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Patent 2085342 Summary

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(12) Patent Application: (11) CA 2085342
(54) English Title: STABLE AQUEOUS DRUG SUSPENSIONS
(54) French Title: SUSPENSION AQUEUSE STABLE DE MEDICAMENT
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61K 9/50 (2006.01)
  • A61K 9/127 (2006.01)
  • A61K 9/16 (2006.01)
  • A61K 9/00 (2006.01)
(72) Inventors :
  • KAPLAN, MILTON R. (United States of America)
  • LEW, CHEL W. (United States of America)
  • LAMB, CATHERINE S. (United States of America)
(73) Owners :
  • KAPLAN, MILTON R. (Not Available)
  • LEW, CHEL W. (Not Available)
  • LAMB, CATHERINE S. (Not Available)
  • KALMO ENTERPRISES, INC. (United States of America)
(71) Applicants :
(74) Agent: AVENTUM IP LAW LLP
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 1991-06-13
(87) Open to Public Inspection: 1991-12-15
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US1991/004198
(87) International Publication Number: WO1991/019486
(85) National Entry: 1992-12-14

(30) Application Priority Data:
Application No. Country/Territory Date
538,183 United States of America 1990-06-14

Abstracts

English Abstract

2085342 9119486 PCTABS00008
Finely divided drug particles are coated with a lipid or
bioadhesive polymer to form microspheres (226) having a particle size of
about 550 micrometers or less, and coated with two or more
enteric coatings, at least one of which is water insoluble, to form
microcapsules. The resultant microcapsules can be suspended in an
aqueous solution to form stable oral doses of the drug.


Claims

Note: Claims are shown in the official language in which they were submitted.


WO 91/19486 PCT/US91/04198
33

We claim:
1. A microcapsule comprising a microsphere core particle
comprising a solid drug particle in a matrix of a lipid or
bioadhesive polymer encapsulated in two or more enteric
coatings, at least one coating being impervious to water, said
microcapsules having a particle size of 1500 micrometers or
less.

2. A microcapsule according to claim 1 wherein said drug is
selected from the group consisting of erythromycin or
erythromycin ethyl succinate.

3. A microcapsule according to claim 1 wherein said drug is a
penicillin.

4. A microcapsule according to claim 3 wherein said drug is
selected from the group consisting of ampicillin, amoxicillin,
and penicillin V, their salts and hydrates.

5. A microcapsule according to claim 1 wherein said matrix is a
lipid.

6. A microcapsule according to claim 1 wherein said matrix is a
bioadhesive polymer.

WO 91/19486 PCT/US91/04198
34

7. A microcapsule according to claim 1 wherein said one coating
is insoluble in water at neutral pH and soluble in fluid having
a pH of less than 5.5.

8. A microcapsule according to claim 7 wherein a second coating
is soluble in fluid having a pH of more than 5.5.

9. A microcapsule according to claim 1 wherein the microsphere
core particle comprises a solid drug particle in a bioadhesive
polymer matrix encapsulated in two or more enteric coatings, at
least the outer coating being impervious to water.

10. A microcapsule according to claim 1 having a particle size
of from about 250 to about 550 micrometers.

11. A microcapsule according to claim 1 wherein said
microsphere has a particle size of from about 105 to about 500
micrometers.

12. A microcapsule according to claim 1 wherein said
microsphere has a particle size of from about 250 to about 355
micrometers.

WO 91/19486 PCT/US91/04198


13. A method of making microspheres which comprises
a) admixing solid drug particles having a particle size of
less than 500 micrometers with a matrix of a lipid or a
bioadhesive polymer to form a slurry,
b) forming microspheres having a drug core and a matrix
coating thereon having a particle size of between about 105 to
500 micrometers, and
c) solidifying said microspheres.

14. A method according to claim 13 wherein said forming
comprises dropping said slurry onto a disc rotating at high
speed whereby said slurry is divided into droplets.

15. A method according to claim 13 wherein said forming
comprises extruding a drug particle slurry in a matrix material
of a liipid or bioadhesive polymer through a nozzle rotating at
high speed.

16. A method of making microcapsules which comprises
encapsulating the microspheres of claim 10 with two or more
enteric coatings, at least the outer one of which is water
insoluble.

17. A method according to claim 16 wherein the outer coating is
water insoluble at neutral pH but is soluble in a fluid at a pH

WO 91/19486 PCT/US91/04198
36

below 5.5 and the inner coating is soluble in a fluid having a
pH over 5.5.

18. A stable medication comprising a sugar syrup containing a
suspension of the microcapsules of claim 1.

Description

Note: Descriptions are shown in the official language in which they were submitted.


WO91/19486 PCl'/US91/04198
~,.'`.', 1 2~342


STABLE AQUEQUS DRUG SUSPENSIONS
This invention relates to aqueous suspensions of
encapsulated drugs having improved stability and process for
making such suspensions.
BACKGROUND OF THE INVENTION
Drugs such as amoxicillin, ampicillin, penicillin V and
erythromycin are antibacterial drugs which are available for
oral dispensation in a gelatin capsule containing a specified
dosage amount of the drug. For patients who have difficulty
swallowiny capsules, e.g., the very young and the very old, the
drugs can be suspended in an aqueous solution, such as a sugar-
type syrup. However, the drugs are quite unstable in water,
even when stored at temperatures of about 4C, and very
unstable at room temperature. Thus the drug solutions or
suspensions have a very short shelf life, even at }ow
temperatures. Further, they have an unpleasant taste which
makes them unpalatable.
E3eta-lactam antibiotics are orally inactive, and must be
combined with an enhancer to promote their absorption into the
body of the patient. Such enhancers are known, for example see
US Patent 4,525,339, and include aliphatic fatty acids or acid
glycerides. The fatty acids are generally C2 to Cl8 fatty acids,
which can be straight or branched chain, saturated or
unsaturated, their mono--, di- or triglycerides or mixtures
thereof, and can also be partial or total esters of propylene

W O 91/19486 P ~ /US91/04198

~,3~34~ ` i
glycol, polyethylene glycol and carbohydrates of C2 to C1z fatty
acids and pharmaceutically acceptable esters and ethers of said
glycerides. Encapsulating the drug in the enhancer is known
also.
It would be desirable to be able to formulate these drugs
so that they would be stable to long te~m storage, i.e., for up
to about 18 months, even at room temperature in liquid form. In
order to do that, the drug would have to be coated uniformly
and completeIy with a water-impervious coating. Further, in
order for the drug to stay suspended in an aqueous solution or
emulsion for administration in liquid form, the particle size
of the coated drug particles would have to be very small, on
the order of 1500 micrometers or less; otherwise the drug
particles would settle out o~ the solution or suspension, and
the dosage would be inaccurate.
A suitable coating or encapsulant material must be
impervious to water, but must dissolve in the stomach or other
appropriate portion of the digestive tract, depending on the
drug to be administered and the dosage required, for absorption
by the patient. Coatings having particular solubility
characteristics can be used to provide controlled or delayed
release o~ the drug in the patient.
Un~ortunately, no one encapsulant coating is known to date
that is effective to carry out all o~ these objectives. Thus
there is a need to be able to apply more than one encapsulant

WO9l/19486 2 0 g ~ 3 ~ ~CT/V~9l/04198


material, successively and uniformly, over very small particle
size granules of the drug to be administered. The preparation
of small microspheres, i.e. having a particle size less than
about 500 micrometers, microspheres containing the drug and
then encapsulating them in a series of encapsulants,that would
provide enhancement, taste masking, controlled release and
protection from moisture would be highly desirable.
SUMMARY OF THE INVENTION
We have found that microspheres comprising drug par~icles
which have a particle size of up to about 550 microns, coated
with a matrix material of a lipid or a bioadhesive polymer, can
be encapsulated uniformly and completely within mu}tiple
coatings, at least one of which is impervious to moisture, to
produce microcapsules which are insoluble in water at about
neutral pH, but which are soluble at acid pH. The microcapsules
have a maximum particle size of about 1500 micrometers so they
will stay suspended in an a~ueous solution. The microcapsules
can be tailored to have other features, such as successive
layers of encapsulants having differing solubility
characteristics.
The microspheres are made using high speed rotation,
e.g., a rotatiny disc method, that forms uniform, spherical
particles of the required size. The microspheres are
encapsulated with two or more coatings having differing
solubility characteristics. The resultant water impervious

WO91/19486 ~ PCT/US91/04198
~ 73~


microcapsules can be admixed with aqueous solutions to form
stable suspensions or mixtures that have a long shel~ life in a
concentration to provide dosage amounts of the drug that can be
taken orally.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is a cross sectional view of a high speed
rotating disc system for preparing the microspheres of the
invention.
Figure 2 is a cross sectional view of a centrifugal
extrusion apparatus also used for preparing the microspheres
and microcapsules of the invention.
Figure 3 is a cross sectional view of an air suspension
chamber for encapsulating the microspheres of the invention;
DETAILED DESCRIPTION OF THE INVENTION
The microspheres and microcapsules described in this
invention can be prepared using a variety of methods, including
but not limited to, a rotating disc system, spray drying, a
centrifugal extrusion nozzle devicet an air susp~nsion cooler,
phase separation and solvent evaporation. In the ~ollowing
paragraphs some of the procedures that can be used to prepare
the microcapsules described hereinafter are set forth in
detail. Variations will be known to those skilled in the art.
Microspheres of the de~ired particle siza, i.e., less
than 550 micrometers, and pre~erably between about 250 to 500

WO91/19486 PCT/US91/04198
j ~ 20~53~2

micrometers, can be made using a high speed rotating disc
system as shown in Figure 1.
Referring to Figure 1, the high speed rotating disc
system 10 comprises an emulsion feed tube 12 which is situated
over and feeds onto a rotating disc 14. The disc 14 is rotated
by means of a motor 16. The disc 14 and the motor 16 are
enclosed in a chamber 18. The chamber 18 serves to dry or cool
and solidify the microspheres and to collect them in a
collection area 20. The chamber 18 is also fitted with a filter
lo 22 and an exhaust system 24. The disc 14 is situated some
distance above the collection area 20 to allow time for
solidification of the microspheres.
In operation, a slurry of the solid drug particles, which
are finely divided below about 100 micrometers, and a suitable
matrix, e.g., a lipid or bioadhesive composition, is fed to the
feed tube 12 and dropped onto the rotating disc 14. ~roplets or
microspheres are thrown out from the periphery of the disc 14
due to the centrifugal forces developed by the high speed
rotation of the disc 14, and fall by gravity to the collection
area 20 of the chamber 18. The small spherical liquid droplets
or microspheres are dried/cooled and solidified during this
free fall, and are then collected. If desired, the microspheres
can be sieved to collect a desired particle size distribution.
For a disc about 4 inches in diameter rotating at about 2000
rpm, and a drug particle size of a~out 50 micro~eters, the

WO91/19486 PCT/~S9~/041g8
3 ~ 6

majority of the resultant microspheres have a particle size of
about lOS to 500 micrometers. Control of the rotational speed
of the disc 14 provides control over the size and size
distribution of the microspheres.
Alternatively, and particularly suitably for hot melt
matrix materials, microspheres can be formed in a centrifugal
extrusion apparatus 110 as shown in Figure 2. Referring to
Figure 2, the feed mixture or slurry o~ drug particles in the
heated matrix material is fed through the center tube of a
concentric feed tube 112 by means of a seal (not shown) to a
rotating head 114 fitted with one or more nozzles 116. A
rotating shaft 118 rotates the head 114 at high speed by means
of a motor 119. A mechanical stirrer ~not shown) can be used in
the ~eed tank (not shown) prior to pumping through the feed
tube 112 to provide continuous stirring o~ the drug particles
in the hot melt matrix. As the head 114 rotates, the slurry of
the drug in the matrix material flows through the inner
orifice of the nozz~e, creating a stream of the drug particles
- uniformly dispersed in the molten matrix material. This
extruded rod breaks into individual particles due to the high
speed rotation o~ the head 114. The coated drug particles are
cooled and solidify to form the desired microspheres as they
free fall into the collection area 120. The size of the
resultant microspheres can be controlled and is dependent upon
the feed rate~ the speed of rotation of the head 114 and the

WO9l/19486 PCT/US91/~4198
-~ 7
20~33~
size of the nozzle openings. Microsphere particle siæes o~ from
about 250 to 500 micrometers can be made readily.
In order to form the microcapsules of the in~ention, the
microspheres as prepared above are encapsulated in one or more
water impervious coatinqs.
The microcapsules can be prepared using the apparatus as
shown in Figure 2, except using an additional feed line into
the head 114. The slurry of the drug particles in the heated
matrix mat~rial is fed through the center tube of the
10 concentric ~eed tube 112. The desired encapsulant material and
any additive~ are fed through a separate feed line to the outer
tube 113 of the feed tube 112 to the head 114. The additional
feed line is provided to supply the encapsulant material, e g.,
a water i~pervious polymer dissolved in a solvent, as well as
15 any optional materials desired such as colorants, flavorings,
surfactants and other additives as desired. The slurry of the
drug particles in the matrix material is fed along with the
encapsulant material, to the head 114. The rotation of the head
114 causes the encapsulant or encapsulant mixture to flow
20 through the outer orifice of the nozzle and the drug slurry to
flow through the inner arifice o~ the nozzle, creating a rod of
the drug slurry encased in a sheath of the encapsulant
matarials. I~ an organic solvent is used in the encapsulant, it
i8 vaporized and can be collected through the exhaust (not
25 shown) ~or disposal or recycled as desired.

WO91/19486 PCT/US91/04198
~a~ 3~ 8 ~~`

The microcapsules of the invention can also b~ made in a
modified air susp~nsion coater apparatus as shown in-Figure 3.
The air suspension coater 210 comprises a chamber 212 fitted
with an air distribution plate 216 through which an air atream
passes. A feed line 220 for supplyiny the encapsulant material
is connscted to a hydraulic or pneumatic nozzle 224 which
atomizes the encapsulant material into small droplets which
coat the microspheres.
In operation, the microspheres to be coated 226 are fed
through an entry port 228 in the chamber 2~2. An air stream
supplied by means of a blower is fed into the chamber 212 and
; passes through the air distribution plate 216 to carry the
microspheres smoothly past the head 224 ~or coating with
encapsulant, and then up and over a coating partition 230 where
the coated microspheres are dried and cooled during free fall
back outside the coating partition 230 to begin another cycle
past the nozzle 224. The nozzle 224 is designed to atomize the
coating material to allow a uniform, thin coating to be
applied. In the course of multiple passes of the microspheres
past the nozzle 224, the encapsulant material uniformly coats
the microspheres to the desired thickness. By changin~ the
encapsulant feed to the nozzle 224, successive layers of
desired encapsulant compositions are applied~ Control of the
air volume and temperature, atomizing conditions and rate of
2S application ensures a high degree of uniformi~y of the coatings

WO91/19486 PCT/US91/04198

IA ' ~ '
i 9 20853~2

.
from batch to batch. Further, the closed system of the
apparatus 210 provides excellent control of the conditions
within the coater.
The drugs useful herein can be varied, but those
particularly useful include antibacterial drugs including
erythromycin or erythromycin ethyl succinate, and the
penicillins, their salts, esters and hydrates, such as
amoxicillin trihydrate, ampicillin trihydrate, penicillin V
potassium and the like. These drugs are unstable in water. The
drugs are supplied in solid form. If the drug is upplied in a
larger particle size than de~ired, it can be milled to the
appropriate particle size prior to coating with a lipid
coating.
As used herein, the term lipid includes fatty acids,
whether saturated or unsaturated, such as monobasic aliphatic
carboxylic acids which form esters with glycerol or other
alcohols to make fats, oils, waxes and other lipids. Also
included are the esters and ethers of glycerides, the esters
formed by reaction of the fatty acids with glycerol, such
esters ~ormed ~rom pharmaceutically acceptable weak acids such
as tartaric acid and its diacetyl derivative, acetic acid,
ascoxbic aaid and citric acid, or one having a monophosphate
group to yield the mono-phosphate ester. Suitable ethers are
formed by reaction of the mono- or diglyceride with a
functionally reactive lower alkyl, alkenyl, alkynyl, aryl or

WO91/19486 3~, 1 o PCT/USgl/04l98
i `"`,,

substituted aryl group to produce the corresponding
pharmaceutically acceptable ethar, as is known in the art.
Polyhydric alcohols such as octanol or a carbohydrate polyol,
e.g., sucrose, are also useful in the present invention.
The matrix material can also be a bioadhesive polymer
that will provide a delayed release of the drug. ~he
bioadhesive polymer attaches to the stomach lining or mucin
coating of the stomach, where it hydrates and is absorked,
thereby releasing the drug particles.
Suitable bioadhesive polymers include adhesive materials
such as gelatin, polycarbophil polymers, and Chitosan,
commercially available from Protan of Norway. These matrix
materials provide a delivery system which may provide a lon~
ating dosage ~orm by providing a reduced rate of emptying of
the drug in the stomach, improve bioavailability of the drug,
improve therapy, and increase the contact time of the drug in
the desired absorption area.
The microspheres are made into microcapsules by means of
one or more enteric coatings. The enteric coatings can be
tailored to have the drug absorbed in the body as desired, but
at least one layer o~ enteric coating must be water insoluble
at normal pH. Most antibio~ics are meant to be absorbed in the
intestinal tract, and thus must be protected from the high acid
content gastric fluid of the stomach. Thus successive coatings
may be insoluble in highly acid environments, i.e., pH below




1,,'" .' ' . ' '

WO9~/19486 PCT/US9l/04~98
fr~~l 1 1 2~53~

about 5, but soluble in less acid environments, i.e. pH about
5.5 to 7.5 or higher~
Examples of known enteric coating materials useful herein
include cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropyl methylcellulose phthalate,
polyvinyl acetate phthalate, shellac, methacrylic acid and
methacrylic acid esters and zein. Partially hydrogenated
vegetable oils, stearic acid, hydrogenated tallow
triglycerides, food grade metal stearates, tallow and mixtures
thereof, and the like are used as lipids, carriers and
modifiers for the microspheres. Suitable partially hydrogenated
vegetable oil material is commercially available as Durkee 17
and Durkee KLX from Van den Burgh. Emersol 6349 stearic acid is
commercially available from Emory Industries. Hydroqenated
tallow triglycerides are commercially available as Grocol 600-
E from A. Gross and Co. Suitable tallow flakes are
commercially avaiIable from Anderson Clayton/Hank Products,
Inc. A series of methacrylic acid or methacrylic acid esters
commercially available as EudragitT~ coatings, trademarks of
Rohm Pharma GmbH of Westerstadt, West Germany, have varying
degrees of esterification, and are soluble at varying pH. ~hus
drugs which are meant to be absorbed in the small intestine
will be encapsulated in a first enteric coating that is
insoluble in water but soluble in acidic environment, e.g., the
sto~ach, and a second enteric coating which is insoluble in the

WO91/19486 PCT/US91/04198
~ 12

low pH gastric fluid of the stomach, but æoluble in the less
acid environment of the small intestine. For example,
EudragitT~ E-100 is insoluble at neutral pH but soluble at a pH
less than 5.5; EudragitT~ 1-100-55 and L-30D are soluble at pH
greater than 5.5. Metal stearates incorporated into these shell
materials can increase water repellency. Other enteric coatings
are known which are less soluble and can provide release of the
drug over time, as will be known to those skilled in the art.
To provide both water impermeability, protection of the
drug in the stomach and release in the intestine, and delayed
release in the intestine, a series of enteric coatings will be
applied to the microspheres. The outer layer will be water
insoluble at normal pH, but will dissolve in the stomach (pH
less than 5.5~. The next layer will be insoluble at low pH in
the stomach, but will dissolve and release the drug in the
intestine (pH greater than 5.5). A third layer can provide
delayed release until the drug enters the upper
gastrointestinal tract, where the pH is higher again.
The enteric coatings are dissolved in an organic solvent,
suitably one appxoved for medicinal use, such as acetone,
methylene chloride, or the lower alcohols such a ethanol, or
mixtures of such solvents, and applied to the microspheres as
above. The organic solvents are removed by evaporation during
the processing of the microcapsules.




.

,
.

W091/19486 PCT/US91/04198
~ 3 2~53q~

The amount of coating applied to the microspheres is not
critical, and can vary from 5 to 30% by weight o~ the
microcapsule. It is important that the enteric coating be
applied uniformly over the microsphere to ensure that the
microspheres are protected from moisturel and that a given
dosage of the drug will be released by the coatings at the
appropriate portion and time in the digestive tract. Too thick-
a coating will delay dissolution of the coating and release of
the drug.
The enteric coatings can a1so contain conventional
additives such as suspending agents, emulsifying agents,
essential oils, preservatives, flavoring or coloring agents and
the like, as i5 known to one skilled in the art. Such additi~es
can retain a desired texture, retard hydration or dehydration
of the microsphare ingredients, and provide a uniform color and
appearance.
The invention will be further described in the following
examples, but the invention is not meant to be li~ited to the
details thereof. In tha examples, percent is by weight.
The actual erythromycin and ery~hromycin ethyl succinate
content of the microspheres was determined by high pressure
liguid chromatography (HPLC).
Actual amoxicillin trihydrate content in the microspheres
was determined using an iodimetric titration method, see Code

WO91/19486 PCT/US91/0419X

`3
. of Federal Regulations: Food and Drugs, Vol 21, Chap 1 Part
436.204 (1988), 291.
EXAMPLE 1
Using the rotating disc apparatus of Figure 1, a slurry
containing 30.0% of Erythromycin USP, 44.1 % of Emersol 6349,
18.9~ of Durkee 17 and 7.0% of aluminum stearate EA was heated
to 180F and fed to the disc maintained at a temperature of
160~F.
The resultant microspheres had a particle size
' 10 distribution of 4.3% particles of less than 105 microns; 84.9
: particles of 105-250 microns; and 10.8~ particles of 250-355
micrometers.
~n assay of the microspheres having a particle size of
250~355 micrometers determined the actual Erythromycin content
to be 20.9%.
EXAMPLES 2-13
The procedure of Example 1 was followed except varying
the matrix composition and temperature. In these Examples,
30.0% of Erythromycin was employed. The data summarizing the
matrix composition, the matrix temperature, particle size and
weight % distribution obtained and the actual Erythromycin
content in the microspheres are summarized below in Table I~ In
the Table, D17 represents Durkee 17 E6349 represents Emersol
6349, G 600-E represents Grocol 600-E; Zn St represents food
grade zinc stearate; Mg St represents food grade magnesium

WO91/lg486 P~T/~S91/Q4198
, 15 2Q8334~

stearate: Al St represents food grade aluminum stearate; and A
84K represents Atmul 84K.




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WO 91/194~6 PCT/VS91/04198
3~, 16 ~. `i

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WO91/19486 PCT/US91/04198
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All of the microspheres were satisfactory.
EXAMPLE 14-22
: 5 The procedure for Examples 2-13 was followed except using
23% of Erythromycin. The data are summarized in Table II below,
where the symbols are the same as for Table I.

WO 9l/19486 PCI'/US91/0~198
i~, 1 9 ~S3~2

~BL~ II

Pa~ticle
MatrlY Te~np. Size, Weight
E~ le Co~po~ltiQIl~ DF Micromet~rs X
1456.0Z E6349 190 105-250 15.9
~- 14.0X G600-E 250-355 63.5
7.0% Zn St 35S-500 20.6
1552.5X E6349 190 105-250 39.9
17.5% D17 250-355 60.1
7.0% Z~ St
1670.0% D17 190 105-250 23.9
7.0X Zn St 250-355 76.1
1756.0X E6349 190 105-250 30.4
; 14.0% G600-E 250-355 59.8
7.0X Al St 3S5-500 9.8
1852.5% E6349 190 105-250 67.1
17.5X D17 250-355 32.5
7.0X Al S t
1970.0% D17 190-200 C105 8.2
7.0X A1 St 105-250 46.9
250 355 44.9
2056.0% E6349 190 105-2S0 67.0
14.0X G600-E 250-355 33.0
7.0% Mg St
2152.5% E6349 190 105-250 58.9
17.5X D17 250-355 41.1
7.0 Mg St
2270.0X D17 190 105-250 10.4
7.0% Mg St 250-355 71.4
355-500 18.2




. ` :. ' , - '

'
;, ' ' . . .

WO91/19486 ~ PCT/U591/~4198
~S~ ~ ~' 20

All of the microsp~eres were satisfactory.
EXAMPLES 23-34
Using the apparatus of Figure 2 at a head speed of 2000
rpm, a head temperature of 190F and a shell composition
temperature of 180F, a slurry of the drug in a matrix material
was encapsulated with a single layer of various encapsulant
compositions to produce microcapsules. Equal amounts by weight
of the drug slurry and encapsulant were employed; thus the
theoretical amount of Erythromycin was 15% in the
microcapsules, which were sieved to collect a particle size of
250-500 micrometers for analysis. The data are summarized in
Table III below where the symbols are the same as for Table I
and N 060 represents Neutrene 060 triglycerides.

W O 9l/19486 PCT/US9l/04198
, .
2 1 2~ 2
:
T~BL~ III
,`
Encapsulant Slurry Actual X
Example Com~osition Comso~ition Erythr mq~_n
:
23 90Z D17 Ex3 8.7
lOX Zn St

:.
24 80% E6349 EY3 9.5
20X G600-E

80% E6349 ~s2 5.4
20% G600-E

26 100% D17 EY2 6.1
`:
27 90% D17 Ex2 5.6
10% Zn St
28 90% D17 Ex2 6.1
10% M8 St

29 lOOX D17 Ex3
90% D17 Ex3
lOX Mg St

31 80% E6349 56.0X E6349 6.7
20X N060 14.0X N060
30% Erythro~ycin

32 100% D17 56.0X E6349
14.0% ~060
30% Erythromycln

33 90% D17 56.0Z E6349
10% Zn St 14.0% ~060
30% Eryehromycin

34 90% D17 56.0% E6349
10% Mg St - 14.0% ~60
30X Erythromyci~

WO91/lg486 PCT/~S91/04198

~ b~ 22 ` ~'~.,'~.!
.

EXAMPLES 35-47
Using the apparatus of Figure 3, the microspheres
- prepared as in Examples 1-22 were encapsulated with two or more
layers of various encapsulant co~positions to produce
microcapsules. The enteric coatings were dissolved in a solvent
mixture, as shown, to which was optionally added a dyestuff,
FD&C ~l Lake Blue, or FD&C #6 Lake Yellow. EudragitT~ E-lO0
provides stability in liquid suspension and in the mouth, ~pH
about 7) and is soluble in the stomach tpH less than 5.5).
EudragitT~ L-100-55 will provide protection in the stomach and
release the drug in the intestinal tract (pH over 5.5).
The data relating to the application o~ the coatings are
summarized in Table IV below.




. . .

WO 91/19486 PCI/US9~/04198
i 23
2 ~ 3 ~ 2


'1 C N `O ~ 1~ ~ U'l N O O O ~CI P') ~
O ~--1 ~ N N N ~ ~ ~ N ~ , N e~ N
:E

O O O O O O . O O O O O O O O
r~ _~
O _
~:) '# . O O O O O O O O O O o o

_~ O O O
V _ ~J N N
.C ~
O~
3 o oo ~ o o o o o o o o o o o o o o o o o o o o o
O ~ `O ~ ~ ~ N ~JN N N N ~ N N N N N N N N ~i N N

~ U ~ .
O ~ ~I O ~`I O O O O O O O O O O O O O O O O O O O O O O O
O ~ ~ 1 ~ N 1~ N ~ t~N N t~ 1 N t~ ~`I N ~ ~`J
U
V ~
~ ~ O
C~ 00 C
_1
.
~V~
0 0 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~

O~
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K
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.

W O 91/19486 P ~ /US91/~4198

24 ~.;

The data relating to the amount of the coatings applied
is given below in Table V. where the result was obtained from a
measurement of the amount of shell solution per weight of
microsphere sample used during the coating process. The
resultant microcapsules were in the 250 to 500 micxometer size
range.




.

;

.

U'O 91/19486 PCT/US91/04198
I .ç~ 25

TABLE v 2 ~ 3 ~ 2

Weight x Shell
E~camPle Inner ~Outer
36 14 . 013 . 9
43 13 . O13 . 3
44 13 . O13 . 8
13.013.2
46 13 . 013 . 1
47 13 . 013 . 6




.

WO91/19486 26 PCT/US91/0419B



EXAMPLE 48
Microcapsule samples made as in Examples 35-47 were
evaluated for stability in simple syrup solution by storing for
l and 4 weeks under accelerated shelf-life conditions at 37C.
The amount of antibiotic found in the syr~p was determined. The
data are summarized below in Table VI.

W O ~1/19486 2 7 PCT/US9~/04198
" 1: .
: . TABLE VI 2 Q 3 a 3 ~ ~

Mlcrocapsules, X Release X Relea~e
mD1e1 week 4 week~

<1.0* 6.2
36 0.11 2.4
: 37 <1~0* 2.5
; 38 <1.0~ 2.5
39**<1.0* 3.0
~-97 2.6
41 0.74 2.0
42 1.3 2.9
43 0.76 3.1
44 0.74 2.0
0.81 2.2
: 46 0.74 1.9
47~*0.64 1.6

Estlmated
~* rhese samples were then ~haken a~ 37C for 48
hours. The X release for Example 39 wa~
3.6%; the X release for Example 47 wa~ 1.8Z.

WO91/19486 28 PCT/US91/~4198
f ~ ~
3~
It is apparent that the microcapsules of the invention
are stable in aqueous solution for long periods of time, even
under accelerated temperature conditions.
EXAMpT~ 49
PART A. Microspheres were made following the procedure of
Example 1 u~ing 40.0% of erythromycin ethyl succinate within a
69% Durkee 17 matrix. The matrix temperature was 235F.
The product contained 39.4% of particles 106-250
micrometers in size; and 60.4% of particles 250-355 micrometers
in size;
The actual amount of the antibiotic found in the
microspheres was 3I.2%.
PART B. The procedure of Example 35 was followed to make
microcapsules of the microspheres of Part A. The first coating
was made using EudragitT~ L-3OD and a second coating of
Eudragit~ E-lOO using a solvent mixture of 72.0 parts of
methylene chloride and 24.0 parts of ethanol. The microcapsules
contained 20.0~ of erythrocmycin ethyl succinate.
EXAMPLES 50-55
The procedure of Example 1 was followed to prepare
microspheres except that the drug employed was amoxicillin
trihydrate in varying amounts. The data on microsphere
preparation is summarized below in Table VII.

~ W O 91/194B6 PC~r/US9~/04198
~ ; 2 9 2 0 8 53 ~
v




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V ~ V
~ ~ ~ .
E~ ~ ~ .
1:: L V
_~ _
U ~
X L O O O O O O
r~
X

V
0~ O ~ O ~ O
K o u~ ~t o r~ ~ o o~ o

C~
~ ~ ~ U~ o U~ U~ o U~ o U'~
P1 ~ ~, E , 1, ~ ~, ~, ,
N ~ o ~n o o `D o ~o o o
o u ~ o ~ o u~ In

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~ ~ r~ o o _ o o
E~ ~ _
o~ , .
.Y
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o ~ U~
0 i~
a c: Q ~
13 ~ K K K K o K o o
oo r~ o ~ ~
q~ o ~o ~o 'D

Eil o ~ t U~
X ~ U'~

- WO91/194B6 P~T/US91/04198
~ . 30



EXAMPLES 56-60
The microspheres as in Examples 50-55 were encapsulated
following the procedure of Example 35. The data relating to the
encapsulations are summarized in Table VIII below:




~,,
;
i




,

WO ~1/19486 PCl[/US91/0~198
3 l 2~353~2

o~ o ` ,~
I ~1 1

1~
o o o o
O _~ ~ _1
~: ~
o o o o

,~ L O O O O O
V C ~ ~ ,~

vl o
¢l

O
~ O O O O O O O O
.C ~-t ~ ~ ~ ~J ~ ~ ~
:~~1

~CO~ O O
L '~I ~ O O
.,1 ~
3 w

X ~J~
e o~ c ~ ~ ~ ~ ~ ~
~ 14
~: ~4~
a oo C
_
W'


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E ~o r~ o
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. .

WO91/19486 ~ PCT/US91/04198
~ ~ 32 ¢ !

EXA~PT.F. 6 1
- The microcapsule samples made as in Example 56 using the
microspheres as made in Example 50 were evaluated in simple
- syrup solution by storing for one, four and eleven weeks under
accelerated shelf life conditions at 37C. The amounts of
antibiotic found in the syrup after vigorous shaking is as
follows: 0.0% release after one week; 3~1% release after four
weeks and 26.5~ reiease after eleven weeks.
It is apparent that the microspheres of the invention can
be encapsulated with multiple coatings as desired using the
processes of the invention. The resultant microcapsules are
small in size, are water impervious, and can be tailored so
that the drug is protected in aqueous solutions, and can be
released as desired, and when desired, to optimize the drug's
e~ectlveness. The invention also provides a means of
dispensing a water unstable drug in an aqueous solution that is
stable and which can be stored at room temperature for extended
periods of time.

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 1991-06-13
(87) PCT Publication Date 1991-12-15
(85) National Entry 1992-12-14
Dead Application 1993-12-13

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1992-12-14
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
KAPLAN, MILTON R.
LEW, CHEL W.
LAMB, CATHERINE S.
KALMO ENTERPRISES, INC.
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Representative Drawing 1999-01-22 1 18
International Preliminary Examination Report 1992-12-14 9 237
Office Letter 1993-02-26 1 29
Abstract 1991-12-15 1 87
Drawings 1991-12-15 3 45
Claims 1991-12-15 4 88
Abstract 1991-12-15 1 53
Cover Page 1991-12-15 1 19
Description 1991-12-15 32 827