Note: Descriptions are shown in the official language in which they were submitted.
1~862Z6
The present invention relates to prolonged continuous release pharm~
aceutical preparations containing an ion exchange resin having a pharmacologi-
cally active drug adsorbed thereon to provide a drug resin complex wherein at
least a portion of the complex is treated with a solvating agent and provided
with a diffusion barrier coating.
Prior Art
The basic patent on the use of (uncoated) ion exchange resin drug
complexes to delay release of a drug in the gastrointestinal tract is U.S.
Patent No. 2,990,332. However, such uncoated complexes provide only a
relatively short delay of drug release in comparison with the preparations of
this invention and provide no means for selectively modifying the release
profile. ~
Various coated resins and resin drug complexes have been reported
` (e.g., in U.S. Patents 3,138,525; 3,499,960; and 3,594,470; Belgian Patent
729,827; German Patent 2,246,037; and Brodkins et al, Journal of Pharmaceuti-
cal Science, Vol. 60, pages 1523-1527, 1971), but none are believed to employ
the preparations of the subject invention or to provide the prolonged
continuous release obtainable with the present preparations.
Brief Summary of the Invention
The present invention is concerned with pharmaceutical preparations
comprised of ion exchange resins having a pharmacologically active drug
adsorbed thereon to form a drug-resin complex wherein at least a substantial
portion of the complex particles have been treated with a solvating agent and
provided with a water-permeable diffusion barrier coating whereby a prolonged
continuous release of the drug is obtainable under conditions encountered in
, the gastrointestinal tract.
Detailed DescriDtion
It has now been found that a selective, prolonged contin~ous release
of pharmacologically active drugs, under conditions such as those encountered
_,
~0862Z6
in the gastrointestinal tract, can be achieved by the application of diffusion
barrier coatings to ion exchange resin drug complex particles which have been
treated with solvating agents.
In general all acidic and basic drugs, especially those having short
biological half-lives in the order of up to about 8 hours, are potential
candidates for inclusion in the subject preparations. Examples are phenyl-
propanolamine (PPA), dextromethorphan, ephedrine, pseudoephedrine, paraamino
salicyclic acid, acetyl salicylic acid, phentermine (phenyl-tertiary-butyl-
amine), and acetaminophen. PPA, a symphathomimetic amine drug with a biologi-
cal half life of 3.9 hours in man and a pKa of 9.4 was chosen as a model drugfor use in the bulk of the illustrative examples. The loading of the drug on
the resin particles can be from about 1-90 percent by weight, although 15-50
percent is the normal practical range.
Similarly, a wide range of cationic (for the basic drugs) or anionic
(for the àcidic drugs) exchange resins can be used to form the drug resin
complex, particle sizes normally ranging from about 75 to 1000 um. The
illustrative examples employ Amberlite IR-120, a cationic exchange resin
consisting of 20-30 mesh (590-840 um) spherical particles as a model large
particle resin and Amberlite XE-69, which is 100-200 mesh fractured resin
particles of Amberlite IR-120, as a model small particle resin. The parent
resin of IR-120 and XE-69 is described by the manufacturer as gel-type divinyl-
benzene sulfonic acid cation exchange resin which swells in water with a p~
range of 0-14. Other suitable ion exchange resin candidates include
synthetic ion exchange resins
* Trade Mark
.
:' :
. . . .
0862Z6
. .
`: ~ Wltll dlfferent polymerlc matrices (e. g., methacrylic, acrylic, phenol
`c 1 formaldehyde), ion exchange agents with cellulosic or dextranpolymer matrlces, and inorganic ion exohange matrLces, The resins
; should not have inherent pharmacological or toxLc properties.
- j 5 Adsorptlon of the drug onto the Lon exchange resin partLcles to
form the drug resin complex Is a well-known technique as shown in
U. S. Patent No. 2, 990, 332 and demonstrated In the examples hereinbelow.
In general, the drug Is mlxed with an aqueous suspenslon of the resin
~i and the complex is then dried. AdsorptLon of drug onto the resin Lsdetected by a change In the pH of the reaction medium.
s As shown by the Illustrative examples below, such resin drug
,1 ~ complexes rapidly release the drug In the gastrointestinal tract, e. g.,
an Amberlite IR-120 phenylpropanolamine complex with a 35 percent drug
:~ loadlng released 61 percent of the drug in 60 mlnutes in a 0.1 normal
r; 15 hydrochlorlc acid dissolution medium (Example 1). Initial attempts to
retard this rapid release of drug by the use of diffusLon barrier coatings
were relatlvely Ineffectlve as shown by Examples 1 and 2 below slnce the
coating tended to peel rapidly and the coated partlcles swelled and
tended to fracture when contacted by water or biological fluLds. It
has now been discovered that the tendency of ion exchange resin drug.
complex particles to swell and fracture in biological fluids can be
; overcome by the u se of solvating agents such as polyethylene glycol.
The solvating agent can be added as an LngredLent in the resln drug
complexatlon step or preferably, the partlcles can be treated wlth the
:, I ,
solvatlng agent after complexlng. Thls treatment has not only been
found to help the partlcles retaln thelr geometry, but ha s enabled the
:~
,~ ,. ' ~
' '
-4-
~ .
.
1~862Z6
effective application of diffusion barrier coatings to such particles. A
model solvating agent chosen for use in the illustrative examples is poly-
ethylene glycol 4000, a normally solid hydrophilic agent. Other effective
solvating (impregnating) agent candidates include, for example, propylene
glycol, mannitol, lactose and methylcellulose. Up to about 30 parts by weight
(normally 10-25 parts) of the solvating agent to 100 parts by weight of the
resin has been found to be effective. As shown in Example 3, such pretreat-
ment of drug resin complex particles has enabled the effective application
; thereto of diffusion barrier coatings, resulting in the ability to effectively
prolong the release of drugs from drug resin complexes.
The water-permeable, diffusion barrier coating materials can in
general be any of the conventional synthetic or natural film-forming
materials with diffusion barrier properties and with no inherent pharma-
cological or toxic properties. Ethylcellulose, a water insoluble film
forming agent was used as the model diffusion barrier membrane material in
the illustrative examples. A plasticizer, Durkex 500 vegetable oil, was used
to improve the film forming characteristics of ethylcellulose. The amount of
coating used depends on the degree of drug release prolongation desired.
Conventional coating solvents (such as ethanol or a methylene
chloride/acetone mixture) and procedures can be employed to coat the particles.
In the illustrative examples, coatings were carried out by using an air
suspension spray coating technique using a Wurster coating apparatus.
Techniques of fluid bed spray coating are taught, for example, in U.S. Patent
Nos. 3,089,824; 3,117,027; and 3,253,944. The coating is normally applied to
the drug resin complex, but
,. ?,
* Trade Mark - 5 -
~, . .
~862Z6
alternatLvely can be applied to the resin before complexing wLth the
. ~ drug.
3 DLssolutlon data ln Examples 4-16 below demonstrates that the
prolonged, continuous release of drugs from drug resin complex particles
Is now obtainable by use of solvating agents and dlffusion barrier
coatlngs, and that the dissolution profiles of such coated complexes are
relatlvely unaffected by the various conditions encountered Ln the
gastrolntestLnal tract. It is also demonstrated that variatLon in the
amount of coatlng and/or the use of coated/uncoated complex mixtures
can now be employed to selectively modify the dissolution profile as
, ,.
- deslred. Biological availability studles reported in Examples 17 and 18
: ~,
conflrm the dlssolution profile results and demonstrate practLcal
admlnlstratlon of the subject preparations Ln syrup and capsule form.
~ . .,
. In addltlon to oral adminLstration, the preparations of the subject in-
r' 15 ventlon are also sultable for toplcal, rectal, vaglnal or nasal admln-
; Istratlon In dosages varylng over a wlde range, for example from about
"
O. l to about lOOO mg, dependlng on the nature of the drug and Its
- lntended usage, The composltions can take the form of tablets, powders,
capsules, llquld suspensLons or other conventlonal dosage forms.
,:
., ',~
-6- ,
:'
1086226
ILLU S TRl~ Tl~E 1'XR M P LES
The following dLssolution test apparatus and procedurcs were
used in the examples to slmulate condL~Lons encountered Ln the gas-
trolntestLnal tract: 500 mLllLliters (ml, ) of the selected dissolutLon
5 ,medLum (0. IN.HCl - pH of 1. 2; or 0. IN HCl plus NaCl to show effect
oE chlorlde ions; or 0.lM phosphate buffer - pH of 7.5) was placed In
a one lLter cylLndrical jacketed beaker. The dissolution medlum was
, ;~ malntalned at 37 + 0. 5 C, by clrculating warm water through the
jacket from a water bath. A three-bladed polyethylene stLrrer wa s
~ 10 posltLoned eccentrLcally In the dLssolution beaker and rotated at 60
; , revolutLons per mLnute. A ~olymer foam cylindrLcal, sparger extending
'~' Into a regular plastic tube was positLoned diametrically opposLte the
stlrrer. The dlssolutlon medlum flltered Into thls tube from where it
was pumped by a finger pump through a polyethylene tube Lnto a five
,, j, 15 centlmeter (cm. ) cell path flow through cell and returned to the beaker.
A double beam ultraviolet spectrophotometer (Beckman Model Dk-2A~
, ~ was used to monltor the changes In the absorptLon at the selected
, ultravlolet wavelength (257 nm for phenylpropanolamLne) as a functLon
,.,
of tlme on a movlng chart as the drug was released from a drug resln
.~- 20 complex sample (equlvalent to 70 mLlligrams of drug) agltated In the
dlssolutlon medlum. The drug released was then expressed as a per-
centage of the total drug present In the resln complex partLcles.
Mlcroscoplc examlnations of partlcles of resln were carried out
J uslng a Bausch and Lomb low power blnocular mlcroscope (objectlve
2 5 X3 and eyepLece X10) .
Dlffuslon barrler coatlngs were carrled out usLng an alr suspen-
:
-7- ,
.
086ZZ6
,
sion coating technique employing a Wurster coating apparatus (such as made by
Aeromatic U.S., Inc., Glatt Air Techniques, Inc. and Dairy Equipment Corp.).
Examples 1 and 2 illustrate the effect of omitting the diffusion
barrier coating (such as ethyl cellulose) and/or the use of pretreatment
agents (such as polyethylene glycol) from drug resin complexes based on
phenylpropanolamine (PPA).
EXAMPLE 1
a. Preparation of Amberlite IR-120 Phenylpropanolamine Complex
(35% theoretical load):
Amberlite IR-120 Resin-Hydrogen Cycle (10% moisture) 3611 gm
Phenylpropanolamine Base 1750 gm
Procedure:
The resin was placed in about 10 liters of deionized water. ~ -
The phenylpropanolamine base was added with low agitation.
- The mixing was continued for 5 hours. Initial pH of the
slurry was 2.5. pH of the suspension during addition of
phenylpropanolamine was 8Ø The final pH of the suspension
; was 1.7. The resin complex was collected on a buchner
funnel and tray dried at 45 C in an air oven. The following
dissolution was obtained on the uncoated resin drug complex.
% PHENYLPROPANOLAMINE
TIME, MINUTES RELEASED IN O.lN HCl
32
48
61
~ Mlcroscopic examin-tion showed sm m fractursd rssin particles.
i - 8 -
~86226
b. Coating of (2) above:
IR-120 - PPA resLn complex from (a) above 100 gm.
Ethy lcellulo se 3 gm.
. ~ Ethanol 95% 60 ml.
Procedure:
Ethylcellulose was dlssolved ln ethanol. The resin complex
was placed in a fluLd bed coating apparatus and fluidlzed.
The ethylcellulose solution was slowly applled to the
,~ fluldlzed resin particles at room temperature. After all ofp 10 the solutLon was applLed, the partlcles were further dried
..
- for a few mLnutes.
. ~ Mlcroscopic examination of the particles revealed that the
`''
; coatlng was uniformly applied. There were some broken
- partlcles present too:
The followlng dissolutLon data was obtalned:
: .
': % PHENYLPROPANOLAMINE
; TIME, MINUTES RELEASED IN~QlN HCl
15 15
30 26
, 20 60 ` 42
The data shows that some retardation of dissolution of the
drug resin complex Is achieved by coatlng the partlcles,
i,
., though not to a slgnlfLc2nt extent.
EXAMPLE 2
Example 1 was substantially repeated uslng 550 gm. of Amberllte
XE-69 Phenylpropanolamlne Resln Complex (about 25% drug load) as
the core materlal; 75 gm. of ethylcellulose (50 cps) and 30 gm. of
`
.
`".` `-` 1()862Z6
;``.
: of Durkex 500 refined vegetable oil as the coating agents; and 140 ml. of
: acetone and 1260 ml. of methylene chloride as the solvents.
~- The coating agents were dissolved in the mixed solvents with
stirring and quantitively applied on the core in a 6 inch fluid bed apparatus
at the rate of approximately 8 ml./minute (total time - 205 minutes). The
inlet air temperature range was 140-160F. The outlet air temperature range
was 88-95F.
The average particle size of the coated particles was 96 um.
Microscopic examination of the particles showed the coating of the particles
to be peeling.
, The following dissolution data was obtained:
% PHENYLPROPANOLAMINE
RELEASED IN 0.lN HCl
TIME, MINUTES COATED UNCOATED
57 82
.
76 88
87 92
91 95
The data again shows that coating alone only leads to slight
retardation of dissolution.
Repeats of Examples 1 and 2 produced equivalent results, the coating
being observed to peel readily in all the tests. Also, when the coated
particles were brought in contact with water, they swelled considerably and
tended to fracture. These problems were overcome when the ion exchange
resin drug complex particles were treated with polyethylene glycol 4000 as
;described in the following example:
.
- 10 -
~86226
`'
EXAMPLE 3
a. Preparation of Amberlite IR-120 Phenylpropanolamine Complex:
Amberlite IR-120 resin (hydrogen cycle - 10% moisture) 2167 gm.
Phenylpropanolamine 1050 gm.
The resin was placed in 7 liters of deionized water in a
- suitable beaker and mixed for 20 minutes to hydrate. Initial
pH wasnoted to be 2.5. The phenylpropanolamine base was
gradually added with mixing. It was then set aside. The final
pH was 1.7. The resin complex was collected on a buchner
funnel and tray dried in an air oven at 45 C.
b. Preparation of Polyethylene Glycol Treated complex:
Resin Complex from (a) - 900 gm.
Polyethylene glycol 4000 100 gm.
The resin complex was placed in a suitable jacketed planetary
mixer. The polyethylene glycol 4000 was added and gently mixed
with application of gentle heat. When the polyethylene glycol
4000 completely melted (56 C) the heat was turned off. The
mixing was continued until the temperature returned to room
temperature. The resin particles were gently passed through
#20 mesh screen to remove any agglomerates. Very few
agglomerateswere noted to be present. The following dissolution
data was obtained:
% PHENYLPROPANOLAMINE
TIME, MINUTES RELEASED IN 0.lN HCl
26
39
47
-- 11 -- :
~86226
:'`
c. Preparation of Coated Complex from b.
100 gm. of the polyethylene glycol treated resin complex
from (b) above was placed in a fluid bed spray coating
apparatus and fluidized and coated with a solution of
ethylcellulose (10 cps) in ethanol 95% (6 gm. in 300 ml.).
, The coated particles were dried for a few additional minutes
after all the solution had been applied. The coated beads
; were examined microscopically and were observed to possess
; fairly good coating.
, . . .
. ~
The following dissolution data was obtained:
% PHENYLPROPANOLAMINE
,~ TIME, MINUTES RELEASED IN 0.1N HCl
9 "
18
28
~ This data indicates that good retardation of the dissolution
-~ rate of drug resin complex particles is obtained by application
of a diffusion barrier coating when the particles are treated
with agents such as polyethylene glycol.
The following examples (4-16) illustrate application of the above
discovery to prepare formulations representative of the subject invention:
EXAMPLE 4
a. Preparation of Amberlite IR-120 PhenyIpropanolamine Resin
Complex:
Amberlite IR-120 resin (wet hydrogen cycle) ` 600 gm.
(288 gm. dry)
Phenylpropanolamine base 155 gm.
,~
- 12 -
--- 1086ZZ6
Polyethylene glycol 4000 72 gm.
DelonLzed ~,vater 1000 ml.
72 gm. of polyethylene glycol 4000 was dlssolved in 1000
ml, of deionized water. The resin was added to this
` 5 solution with gentle mlxing. Phenylpropanolamine was
, j added gradually with gentle mLxing, The mixing was
- contlnued until the pH dropped to 1, 9. It was then set
, aslde for 24 hours. The solution was drained off from the
' ¦ resln complex.
b. Preparation of Coating Solution
Ethylcellulose (50 cps. ) 5 gm.
Durkex 500 - refined vegetable oil 2 gm.
, Ethanol 95% 200 ml.
.,
Durkex 500 was added to ethanol 95% with stLrring. The
solutLon was warmed to 45C. Ethylcellulose 50 cps was
dlssolved In It wlth mlxlng, The solutlon was malntalned
at 45C durlng the coatlng,
c. Coatlng of Amberllte IR-120 - Phenylpropanolamlne Resln Complex
178. 6 gm, of the resin complex from (a) (100 gm. dry resin)
was ~laced In the fluid bed coating anpar~tu~. Th.~ rpcin
; I complex was fluidized and partially dried (time 25 mlnutes)
. .
at room temperature. The coatlng solution (b) was then
sprayed on the resin complex gradually until all of the
solutlon had been applled (tlme 90 mlnutes), The alr sup-
ply wa s at room temperature, The coated partlcles were
drled for 5 more minutes at the end of the appllcatlon of
_13_
.
.
` I 1086Z26
the coatLng solution. The dry coated partlcles were
. ,
gently screened through #20 mesh screen.
Microscoplc examination showed the partLcles to be
smooth and unlformly coated. No fractured partLcles
were noted to be present.
The partLcles had a moisture content of 4%. Phenyl-
propanolamine content was 31. 6%.
The followLng dLssolutLon was obtaLned. Good retar-
datLon of the dissolution rate Ls evLdent by comparLson
of the uncoated control (data ln second column) to the
dissolutlon data for the coated partLcles ~third, fourth
. i:
and fifth columns) regardless of the pH of ionic concen-
tratLon of the med ia .
', .,
,.'- .-. .
... .
. :.
,,",~
:,
; ,,1 . :
I
.,
~1 , . (
~~4-
.,i :
86ZZ6
~`
cn ~
Q, ~r o ~ ~ o a~ o ~ . .
., ~ ~ ~
o m
,f' +
~ ~ ~ ~V ~
. . ~ o ~; Z L~ o ~ ~-
. ~ C~ ._
o
" ~i
. ' O o
., . ~ '
". "' ~Y;
'" ~
a~ v
.' E , V
0~ u~
,~- ~,oo
, ,j
In O O O O O O O
'. .
'., . . .
:
'. ' ` ' ` .
` ` ~086ZZ6
EXA~PLE 5
The above example was repeated to indicate reproducibility.
a. Preparation of Amberlite IR-120 Phenylpropanolamine Resin
Complex
Amberlite IR-120 resin "wet" (hydrogen cycle) 600 gm.
(288 gm. dry)
- Phenylpropanolamine base 155 gm.
Polyethylene glycol 72 gm.
Deionized water 1000 ml.
72 gm. of polyethylene glycol 4000 was dissolved in 1000 ml. of
deionized water. The resin was added to this solution with gentle
mixing. 155 gm. of phenylpropanolamine was added gradually with
gentle mixing. The mixing was continued until the pH dropped to
2Ø It was then set aside for 24 hours. The solution was
drained off from the resin complex.
b. Preparation of Coating Solution
Ethylcellulose (50 cps.) 5 gm.
Durkex 500 - refined vegetable oil ` 2 gm.
Ethanol 95% 200 ml.
Durkex 500 was added to ethanol 95% with stirring. The solution was
warmed to 45 C. Ethylcellulose (50 cps3 was dissolved in it with
mixing. The solution was maintained at 45C during the coating.
- 16 -
`
~86ZZ6
C. Coating of Amberlite IR-120 - Phenylpropanolamine Resin Complex
178.6 gm. of the resin complex from (a) (100 gm. dry resin)
was placed in the fluid bed coating apparatus. The resin
complex was fluidized and partially dried at room temperature.
The coating solution (b) was then sprayed on the resin complex
gradually until all of the solution had been applied. The
air supply-was at room temperature. The coated particles
were dried for 5 more minutes at the end of the application
of the coating solution. The dry coated particles were gently
screened through #20 mesh screen.
Microscopic examination of the particles showed the particles
to be smooth and uniformly coated. No fractured particles
were noted to be present. The final moisture was 3.6%.
Phenylpropanolamine content was 30.7%.
The following dissolution data was obtained in 0.1N HCl and
O.IM phosphate buffer pH 7.5.
% PHENYLPROPANOLAMINE RELEASED IN
TIME, HOURS 0.lN HCl0.lM PHOSPHATE BUFFER pH 7.5
0.25 3.0 4.2
0.50 6.3 8.9
1.0 13 17
1.5 18 24
2.0 25 30
3.0 34 40
; 4.0 42 49
5.0 48 52
6.0 55 62
7.0 59 6
.
'
- 17 -
;: .
.
.. . . . ~ ~
~86Z26
As can be seen the dLssolution data are slmllar to the data
obtalned In Example 4.
Both these examples show that the dlssolution rate of drug from
a resln drug complex such as Amberlite IR-120 phenylpropanolamine can
5 be significalltly modified by the application of a dlffusion barrier coating
isuch as that of ethylcellulose and the use of a treating agent such as
polyethylene glycol.
The examples also show that the rate of drug release from
ethylcellulose coated particles are not signlficantly affected by pH or
10 hlgh lonic concentration.
Dlssolutions have also been carrled out in dlstllled water on
these coated resln complexes as well as uncoated resln complexes. No
~.
slgnlflcant release of drug have been noted from either.
EXAM PLES 6 - 8
;~ 15Examples 4-5 were agaln repeateà In 500 gm. (Example 6) and
; 1000 gm. (Example 7) quantltles. The dlssolutlon data from these ex-
amples as well as from Examples 4-5 are summari~ed in Table 1 below.
Example 8 the data for whlch is also summarlzed In Table 1
Illustrates how the present dlscovery can be utilized in practice to
20 achleve desired dlssolution profiles for drugs Intermediate between the
rates for the uncoated and coated drug resln complexes by uslng mixtures
- ~ thereof. The Example 8 dissolution proflle Is achieved by preparing a
mlxture of 30 percent of the uncoated IR-120 PPA resin complex and 70
percent of the coated resin complex of Example 7.
-18-
: '
'
.
1~86ZZ6
.
J C~ ISL' I
't
'1
~ o ~r
r~ I ~D Ln
,' o Ln ~ a7
~ I U~ Ln Ln I ~Lt
' ~.
~- Ln l n ~r ~ I ~
. ~
,, '
. . . . ~ Ln O
~r
. .,
:i t~ ~ o ~ Ln
'. s~ Is.~ s~ s.~ ~ Ln
", ..... , _ ~a
. ! . ~ r~ Ln C~ Ln r~ ' I
E-l S.~l I C~l N S.~ S~ ~r
~ ~ i'
_
~, . O Ln r_ ~, I I I o
. - J
. ~ .
,,' ' a) _;
s . ~ ~
., . ~ ~,:
:~ S ~e Ln
O ~ I ~ 3
`,.' ~
~ ~ ~ ~0
$ O C ~ Ln ~ 1` ~ li
. !
_19_
.
.
~086ZZ6
Another means of adjustLng the dissolution profile made possible
by the present dLscovery is to vary the amount of coatlng, The follow-
, Ing example illustrates the result of using one-half the amount of
coating materials employed Ln Examples 4-5.
EXAMPLE 9
a. Preparation of Amberlite IR-120 Phenylpropanolamine Resin
Complex:
Amberlite IR-120 resin "wet" (hydrogen cycle) 1800 gm.
(864 gm. dry)
10 Phenylpropanolamine base 465 gm.
- ^ Polyethylene glycol 4000 216 gm.
, - Delonized water 3000 ml.
216 gm. of polyethylene glycol 4000 was dlssolved in 3000
- ml. of delolzed water. The resln was added to thls solutlo n
, 15 wlth gentle mlxlng. 465 gm. of phenylpropanolamine was
... .
,, added gradually wlth gentle mlxlng. The mlxlng was contlnued
untll the pH dropped to 2. 0. It was then set aside. The
solutLon was dralned off trom ~he resin comple c.
b, Preparatlon of coatlng solutlon:
~0 Ethylcellulose 50 cps. 2. 5 gm.
n lrkf!~ ~no r~f~ned ve~eta~le oil 1 gm, I
J Ethanol 95% 100 ml.
Durkex S00 was added to ethanol 95% wlth stlrrlng. The
solutlon was warmed to 45C. Ethylcellulose (50 cps,)
was dlssolved In lt wlth mlxlng. The solution was maln-
talned at 45C durlng the coatlng.
c. Coatlng of Amberllte IR-120 - Phenylpropanolamlne Resln
Complex:
. I , . .
-20~
:
~86ZZ6
I
181. S gm. of the resLn complex from (a) (100 gn). dry
basls) was placed In the fluid bed coating apparatus.
The resln complex was fluidized and partlally dried at
room temperature. The coatlng solul:ion (b) was then
sprayed on the resin complex gradually until all of the
solutLon had been applied, The alr supply was at room
temperature . The coated particle s were drled for 5 more
7 ~ mlnutes at the end of the appllcation of the coatlng
solutLon. The dry coated partlcles were screened through
#2 0 me sh screen.
'
Mlcroscopic examinatlon of the partlcles, showed the partlcles
to be smooth and uniformly coated. No fractured particles
were noted to be present. The fLnal moisture was 6. 5%.
Phenylpropanolamine content was 30.1%.
' ' :
~ 15 The following dlssolutlon was obtalned:
..
: % PHENYLPROPANOL~MINE
TIME, HOURS RELEASED IN 0. lN HCl
0.25 12
0. 50 23
~ 20 1. 0 37
; ~
1~5 48
,1 2.0 54
3.0 66
4.0 73
5.0 78
6.0 81
7,0 85
-21-
~0862Z6
: ~,
The above data shows that the retardatlon of dissolution is a
functlon of the amount of coatlng applied.
The following examples (10-15) illustrate the subject Invention
uslng Amberlite XE-69 in place of the Amberlite IR-120 used in Examples
5 4-9.
ExamPle 10
a. Preparation of Polyethylene Glycol Treated Amberlite XE-69
Phenylpropanolamine Resin Complex
' Amberllte XE-69 - Phenylpropanolamlne Resln 3000 gm.
Complex (24% drug load)
.
Polyethylene glycol 4000 7 50 gm.
DelonLzed water 3000 ml.
The polyethylene glycol was dissolved In the delonlzed water
and the Amberllte XE-69 phenylpropanolamlne complex added
to lt and mlxed. The mlxture was set aslde for an hour
s and then placed In an air oven and allowed to dry at 58C
untll the moisture was about 10 %. It was then screened
through a 100 mesh screen prior to coatlng. The average
particle size was observed to be 82 um.
r 20 b. Preparatlon of coatlng solutlon:
Y1C~11U1GSG ~)(; C~;, 74. 9 g~
, Durkex 500 (reflned vegetable oll) 29. 7 gm.
Acetone 140 ml.
Methylene Chlorlde - sufflclent quantity 1400 ml.
; ¦ 2 5 to make
~, . ~'
.
-22-
. __._,_ .. .. . . . . . . . . . . .
10862Z6
Ethylcellulose and the vegetable oLl were dlssolved In the
solvents,
c. Coatlng Procedure
The above resin drug complex core materLal was fluidlzed in
' 5 a sultable fluid bed apparatus that had been provided with a
fllter bed to retain flne particle materials, The coating
solutLon was applied continuously to the particles at 8, 5 ml,/
minute, ~Application tLme: 182 mlnutes) The solvent was
allowed to evaporate off contlnuously as Lt was applied, The
temperature of the inlet alr ranged between 140-153F, The
temperature of the outlet air ranged between 87-97F, A
screen analysis was obtained on the coated particles, The
average particle size was observed to be 115 um,
MLcroscoplc examination showed the particles to be uniformly
coated. When treated wLth water, the partlcles did not
swell as much as the uncoated particles.
- The followlng dlssolution was obtalned: Retardatlon of dls-
solutLon Is evldent In the coated product.
.~ . I'
:
''''
1 1
- -23- ~
D ~ I
10862Z6
~ E u~
~ ~ O ~ U~ o o~ ~ _
E~ ~ F~ N t~) In U) ~D ,1~
~ O ~
~n . ~
~ O ,~ I
b _ ~ Il
K _ .
a~ W_ .
., ~ I . I
, O ~c~
E I .
V I N O!) C~l U~ 1
~, C,
~;
: ~
., ~ . i.
.- ~_ Lr) O ~ '
.. E~ C N U) o ~ O O O O O O l
O O _~ _ N C~ ~r U)
~I
~, ~ ' ' ' ' -
' ' . ~ ' ' . '
~86ZZ6
',
EXl~MPLES 11-15
Table 2 below summarlzes the dlssolutLon data obtalned from
four additlonal runs (Examples 11-14) of coated XE-69 PPA particles
prepared as In Example 10 in comparison to the uncoated control.
t As with Example 8, the Example 15 data agaln illustrates
adjustment of the dissolution profile by using a 30/70 mixture of
uncoated and coated particles from Example 10.
'.
-':
'
.
'
:'', ,
:~, .
'. ,' ,
.~
'.' .1
:~
,., .
'I
~
,
I
. j , .
-25-
. ` 1~862Z6
.
.
.` - . . .
` , :
i
'''' .,
f` tD ~ .
`:
'."' . U~ .1 1 1 1 I t~
''' ,
~r
. .
~ ~1 ~
'' -, ~ ~ IIIII~D
. m V
~.:, o~
'....................... '~ u~
. ~ ~ ",
to .... _
. . ~
~ C~ C~ . OD ~ U~ ~
., ~: ~ _~ ~ ~ ~ U~
., ~
~O ." 00 ~ t~ _~
:, ~ ` I
: ! ~ ,
, , j .
: ', o a) c~~ ~ _ i
X O O
Il
'.~'
' I
-26- ~
'',' ' '
. .
1086ZZ6
MPLE ]6
This example ShO~AI~S the usc of high load of drug in the fine particle
resin complcx. The retard_tion of the drug release after coating from these
small sized, high drug con'ent particles is as significant as in the examples
with lower drug concentration previousiy described (Examples 10-15).
- ¦ The Amberlite IRF-66 resin used herein is the same as Amberlite XE-69
except that it has a higher heavy metal limit and thus is given a different
grade number. This particular batch of IRF-66 met the XE-69 heavy metal
limit and thus is in fact the same product.
a. Preparation of Amberlite IRF-66 Phenylpropanolamine Resin Complex
high load.
Amberlite IRF-66H hydrogen cycle fine particle resin 1740 gm.
Phenylpropanolamine base 1260 gm.
: ,
Deionized Water 6 liters
., 15 The Amberlite IRF-66H resin was suspended in about 6 liters of
tleionized water with stirring. The phenylpropanolamine base
was gradually added. The stirring was continued till the reaction
was complete as noted by stabilization of pH. The resin complex
was then collected on a buchner funnel, washed with deionized
: 20 water and dried. The dried product was screened throl]qh a #~n
mesh screen and assayed. Phenylpropanolam.ine content was
found to be 37.7 %* The average particle size was observed to
,
be 82 ,um.
b. Preparation of Coated ~mberlite IRF-66 Phenylpropanolamine Resin
-~ , 2 5 Complex.
., . I
~ ` -27-
, .
Revised: Vll/77
.
;
1~ Z6
Amberlite IRF-66 Phenylpropanolamine Resin Complex 440 gm.
(37.7%* drug load)
Polyethylene Glycol 4000 110 gm.
Purified Water 176 ml.
The Amberlite IRF-66 phenylpropanolamine resin complex was
placed in a suitable mixer. The polyethylene glycol 4000 was
dissolved in the specified quantity of deionized water and added
gradually to the resin complex in the mixer. The mass was well
mixed and dried in a fluid bed drier. The dried material was
then screened through #60 mesh screen. The screened particles
were then coated in a fluid bed coating apparatus with the
following coating solution: -
Ethylcellulose 50 cps 75 gm.
Durkex 500 (refined vegetable oil) 30 gm.
Acetone 140 ml.
Methylene Chloride 1400 ml.
The coating conditions were as follows: inlet temperature 86-102 F,
outlet temperature 74-88 F, coating time 160 minutes. Rate of
application of coating solution: 8.75 ml/minute. The coated
material was screened through a #40 screen to discard any unusually
large particles. The average particle size of the screened
particles was observed to be 155 ym. ~icroscopic examination showed
the particles to be well coated. The following dissolutions were
obtained on the uncoated and coated Amberlite IRF-66 phenyl-
propanolamine resin complex. The retardation of dissolution in
th~ coated product is evident.
'.~
~, .
, .
- 28 -
,
1~86Z;Z6
:
As dcscribcd in the other examples coatcd/uncoated miicturcs of
these high load drug resin complexes can be made to match any
d~sired dissoiution profile.
% PHE~YLPROPANOLAMINE RELEASED
¦- 5 IN 0. lN HCl
:
'
;~ Time
Hrurs Uncoated Co~plex Par icles Coated Complex Particles
:~ 0. 25 . 79* 14*
. 50 - 85* 22*
l. 0 87* 28*
; l. 5 89* , 32*
.~ , 2 0
, . __ 34* ~`
. 3. 0 -- 39* ,-~
4. 0 _~
43*
. - r~
'; 7 ':
' '~
. . ', ' ~,
' :9.'
., . . '`~
,'~ I '' ' '
~" i '':
i; j '`'1';'
.' i ~"~.
'' i ~,.
.'. j ,~.
' i :
29-
. , . '~
Revised: 7/11/77 `~:
1~862Z6
EXAMPLE 17
BioavailabLlity studies were conducted on dogs using the coated
and uncoated resln drug complex particles as a prellmlnary to testing
the same In man:
a. Amberllte IR-120 PPA Resln Complex - A crossover study
5 using four dogs compared the urlne recovery and blood levels of PPA
obtained after adminlstratlon of the IR-120 PPA resin complex coated
or uncoated (from Example 4) at 10 mg. of PPA/kg. of body welght.
The results showed slgnlflcant dlfferences In the blood drug concen-
`: tratlon profLle for the two formulations in the anlmals. The apparent
- 10 elLmlnatlon half-life for PPA in the coated sample wa s observed to be
13. 3 hours versus 8. 6 hours wlth the uncoated sample.
b. Amberllte XE-69 PPA Resin Complex - The crossover study'
was repeated uslng the XE-69 PPA resin complex coated and uncoated
(from Example 10) with slmilar results. The apparent elLmlnatlon
15 half-lLfe for PPA In the coated sample was observed to be 9. 5 hours
as agaLnst the uncoated sample value of 4. 4 hours.
EXAMPLE 18
Based on the data from the dog bloavailability studies prolonged
release dosage forms were formulated for human study to contain mlx-
" ~ tures of coated and uncoated particles such that a fraction of the
- ~ mlxture was readily available as the priming dosage (the uncoated
- ' partlcles) and the remainlng fractlon as the prolonglng dosage (the coated
partlcles). Inltlally a deslrable dlssolutlon proflle for PPA was
selected and all drug resln complex mlxtures were prepared to meet thls
ideal dissolution proflle.
,,
-30 -
.
1~)86~Z6
~ Ten healthy volunteers participated in this crossover bioavail-
; ability study. The following five formulations were evaluated as per the
; dosages given for each formulation:
' A. 10 ml. every 12 hours of a resin drug complex suspension of
(1) The 70/30 coated/uncoated mixture of the XE-69 PPA resin complex of
Example 15 in an amount equivalent to 37.5 mg. of PPA hydrochloride per 5 ml.;
(2) Amberlite XE-69 chloropheniramineresin complex uncoated in an amount
` equivalent to 4.0 mg. ofchloropheniramine maleate per 5 ml.; and
(3) Flavored syrup base sufficient to make up the remaining 5 ml.
B. 5 ml. every 6 hours of a formulation equivalent to formulation
A except that the syrup base contains the drugs as their salts in solution
rather than the drug resin complex particles.
C. 2 capsules every 12 hours of a resin drug complex capsule
containing the same ingredients as in formulation A except that corn starch
is substituted for the flavored syrup base.
:
D. 2 capsules every 12 hours of a resin drug complex capsule
, as in formulation C except that the resin in the resin complex is Amberlite
IR-120 rather than XE-69, the IR-120 PPA resin complex mixture being that
~; described in Example 8.
E. 1 capsule every 6 hours of a formulation as described in
formulation B except that corn starch is substituted for the syrup base.
;~ H~parinized blood samples were collected from each volunteer at
0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours. A 6 ~ and 7 hour
collection was taken from those subjects receiving regimens B and E. Also,
two 24 hour urine collections were obtained from each
. .
- 31 -
1~86Z26
subject. The plasma was separated from each blood sample and
`, analyzed for drug content.
The data show that:
1. The maxlmum plasma levels derived from the Amberlite XE-69
resln complex coated formulatlons A and C are equivalent to those
obtalned from the soluble salts formulatlons B and E. Those from
the AmberlLte IR-120 preparation (D) are less than those produced by
(E) .
2. The 12 hour plasma levels obtalned from all resin formulations
are equlvalent to or greater than the minimum level, at 6 hours reached
-: by the sa lt formu lat io n s .
,..
3. The absorptlon rate of Phenylpropanolamlne appears to be
: sllghtly greater when it has been administered as the salt formulatLon.
CorrespondLngly, the peak leve!s are delayed for the drug derlved from
:
, 15 the resln complex formulatLons.
: 4. From area under plotted curve measurements, the bloavaLl-
ablllty of drug derlved from Amberlite XE-69 formulatlons Is equlvalent
to (or greater than) that obtalned wlth the salt formulatlons. The data
are conflrmed from urlne recovery results. Whlle urlne recovery appears
to Indlcate that the IR-120 formulatlon Is bloequlvalent to the salt
formulatlon, area under the curve measurement suggest that It may not
r be as s~eat. The results from the bloavailability study indicate that
Amberllte X~-69 Phenylpropanolamine formulations prepared as descrlbed
In thls Inventlon possess the deslrable propertles of a prolonged release
dellvery system, that is (a) qulck release properties as demonstrated by
the rapld onset of plasma levels; and (b) delays of peak and prolon-
gatlon of plasma levels that Indlcate prolonged release.
` ~ -32- ~
.. :
' ~ .
1~86ZZ6
5. Comparison of the drug recovered in the urine demonstrates
bioequivalency of these modified resin formulations and the salt formulations.
Further, these modified resin formulations resulted in maintenance of blood
levels over a 12 hour interval after administration of a single dose. The
blood levels at peak were not greater than the accepted safe blood levels of
the PPA salt. Also, at 12 hours, the values are equal to or greater than the
minimum levels observed 6 hours after administration of the generally accepted
efficacious salt dose regimen.
6. The data confirms the dissolution profile results indicating
that effective prolonged release of drugs are achieved by employing the
formulations of the subject invention.
The following exampies illustrate the use of other drugs within the
scope of the subject invention:
EXAMPLE 19
Dextromethorphan: Dextromethorphan (pKa 8.25) has no analgesic or
addictive properties. It acts centrally to elevate the threshold for
coughing. Its effectiveness in patients with pathologlcal cough has been
demonstrated to be about the equal of codeine. Unlike codeine it rarely
produces drowsiness. Its toxicity is quite low. The average adult dose
is 10-20 mg., three to four times daily or every 6 to 8 hours a day.
Dextromethorphan is thus a candidate drug for prolonged release dosage form.
a. Preparation of Amberlite XE-69 Dextromethorphan Resin Complex:
Amberlite XE-69-Dextromethorphan resin complex was prepared with a
drug load of 23.5~. ~he .ollowlng dissolution proflle was obe~ined
- 33 -
-:
.
~086226
for dextromethorphan uncoated resin complex.
% DEXTROMETHORPHAN
TIME MINUTES RELEASED IN 0 lN ~1
; ~ 15 21
43
` 1 90 71
120 73
; 180 76
240 79
300 80
The uncoated resin complex appears to be slightly faster In
dlssolutlon profile than the deslrable Ideal vlz - about 50% released
In about two hours. Therefore It mlght be beneficlal to have a
15 mlxture of coated/uncoated resln complex to provide the " Ideal"
dlssolutlon.
` - b. Preparatlon of Polyethylene Glycol treated Amberllte XE-69
Dextromethorphan resln Complex:
Amberlite XE-69 Dextromethorphan 1840 gm.
resln complex
J Polyethylene glycol 4000 460 gm.
Delonlzed water 736 ml.
' ~ The resln complex was weighed Into a planetary mixer bowl.
The polyethylene glycol was dlssolved in the water and the flnal
25 solutlon was added to the resln complex slowly wlth mLxing. The
materlal was dried In an oven at 50C and then screened through a
60 mesh screen. -
., .
~ -34-
',.,'
: ;
1086ZZ6
c. Preparation of coated Amberllte XE- 69 Dextromethorphan Resln
Complex (low level coatLng)
Gore:
Amberlite XE-69 Dextromethorphan 550 g
Resln complex polyethylene glycol treated
(from b above)
CoatLng:
Ethylcellulose 50 cps 37. 5 g
~ Durkex 500 - reflned vegetable oll15. 0 g
Solvent:
. Acetone 70 ml
. Methylene Chlorlde 700 ml
..
- The coatlng agents were dlssolved In the solvents as descrLbed
In the prevlous examples and the solutlon applled on the core material
15 - In a fluld bed apparatus. The Inlet alr temperature ranged from 120
: ,-130F and the outlet alr temperature ranged from 77-92F.
.., .
.The followlng dlssolutlon data was observed:
% DEXTROMETIIORPHAN RELEASED .
TIME, MINUTESIN 0. lN HCl
2015 7
. 30 14
:,: 60 22 ,i .
29 i
r 12 0 3 4 . . .
. I 25It can be readlly seen from the above data that dlssolutlon has
been well retarded.
d. Preparation of coated Amberlite XE-69 Dextromethorphan
Resln Complex (hlgh level coatlng)
. I .
.:'' i ~ . ,
.
-35- .
: ~
~ -
i~86;;~Z6
Core:
Coated XE-69 Dextromethorphan301, 5 g
', Resln complex from c above
Coatln~: '
Ethylcellulose 50 cps. 9. 37 g
Durkex 500 - refined vegetable oll 3. 75 g
; ¦ Solvent:
Acetone 17. 5 ml
Methylene Chlorlde 175 ml
The coatlng of the core from (c) above was contlnued further In
. .
thls experlment wlth the coatlng solutlon as glven above. Thls formula
; provlded twlce the level of coating provLded under (c).
. ,
: The followlng dlssolutlon was obtalned:
- % DEXTROMETHORPHAN RELEASED
15TIME, MINUTES IN 0. lN HCl
"~;
~ 30 5
;- 60 1l
' : ' 90 ' 15
120 19
: It ls evldent from the above data that Increaslng the level of
coatlng decreases the dlssolutlon of dextromethorphan from the resln
;` I :J
complex partlcles. Thus coated/uncoated mlxtures of dextromethcrphan
resln complex can be made to match any deslrable dlssolutlon proflle
, 25 as exempllfLed under phenylpropanolamlne examples. ~,
EXAMPLE 20
Pseudoephedrlne- Pseudoephedrlne ls a sympathomlmetlc agent.
It ls used ln the dose range of 25-60 mg. It has been used as a
:.
.
-36-
'.~ '
~-~
1~86226
nasal and bronchlal decongestant In doses of 60 mg twlce or three tlmes
dally. It has a pKa of 9.7 and a blologlcal half llfe of 5-7 hours In
m.an. Pseudoephedrlne Is thus a candldate for prolonged release dosage
form.
a. Preparatlon of Amberllte XE-69 Pseudoephedrlne Resln Complex:
d - Pseudoephedrlne Hydrochloride 317.4 gm
Amberllte XE-69 Sodium (anhydrous) 776.0 gm
Delonlzed water 3240 ml
The pseudoep~ledrlne hydrochlorlde was dlssolved In water and
10 the Amber11te XE-69 added and the two mlxed for 6 hours. The drug
. resln complex was washed, dried, and screened through a 60 mesh
screen.
The followlng dissolutlon was obtalned:
% PSEUDOEPHEDRINE RELEASED
15 TIME, MINUTES IN 0. lN HC1
2 15 64
66
67
68
: 20 As Is evldent from the data the Initlal release of the drug Is very
rapld and, therefore, coating the resln drug c omplex should be benefi-
clal In prolonglng dlssolutlon of the drug.
b. Preparatlon of Polyethylene glycol treated Amberllte XE-69
Pseudoephedrlne Resln Complex:
25 Amberllte XE-69 Pseudoephedrine 950 gm
Re s In co mp lex
Polyethylene Glycol 4000 216.1 gm
Delonlzed watet 345 ml
}~ . ..
-37-
:
: ~
~62Z6
The resin complex was weighed into a planetary mixer bowl. The
polyethylene glycol was dissolved in the water and the solution was added to
: the resin complex slowly with mixing. The material was dried in an oven at
45 C and screened through #40 mesh screen. It was then screened through #60
screen prior to coating.
`~ c. Preparation of coated Amberlite XE-69 pseudoephedrine resin
Complex:
Core:
: Polyethylene glycol treated XE-69550 g
Pseudoephedrine Resin complex product
from (b) above
- Coating:
Ethylcellulose 50 cps. 75 g
Durkex 500 refined vegetable oil30 g
Solvent:
Acetone 140 ml
Methylene Chloride, sufficient to make 1400 ml
The coating agents were dissolved in the solvents as described in
the previous examples and the solution applied on the core material in a
fluid bed apparatus. The inlet air temperature ranged from 119-144 F. The
outlet air temperature ranged from 68-80 F.
The following dissolution data was obtained:
% PSEUDOEPHEDRINE RELEASED
TIME, MINUTES IN 0.lN HCl
12
17
23
27
120 31
L
- 38 -
lOB6ZZ6
It Is evldent from the above data that coatlng retards the
dlssolutlon of pseudoephedrene from resln drug complex particles. Thus
coated/uncoated mixtures of pseudoephedrine resin complex can be made
to match any desirable dlssolutlon profl~e as exemplified under phenyl-
5 propanolamine examples.
;~ EXAMPLE 21
Ephedrlne: Ephedrine Is also a sympathomimetic agent. It Ls
used In the dose range of 15-60 mg by mouth three or four tLmes a day.
It ls of value In preventLng spasm In asthma. It has a pKa of 9. 5 and
10 a blolog Ical half llfe of about 6 hours In man.
- Ephedrlne Is, therefore, a candldate for prolonged release dosage
form,
a. Preparatlon of Amberllte XE-69 Ephedrlne Resln Complex:
, ,
- The Amberllte XE-69 EphedrLne Resln Complex was prepared as
'
15 descrlbed In Example 20.
. .,.
; ,s The followlng dlssoLutLon was obtalned:
% EPHEDRINE RELEASED ON
TIME, MINUTES 0. IN HCl
63
.~ 20 30 66
68
69
As ls evldent from the data, the Inltlal release of the drug Is
O . very rapld and, therefore, coatlng the resln drug complex partlcles should
25 be beneflclal In prolonglng dlssolutLon of the drug,
b, Preparatlon of Polyethylene glycol treated Amberllte XE-69
Ephedrlne Resln Complex:
Amberllte XE-69 Ephedrlne Resln Complex 978, 0 gm
.
` -39-
,
. .
1~86ZZ6
Polyethylene glycol 4000 225. o gm -
Delonlzed water 359 ml.
The resln complex was weIghed into a planetary mlxer bowl. a
The polyethylene glycol was dissolved in the water and the solution
5 was added to the resLn comolex slowly with mixing. The materlal dried
In an oven at 45C and screened through #40 mesh screen. It was
then screened through $~60 screen prior to coatlng.
c. Preparation of coated Amberlite XE-69 EphedrLne resin complex:
Polyethyiene glycol treated XE-69 ~s
Ephedrlne Resln Complex product550 g
- from (b) above
Coatlng:
. Ethylcellulose 50 cps. 75 g 2i
Durkex 500 refined vegetable oll 30 g
. 15 Solvent:
: Acetone 140 ml
Methylene ChlorLde Sufficlent to make 1400 ml.
~i The coatlng agents were dlssolved In the solvents as descrlbed
r'~' In the prevlous examples and the solutlon applied on the core materLal
20 In a fluld bed apparatus. The Lnlet air temperature ranged from 121-
140F. The outlet aLr temperature ranged from 68-84F.
¦The followlng dlssolutlon data was obtalned:
... ..
,
.
:
`:
~j _40_
,,'~
;, _ ' :
~-~
` 1~86ZZ6
.
% EPHEDRINE RELEASED IN
TIME, MINUTES0. lN HCl
11
' 16
~0 22
26
' ! 120 29
It ls evldent from the above data that coatlng retards the dis-
: j
solutlon of ephedrine from resln drug complex partlcles. Thus coated/
10 uncoated mlxtures of ephedrine resin complex can be made to match any
deslrable d~ssolutlon profile as exemplifLed under phenylpropanolamlne
:, example s.
',: ''-
~ EXAMPLE 22
,- '- Phentermine (or phenyl-tertiary-butyl-amine) is a sympathomimetic
15 agent. It is used as an anorectic drug. It is rapidly absorbed from the
'j gastrointestinal tract in the free form. Blood levels obtained in humans
w,ith the hydrochloride salt in doses of 15 mg. and 30 mg. have produced
rapid peak concentrations. Phentermine resin complex, according to
U. S. patent 2, g90, 332, has been used to delay the release of the drug
~- 20 in the gastrointestinal tract. The followin~ experiments indicate that
'; the release of phentermine mav be further pro1On~ed when the phentermine
' ~, , resin complex is subjected to the SCOp2 of this invention. These phen-
termine resin complex particles are 20-60 mesh (250-840 ,um).
j .
a. Preparation of Coated Amberlite IR-120 Phentermine Resln
complex - lower level - coating
'':
-
, -41-
."
"
- . .. .
-
~- , . . ~ .
. .
~862Z6
Amberlite IR-120-Phentermine Resin Complex 270 gm.
(20 . 9 3% drug load)
Polyethylene Glycol 4000 30 gm.
Deionized Water 96 ml.
The Amberlite IR-120 phentermine resin 0mplex was placed in
a suitable mixer. The polyethylene glycol 4000 was dissolved
in the specified quantity of deionized water and added gradually
to the resin complex in the mixer. The mass was well mixed and
dried in a fluid bed drier. The dried material was then screened
10 ~ through a $~16 mesh screen. The screened particles were then
coated in a fluid bed coating apparatus with the following coating
- i solution: ,
Ethylcellulose 50 cps 10 gm.
Durkex 500 - refined vegetable oil 4 gm.
.. .,
Acetone 40 ml.
; Methylene Chloride sufficient to make 400 ml.
:;
, Coating conditions - inlet temperature 94-101F. Outlet tempar-
..,
ature 76-86F. Coating time 49 minutes. Rate of application of
~1 the coating solution 8.1 ml/minuta. Twenty grams of the coated
!.,' 20 particles were removed. The phentermine content in the particles
i~ was found to be 17. 53%. The dissolution results are summarized !i
!'f~ ¦ in the table at the end of the example.
~; ¦ b. Preparation of coated Amberlite IR-120 phentermine resin complex -
~ , hlgher level of coating.
., i
,,
--4 2--
' ' ' ~
)86ZZ6
The remaining coated Ambcrlite IR-120 phentermine resin
complcx form (a. ) above (approximately 294 gm. ) was furthcr
coated with the following solution:
Ethylcellulose 50 cps 5 gm.
Durkex 500 - refined vegetable oil 2 gm.
Acetone 20 ml.
Methylene Chloride sufficient to make 200 ml.
The coating conditions were: inlet temperature 88-103 F, outlet
temperature 78 -8 7 F; coating time 6 5 minute s . The phentermine
content in the finished product was found to be 16.14%. The
dissolution results are summarized in the following table. Some
. retardation in the release of phentermine due to coating is
. evident. The higher level of coating provides more retardation
. ~. han the lower level of coating.
. .,
-~ - 15 % PHENTERMINE RELEASED
::
:~ IN 0. lN HCl
, ~ , '
TimeUncoated Coated Complex Coated Complex
HoursCornp.lex (lover level coating) (hi~her level coating
1. 0 30 28 27
2 0 1. 5 4 0 3 5 3 2
2. 0 44 40 3
3. 0 51 45 41
' ~ 4.0 55 48 -
5. 0 60 50 -
,,
Thus, coated/uncoated mixtures of phentermine resin complex
can be made to match any desirable dissolution profile.
, ~ '
-43-
.
.
,
' , '
,
