Note: Descriptions are shown in the official language in which they were submitted.
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16 Disclosure of the Invention
-
17 Certain novel ionene polymers, and in particular
18 poly-[~methyl-(3-trimethylammoniopropyl)iminio3trimethylene
dichloride], are highly efficient as bile acid sequestrants.
~oly-[~methyl-(3-trimethylammoniopropyl)iminio}trimethylene
21 dichloride] is, however, extremely hygroscopic and, when
22 exposed to air, even at relatively low humidities, rapidly
23 deliquesces to form initially a sticky, unworkable product,
24 and finally a solution of the polymer. This hygroscopic
characteristic has presented a for~idable problem in the
26 formulation of poly-[t~ethyl-(3-trimethylammonio?ropyl)
27 iminio~trimethylene dichloride] and, even when such formula-
28 tion, e. g. by encapsulation or tabletina, is conducted
29 under anhydrous conditions, the resulting tablets and
capsules rapidly absorb water under normal atmospheric
31 conditions (the coatings of such capsules being permeable
32 to water) to produce unsatisfactory adhesive, caking products.
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1 Compositions comprising substantially uniform
2 pulverulent mixtures oE poly-[~methyl-(3-trimeth~la~monio-
3 propyl)iminio}tri~ethylene dichloride] ,lith various
4 pharmacologically acceptable solid carriers, such as
powdered silica, starch, talc, cellulose and kaolin, when
6 prepared by thoroughly dry-mixing the components (as in a
7 ball mill) under substantially anhydrous conditions, are
8 adhesive in character, and ordinarily become stic~y and
9 caking ater relatively short exposure to air at 25% rela-
tive humidity.
11 It is no~J discovered that substantially non-
12 adhesive, powdered poly-[~methyl-(3-trimethylammonio-
13 propyl)i~inio~trimethylene dichloride] adsorbate co~.posi-
1~ tions, which remain free-flowing and non-caking, even after
prolonged contact with moist air of 76% relative humidity,
16 are prepared by forming a substan-tially uniform suspension
17 of a finely-divided, solid aggregate, pre~erabl~ micron-
18 sized fumed silicon dioxide~, in an a~ueous solution of
19 poly-[~methyl-(3-trimethylammoniopropyl)i~inio}trimethylene
dichloride], evaporatively removing the water from the
21 ~ Fumed silicon dioxide is prepared b~ burning silicon
22 tetrachloride in a flame of hydrogen and oxygen to produce
23 primary spherical particles which, while still semi-molten,
24 fuse into clusters of sucn particles called aggregates;
these aggregates, during further cooling and collecting
26 become physically entangled to form agglomerates. The
27 latter, upon dispersion in an aqueous solutionj can dis-
28 entangle to reform aggregates. Fu~ed silicon dioxide so
29 prepared, is supplied in the form of a light, flufLy, pure
white, non-toxic, pharmacologically acceptable powder,
31 approvecl by PDA for use as a direct food additive, under
32 the tradename Cab-O-Sil, by Cabot Corporation, 125 High
33 Street, Boston, ~assachusetts. ~ similar non-~oxic, ~DA
3~ approved, micronized synthetic silica is supplied under
the tradename SYLOID silica aerogel by r~l. R. Grace and
36 Co., Davison Chemical Division, Charles and Baltimore
37 Streets, Baltimore, ~aryland.
.
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1 suspension, and drying the adsorbate composition thus
2 produced. It is ordinarily preferred to employ ap~roxi-
3 mately e~ual weights, on a dry basis, of fumed silicon
4 dioxide and ~oly-[~methyl-(3-tri.methyla~onioprop~l)iminio}
trimethylene dichloride], althouqh substantially non-
6 adhesive adsorbate compositions are prepared utilizing a
7 weight ratio of about 40 parts fumed silica to 60 parts
8 ~olymer; fumed silica-polymer adsorbatescontaining up to
9 75% fumed silica are likewise non-adhesive, and effective
as bile acid sequestrants, but are not ordinarily employed
11 because o~ their increased proportion of fumed silica
12 material.
13 The process of preDaring these adsorbate composi-
14 tions is ordinarily conducted by first forming a substantially
uniform suspension of fumed silica in approximately ten to
16 fifty times its weight of water, and slowly adding to this
17 suspension, with rapid stirring, a dilute (preferably about
18 5%) a~ueous solution of poly-[~methyl-(3-trimethylammonio-
19 propyl)iminio}trimethylene dichloride]. The rate of addition
is ordinarily adjusted so as to be co~plete in about 5 to 15
21 minutes, and the resulting milky suspension is stirred
22 vigorously for a short period of time, e. g. about 5 to
23 15 minutes. The suspension is then evaporated to dryness
24 under reduced pressure, ~hile stirrin~ and maintaining the
temperature within the range of about 25C. to aooC; the
26 temperature should not exceed 50C. during this evaporatlon
27 step, since some discoloration of the polymer can occur
28 above this temperature. The residual powdered silica-
29 polymer adsorbate composition is then dried in vacuo at a
temperature of about 25C. to 40C.
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It is a preferred feature of the present inventionthat it is not necessary to employ isolated solid polymer for
preparing the dilute aqueous solution of poly-~ methyl-
(3-trimethylammoniopropyl)iminio}trimethylene dichlorid ~
employed in the above-noted procedure for preparing the fumed
silica-polymer adsorbate composit:ion. Instead, the aqueous
polymerization reaction solution can itself be employed in
this procedure, thereby avoiding the isolation, drying and
storage of the highly-hygroscopic poly- ~methyl-(3-trime-thyl-
ammoniopropyl)iminio}trimethylene dichlorid~. This preferredmethod thus results in the direct production, from the aqueous
polymerization reaction solution, of the desired poly-
methyl-(3-trimethylammoniopropyl)iminio}trimethylene
dichlorid~/'-fumed silica adsorbate composition in a non-
adhesive form adapted for pharmaceutical formulation.
These poly-~methyl-(3-trimethylammoniopropyl)-
iminio3trimethylene dichlorid ~ -fumed silica adsorbate compo-
sitions are characterized in that the polymer, as shown by
microscopic examination, forms a thin film on the surface of
the fumed silica, in contrast to compositions prepared by dry-
mixing the components, wherein the poly-~methyl-(3-trimethyl-
ammoniopropyl)iminio}trimethylene dichlorid~ component,
although intimately associated with the fumed silica, is
present in the form of discrete granules. As might be expect-
ed from these observed structures and the necessarily greater
surface area possessed by the polymer film in the fumed
silica-polymer adsorbate compositions, the hygroscopicity of
the adsorbate compositions is appreciably greater than that of
the composition prepared by dry-mixing the components, wherein
the polymer is present in the form of discrete granules. It
is indeed surprising tha-t, in spite of their greater hygro-
_ ~ _
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scopicity, the presently invented fumed silica-poly-~methyl-
(3-trimethylammoniopropyl)iminio}trimethylene dichlorid ~-
adsorbate compositions remain completely non-adhesive, non-
caking and free-flowing after several days exposure to moist
air at 76% relative humidity, whereas the compositions
obtained by dry-mixing the same components become adhesive
and caking even after a few hours exposure to moist air of
35% relative humidity.
Effective lowering of cholesterol blood levels is
obtained by the oral administration of remarkably small
dosages of the poly-~methyl-(3-trimethylammoniopropyl)iminio}
trimethylene dichlorid ~-fumed silica adsorbate compositions
of this invention. This enables a flexibility of formulation
previously unavailable. These poly~methyl-(3-trimethyl-
ammoniopropyl)iminio}trimethylene dichlorid~-fumed silica
compositions are light, fluffy, pulverulent powders, and are
suitably used as such, or admixed with appropriate amounts of
conventional pharmaceutically acceptable binders and/or
additional solid carrier agents, such as starch, gelatin,
sugars, as glucose and lactose, methylcellulose, natural and
synthetic, talc, synthetic gums, and the like. The compo-
sitions are preferably made into unit dosage forms such as
tablets or filled gelatin capsules or, if desired, the
premeasured dose may be enclosed in a foil or paper envelope
which can be readily torn open and added to edible liquids
such as fruit juices or other beverages. The unit dosage
may also include supplementary vitamins and minerals. The
unit dose composition may comprise from 10~ to 99% by weight
of the poly- ~methyl-(3-trimethylammoniopropyl)iminio}
trimethylene dichlorid~-fumed silica adsorbate composition,
the remainder being carriers, flavorings, excipients, flow
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1 a~ents and the like. In such unit dose, the ac-tive pol~mer
2 may comprise from 100 millic3rams to up to 10 grams in po-"der
3 packets
4 For convenience of administration, it is preferred
to employ tablets or capsules containing 300-600 milligraMs
6 of adsorbate compositions comprising equal amounts of fumed
7 silica and poly-[~ethyl-(3~trimeth~1a~onio2ropyl)iminio~
8 trimeth~lene dichloride]. Such unit dosage compositions would
9 thus provide about 150-300 milligrams of the bile acid seques-
trant polymer, pol~-~tmethyl-(3-trimethylammoniopropyl)iminio}
11 trimethylene dichloride]; a capsule or tablet containing 600
12 milligrams of adsorbent composition taken four times per day
13 would thus provide a daily dosage of 1.2 grams of poly-[~methyl-
14 (3-trimethylammoniopropyl)iminio}trimethylene dichloride].
~I.ultiple dosages, e.g., two or three tablets or capsules
16 can of course be taken at one time if desired. In the case
17 of tablets, a plastic film can be applied, if desired, to
18 seal the tablets from moisture, and to masl~ the taste of the
19 poly-[{methyl-(3-trimethylammoniopropyl)iminio~trimethylene
dichloride] in ways well known in the art. An enteric coat-
21 in~ such as fats, fatty acids, waxes and mixtures thereof,
22 shellac, ammoniated shellac, and cellulose acid phthalates,
23 may also be applied by techniques well known and accepted.
24 The following examples illustrate methods of carry-
ing out the present invention, but it is to be undèrstood
26 that these examples are given for purposes of illustration
27 and not of limitation.
:
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2 A mixture of about forty grams of fumed silicon
3 dioxide and 1100 ml. of water is stirred viyorously until
4 a thin, lum~-free, substantially uniform suspension is
obtained. This suspension is stirred while slowl~7 adding
6 thereto a solution of orty grams of anhydrous poly-~methyl-
7 (3-trimethylammoniopropyl)iminio}trimeth~lene dichloride]
8 in 300 ml. of water. ~he resulting suspension is evaporated
9 to dryness under reduced pressure, and the residual adsor-
~ate is dried in vacuo for a period of about 15 hours and
11 milled to give about 35 grams of a white, fluf~y, free-
12 ~lowing, non-caking powder containing about 5% 0c adsorbed
13 moisture. This adsorbate remains free-flowing and non-
14 caking upon exposure for three days to moist air of 76%
14 relative humidity.
EXA~A~LE 2
16 A mixture of 122.61 mg. of fumed silicon dioxide
17 is suspended in 5 ml. of water using a high speed stirrer.
18 A solution containing 121.1 mg. anhydrous weight of poly-
19 [~methyl-(3-trimethyla~moniopropyl)iminio7trimethylene
dichloride] in 3 ml. of water is added slowly whlle agita-
21 tion is continued. ~he resulting milky suspension is
22 evaporated ~o dryness ln vacuo, and the residual adsorbate
23 is further dried in vacuo to give a ~umed silica-poly
,__
24 [~methyl~(3-trimethylammoniopropyl)iminio~trimethylene
dichloride] co~position in the form of a fluffy, white,
26 free-flowing, non-caking powdery adsorbate which, upon
27 ex~osure to laboratory atmosphere (relative humidity
28 approximately 35%) for a period of 15 hours, fully retains
29 its ~ree-flowing and non-cakinq characteristics.
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EXAMPLE 3
A mixture of 1.34 g. of fumed silicon dioxide is
suspended in 60 ml. oE water using a high speed stirrer. A
solution containing 1.34 g. anhydrous weight of poly-~methyl-
(3-trimethylammoniopropyl)iminio}trimethylene dichlorid ~ in
30 ml. of water is added slowly while agitation is continued.
The resulting milky suspension is stirred vigorously for
approximately one-half hour, and then evaporated to dryness
in vac~uo, and the residual adsorbate is further dried ~n va~uo
to give approximately 2.5 g. of a fumed sili.ca-poly- ~methyl-
(3-trimethylammoniopropyl)iminio}trimethylene dichlorid
composition in the form of a fluffy, white, free-flowing,
non-caking powdery adsorbate. This material remains free~
flowing and non-caking after prolonged exposure to air at 76
relative humidity.
The poly- ~methyl-(3-trimethylammoniopropyl)iminio3-
trimethylene dichlorid ~, utilized as the bile acid seques-
trant polymer component of the adsorbate compositions prepared
as described in foregoing examples, as well as other ionene
quaternary polymers and pharmacologically acceptable salts
which may also be used as the polymer component in such
adsorbate compositions, may be synthesized in accordance with
various procedures described in U.S.P. 4,016,209, April 5,
1977.
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1 The chemical structure o~ the polymer components,
2 which are referred to in the instant specifications and claims
3 as "ionene quaternary polymers" and in ~thich the anion and
4 termlnal groupings can vary dependiny on the synthesis pro-
cedure employed, may be represented by the following for~ula:
6 z _ ~ CH2CH2CU~ ~ CH3 t~n+2+V) m~-
H2CH2CH2M (CH3) ~H2CH2CH2N (CH8)3
n
7 wherein n is the number of repeating units in the polymer;
8 Y is a mono- or poly valent, pharmacolo~ically acceptable
9 anion, a is the anionic charge on Y,and m is the reciprocal
1 10 of a; 1^l is propyl, hydroxypropyl, allyl, or an alkoxypropyl
11 such as ethoxypropyl or methoxypropyl; or r~7 may be halo-
12 propyl (such as chloropropyl, bromopropyl or iodopropyl)
13 which is preferably converted, by reaction with ammonia,
14 to a primary ammoniopropyl or, by reaction with an amine,
to a secondary, tertiary or quaternary ammoniopropyl
16 ~rouping, for example an alkylammoniopropyl such as methyl-
17 ammoniopropyl, a dialkylammoniopropyl such as dimethyl-
18 ammoniopropyl, or a trialkylammonioDropyl such as
19 trimethylammoniopropyl; and Z is allyl, N-trimethylammonio-
propyl-N-methyl-3-aminopropyl or M-trimethylammoniumpropyl-
21 N,N-dimethyl-3-ammoniopropyl; or Z may be halopropyl (such
22 as chloropropyl, bromopropyl or iodopropyl~ which is pref-
23 erably converted, by reaction with ammonia, to a primary
24 ammoniopropyl or, by reaction with an amine, to a secondary,
tertiary or quaternary ammoniopropyl grouping, for example
26 an alkylammoniopropyl sucll as methyla~moniopropyl, a dial~yl-
g _
15970
r,~;
1 ammoniopropyl such as dimethylammoniopropyl, or a trial~yl-
2 ammoniopropyl such as trimethylammoniopropyl; and ~' is the
3 number of positivel~ charged nitrogens (M~) in the r~1 and Z
4 groupings,
Various changes and modifications may be made in
6 carrying out the present inventi.on without departing from
7 the spirit and scope thereo~ ]:nsofar as these changes and
8 modifications are within the purview of the annexed claims,
9 they are to be considered as part of this invention.
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