within the definition of proteins and
peptides are functional derivatives, such as glycoproteins. Typical
examples of proteins that may be used include enzymes, hormones and blood
plasma products. DNase and trypsin are specific examples. Others include
growth hormone, calcitonins, interferons, interleukin-1 receptor and low
molecular weight heparin.
The therapeutic agent may in particular be any of those described in
WO-A-9632149. Insulin that is used in the invention may be of any suitable
form. It may be, for example, bovine or human insulin. Results that have
been obtained, regarding the stability of bovine insulin, apparently apply
also to human insulin.
Claim 1 of 7 Claims
What is claimed is:
1. A process for the preparation of microparticles, which comprises
spray-drying a substantially pure solution of a therapeutic agent to form
microparticles that consist essentially of the therapeutic agent having
therapeutic activity when administered to the lung, wherein the agent is
insulin and wherein the method comprises:
providing a solution comprising Zn-insulin dissolved in acid;
adding alkali to the solution to produce a pH of the solution greater than
spray drying the solution to form the microparticles.
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