Dry powder composition of hydroxyethyl starch suitable for reconstitution

The present invention relates to a dry powder composition of hydroxyethyl starch suitable for reconstitution and comprising hydroxyethyl starch of a molecular weight of up to about 2,000,000, a degree of substitution of from about 0.4 to about 0.7, and containing less than about 0.5 parts by weight of ethylene glycol per 100 parts of the hydroxyethyl starch, the hydroxyethyl starch comprising from about 4% to about 40% by weight of the composition. The composition includes at least one soluble component in addition to the hydroxyethyl starch chosen from dextrose, lactose or mannitol.

BACKGROUND OF THE INVENTION 
Colloids are frequently used in the resuscitation of hypovolemic patients 
with shock. Potential benefits of maintaining or increasing plasma colloid 
osmotic pressure include the rapid restoration of the circulating plasma 
volume and the avoidance of excessive fluid accumulation, particularly in 
the lung U.S. Pat. No. 3,523,938 issued Aug. 11, 1970, for Starch Plasma 
Expanders and Process of Preparation describes the preparation and use of 
hydroxyethyl starch as a plasma volume expander. HESPAN is a plasma volume 
expander, made as described in U.S. Pat. No. 3,523,938 and currently sold 
by E. I. du Pont de Nemours and Company, and which uses a fraction of 
hydroxyethyl starch known as hetastarch. Hetastarch, synthesized by the 
hydroxyethylation of polysaccharides, contains polymers of a wide range of 
sizes, 90% of which have a molecular weight of between about 10,000 and 
1,000,000 and has a number average molecular weight of about 69,000. 
Average molecular weight and molecular weight distribution are useful 
parameters in defining heterogeneous polymers such as hydroxyethyl starch. 
Polymer molecular weights are defined several different ways depending on 
the particular needs. 
The number average molecular weight is the most useful term for the 
clinician concerned with oncotic pressures. The oncotic pressure of 
hydroxyethyl starch is related to the number of macromolecules in solution 
and has been measured as 30 mm mercy. Oncotic pressures for various 
hydroxyethyl starches have been reported. The number average molecular 
weight is defined as the number of molecules in the fraction having a 
specific molecular weight times the molecular weight divided by the number 
of molecules in the fraction. As mentioned before, hetastarch has been 
synthesized with a number average molecular weight of about 69,000. 
The weight average molecular weight is useful to the chemist in defining 
the polymer resulting from a synthetic process. It is defined as the 
summation of the weights of individual fractions times the molecular 
weight of the species within the fractions divided by the sums of the 
weights of the individual fractions. 
Historically, gel permeation chromatography has been used to determine 
molecular weight distribution and to estimate molecular weight. The 
molecular weight ranges from 180 for one glucose unit to well over one 
million for the largest polymer molecule. The distribution of molecules 
for hetastarch is such that at least 80% of the molecules have a molecular 
weight between ten thousand and two million. For hetastarch the average 
molecular weight by gel permeation chromatography is approximately 
450,000. 
Various hydroxyethyl starch fractions with possibly varying characteristics 
are used for different purposes. As described, hetastarch is generally 
used for plasma volume expansion. Pentastarch, as described in U.S. Pat. 
No. 4,873,230, is used for leukophoresis. This fraction has a molecular 
weight of from about 150,000 to about 350,000, degree of substitution of 
from abut 0.4 to about 0.7, and is substantially free of ethylene glycol, 
ethylene chlorohydrin, sodium chloride and acetone. 
An additional fraction, as described in U.S. Pat. No. 4,798,824 issued Jan. 
17, 1989, is intended for use in a perfusate for the preservation of 
organs or in a solution for the preservation of organs, as described in 
U.S. Pat. No. 4,879,283 issued Nov. 7, 1989. This fraction has a molecular 
weight of from about 150,000 to about 350,000, a degree of substitution of 
from about 0.4 to about 0.7, being substantially free of ethylene glycol, 
ethylene chlorohydrin, sodium chloride and acetone, and being 
substantially free of hydroxyethyl starch having a molecular weight of 
less than about 50,000. 
While specific fractions may be preferred for specific uses, use of the 
different fractions can be interchanged in some cases. 
All of the current hydroxyethyl starch products are manufactured as 
solutions. A dry powder composition would be desirable as it would reduce 
costs with regard to shipping and storage as well as providing additional 
advantages. 
SUMMARY OF THE INVENTION 
The present invention relates to a dry powder composition of hydroxyethyl 
starch suitable for reconstitution and comprising hydroxyethyl starch of a 
molecular weight of up to about 2,000,000, a degree of substitution of 
from about 0.4 to about 0.7, and containing less than about 0.5 parts by 
weight of ethylene glycol per 100 parts of the hydroxyethyl starch, the 
hydroxyethyl starch comprising from about 4% to about 40% by weight of the 
composition. The composition includes at least one soluble component in 
addition to the hydroxyethyl starch. 
The dry powder composition can be used for the preparation of formulations 
requiring hydroxyethyl starch and can be reconstituted just prior to use 
thereby reducing cost with regard to shipping and storage. 
Specific fractions of hydroxyethyl starch can be used for the dry powder 
composition, depending on the final solution desired and its purpose.

DETAILED DESCRIPTION OF THE INVENTION 
The solution rate of hydroxyethyl starch is slow. It has been found that 
mixing the hydroxyethyl starch with at least one soluble component, namely 
dextrose, lactose, mannitol or sodium chloride, enhances the dissolution 
rate so that the dry powder composition dissolves in about 6 minutes to 
about 8 minutes. The use of dextrose is preferred. By reconstituting the 
dry powder composition just prior to use, cost is reduced with regard to 
shipping and storage. Moreover, a dry powder composition would obviate the 
need for different size solutions, namely 125 ml, 500 ml, 1 liter, etc. 
which can be made as needed. The dry powder composition would also be 
useful in disaster or crisis situations. The dry powder composition can 
also be packaged by conventional powder fill equipment. 
The feasibility of developing a dry powder formulation to improve the 
reconstitution rate of hydroxyethyl starch was investigated. Two 
approaches were studied. 
(I) Mixing the hydroxyethyl starch with additives geometrically to separate 
the hydrxoyethyl starch particles and to enhance the wetting and 
dispersion during its reconstitution. 
(II) Lyophilizing solutions of hydroxyethyl starch in the presence of 
additives (dextrose, sodium chloride, lactose or mannitol) to change the 
powder matrix properties and to enhance the reconstitution rate of 
pentastarch. 
The reconstitution of the powder from the various preparations was 
conducted by placing 450 ml of water or saline solution into a 500 ml 
intravenous administration bottle containing pre-weighed powder which 
would make 10% pentastarch solution after reconstitution. The bottles were 
shaken using a horizontal shaker with two inches shaking distance, at 168 
shakes/minute. 
The evaluation was rated on a scale of 1 to 6. 
1: All the powder dissolved in 6 minutes, 
2: All the powder dissolved in 8 minutes, 
3: All the powder dissolved in 10 minutes, 
4: 5% remained undissolved at 6 minutes and all dissolved in 12 minutes, 
5: 10% remained undissolved at 6 minutes and all dissolved in 14 minutes, 
6: 25% remained undissolved at 6 minutes and 5% remained undissolved at 16 
minutes. 
The results are summarized as follows: 
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Rating 
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Preparation A: 
Lyophilized powder from a 
4 
solution of 10% pentastarch, 
5% dextrose and 2% glycerol, 
is a white, hard, and porous 
cake. 
Preparation B: 
Lyophilized powder from a 
6 
solution of 10% pentastarch, 
0.9% sodium chloride and 0.5% 
glycerol, is a white, crispy, 
and porous cake. 
Preparation C: 
Lyophilized powder from a 
3 
solution of 10% pentastarch 
and 0.5% glycerol, is a white, 
fluffy, porous cake. 
Preparation D: 
Lyophilized powder from a 
6 
solution of 40% pentastarch 
and 20% dextrose, is a clear, 
glassy chip. 
Preparation E: 
Lyophilized powder from a 
5 
solution of 40% pentastarch 
and 3.6% sodium chloride, is 
a mixture of glassy and porous 
white cake. 
Preparation F: 
Lyophilized powder from a 
5 
solution of 40% pentastarch 
and 2% glycerol, is a dense 
white, and crispy cake 
with no visible pore. 
Preparation H: 
A geometric mixture of penta- 
2 
starch and dextrose. 
Preparation H': 
Same as preparation H; however, 
2 
spray dried pentastarch instead 
of drum dried being used. 
Preparation M: 
A powder mixture of pentastarch 
1 
and dextrose mixed using 1/2 
quart V-blender, is a white free 
flowing powder. 
Preparation M': 
Same preparation as M; however, 
2 
spray dried pentastarch instead 
of drum dried being used. 
Preparation N: 
A powder mixture of pentastarch 
5 
and sodium chloride mixed using 
1/2 quart V-blender, is a white 
free flowing powder. 
Preparation N': 
Same preparation as N; however, 
5 
spray dried pentastarch instead 
of drum dried being used. 
Preparation O: 
A powder mixture of pentastarch, 
2 
dextrose, and sodium chloride 
using 1/2 quarter V-blender, is a 
white free flowing powder. 
Preparation O': 
Same preparation as O; however, 
3 
spray dried pentastarch instead 
of drum dried being used. 
Control: Reconstitution: 90% 5 
Remained undissolved at 5 minutes. 
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A geometric powder mixture of pentastarch and dextrose gave a promising 
result for improving the dissolution rate of the pentastarch. This is a 
simple and straight forward method and the powder mixture provides a 
faster reconstitution rate in the hospital as well as eases the in-house 
preparation of pentastarch solution. The powder mixtures of pentastarch 
and dextrose, by using a small scale V-blender, showed a fast 
reconstitution rate also. This demonstrated that it is feasible to be 
scaled up and still keep the beneficial powder properties. 
An example of a suitable formulation is as follows: 
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Ingredient Amount 
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Pentastarch 50 grams 
Mannitol 0-10 grams 
Sodium chloride 0-10 grams 
Dextrose 0-40 grams 
Water for injection Q.5 to 500 ml 
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