CA1109395A - Non-adhesive ionene quaternary polymer compositions and process - Google Patents
Non-adhesive ionene quaternary polymer compositions and processInfo
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- CA1109395A CA1109395A CA296,622A CA296622A CA1109395A CA 1109395 A CA1109395 A CA 1109395A CA 296622 A CA296622 A CA 296622A CA 1109395 A CA1109395 A CA 1109395A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
Abstract of the Disclosure The invention disclosed herein relates to a novel non-adhesive,free-flowing, pharmacologically acceptable composition comprising ionene quaternary polymers effec-tive as bile acid sequestrants, such as poly-[{methyl-(3-trimethylammoniopropyl)iminio}trimethylene dichloride], adsorbed on a pulverulent, solid aggregate of large sur-face to mass ratio, such as fumed silica. It also relates to the novel process for preparing such adsorbate composi-tions which comprises forming a substantially, uniform suspension of the finely-divided solid aggregate in an aqueous solution of poly-[{methyl-(3-trimethylammoniopropyl)-iminio}trimethylene dichloride], evaporatively removing the water from the suspension, and drying the adsorbate thus produced.
Description
3~S
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.
3~ 15970 1 Compositions comprising substantially uniform
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.
3~ 15970 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.
.
~ 2 --~ 15970 3$S
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.
'\
3~S
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-_ ~ _ . :
, . . . . , ~
3~5 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 . , ~ .
. ~
3~5 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.
:
_APLE l 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.
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.
. ~ ., .
~r~s 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 _ 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.
' ' : ,
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.
.
~ 2 --~ 15970 3$S
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.
'\
3~S
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-_ ~ _ . :
, . . . . , ~
3~5 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 . , ~ .
. ~
3~5 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.
:
_APLE l 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.
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.
. ~ ., .
~r~s 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 _ 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.
' ' : ,
Claims (4)
1. A bile acid sequestrant composition character-ized as being non-adhesive and free-flowing after prolonged exposure to air at 35% relative humidity, which comprises a substantially uniform adsorbate of an ionene quaternary polymer on a fumed silica or silica aerogel, said polymer and silica having a weight:weight ratio of approximately 1:1, said ionene quaternary polymer having the following formula:
wherein n is the number of repeating units in the polymer;
Y is a mono- or poly-valent, pharmacologically acceptable anion, a is the anionic charge on Y, and m is the reciprocal of a; W is propyl, hydroxypropyl, allyl, alkoxypropyl, halo-propyl, ammoniopropyl, alkylammoniopropyl, dialkylammonio-propyl, or trialkylammoniopropyl; Z is allyl, N-trimethyl-ammoniopropyl-N-methyl-3-aminopropyl, N-trimethylammonio-propyl-N,N-dimethyl-3-ammoniopropyl, halopropyl, ammonio-propyl, alkylammoniopropyl, dialkylammoniopropyl or trialkyl-ammoniopropyl; and V is the number of positively charged nitrogens (N+) in the W and Z groupings, which is produced by the process which comprises forming a substantially uniform suspension of a fumed silica or silica aerogel in an aqueous solution of said ionene quaternary polymer, evaporatively removing water from this suspension, and drying the adsorbate thus produced.
wherein n is the number of repeating units in the polymer;
Y is a mono- or poly-valent, pharmacologically acceptable anion, a is the anionic charge on Y, and m is the reciprocal of a; W is propyl, hydroxypropyl, allyl, alkoxypropyl, halo-propyl, ammoniopropyl, alkylammoniopropyl, dialkylammonio-propyl, or trialkylammoniopropyl; Z is allyl, N-trimethyl-ammoniopropyl-N-methyl-3-aminopropyl, N-trimethylammonio-propyl-N,N-dimethyl-3-ammoniopropyl, halopropyl, ammonio-propyl, alkylammoniopropyl, dialkylammoniopropyl or trialkyl-ammoniopropyl; and V is the number of positively charged nitrogens (N+) in the W and Z groupings, which is produced by the process which comprises forming a substantially uniform suspension of a fumed silica or silica aerogel in an aqueous solution of said ionene quaternary polymer, evaporatively removing water from this suspension, and drying the adsorbate thus produced.
2. The bile acid sequestrant composition of Claim 1, wherein said ionene is poly-[{methyl-(3-trimethylammonio-propyl)iminio}trimethylene dichlorid].
3. A non-adhesive, free-flowing, pharmacologically-acceptable bile acid sequestrant adsorbate composition com-prising approximately equal weights of poly-[{methyl-(3-trimethylammoniopropyl)iminio}trimethylene dichloride] and a fumed silica or silica aerogel produced by the process which comprises forming a substantially uniform suspension of a fumed silica or silica aerogel in approximately 10 to 50 times its weight of water, slowly adding to this suspension, with rapid stirring, a dilute aqueous solution of poly-[{methyl-(3-trimethylammoniopropyl)iminio}trimethylene dichloride], and evaporating the water from the resulting suspension under reduced pressure, while stirring and maintaining the tempera-ture of the mixture at about 25°-40°C, and drying the adsorb-ate thus produced.
4. A unit dosage composition characterized as being non-adhesive and free-flowing after a few hours exposure to air at 35% relative humidity which comprises a tablet or capsule of about 150-300 milligrams of poly-[{methyl-(3-trimethylammoniopropyl)iminio}trimethylene dichloride] adsorb-ed onto an approximately equal weight of a fumed silica or silica aerogel produced by the process which comprises forming a substantially uniform suspension of a fumed silica or silica aerogel in an aqueous solution of poly- [{methyl-(3-trimethyl-ammoniopropyl)iminio}trimethylene dichloride], evaporatively removing water from this suspension, and drying the adsorbate thus produced.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76949177A | 1977-02-17 | 1977-02-17 | |
| US769,491 | 1977-02-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1109395A true CA1109395A (en) | 1981-09-22 |
Family
ID=25085598
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA296,622A Expired CA1109395A (en) | 1977-02-17 | 1978-02-08 | Non-adhesive ionene quaternary polymer compositions and process |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS53102958A (en) |
| AT (1) | AT363173B (en) |
| AU (1) | AU518127B2 (en) |
| BE (1) | BE863930A (en) |
| CA (1) | CA1109395A (en) |
| CH (1) | CH636012A5 (en) |
| DE (1) | DE2806707A1 (en) |
| DK (1) | DK46578A (en) |
| ES (1) | ES466892A1 (en) |
| FI (1) | FI67483C (en) |
| FR (1) | FR2381079A1 (en) |
| GB (1) | GB1567294A (en) |
| GR (1) | GR66100B (en) |
| HU (1) | HU177685B (en) |
| IE (1) | IE46408B1 (en) |
| IL (1) | IL53978A (en) |
| IT (1) | IT7848013A0 (en) |
| LU (1) | LU79071A1 (en) |
| NL (1) | NL7801240A (en) |
| NO (1) | NO148838C (en) |
| NZ (1) | NZ186399A (en) |
| PH (1) | PH15263A (en) |
| PL (1) | PL122299B1 (en) |
| PT (1) | PT67663B (en) |
| SE (1) | SE433170B (en) |
| ZA (1) | ZA78913B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5929184A (en) * | 1993-06-02 | 1999-07-27 | Geltex Pharmaceuticals, Inc. | Hydrophilic nonamine-containing and amine-containing copolymers and their use as bile acid sequestrants |
| US6129910A (en) * | 1993-06-02 | 2000-10-10 | Geltex Pharmaceuticals, Inc. | Water-insoluble noncrosslinked bile acid sequestrants |
| US5618530A (en) * | 1994-06-10 | 1997-04-08 | Geltex Pharmaceuticals, Inc. | Hydrophobic amine polymer sequestrant and method of cholesterol depletion |
| US5900475A (en) * | 1994-06-10 | 1999-05-04 | Geltex Pharmaceuticals, Inc. | Hydrophobic sequestrant for cholesterol depletion |
| US5703188A (en) * | 1993-06-02 | 1997-12-30 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
| US5607669A (en) * | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
| US5624963A (en) * | 1993-06-02 | 1997-04-29 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
| TW474813B (en) | 1994-06-10 | 2002-02-01 | Geltex Pharma Inc | Alkylated composition for removing bile salts from a patient |
| US5709880A (en) * | 1995-07-10 | 1998-01-20 | Buckman Laboratories International, Inc. | Method of making tabletized ionene polymers |
| EP0778027A3 (en) | 1995-12-04 | 1998-04-01 | Helmut Univ.-Prof. Dr. Wachter | Use of silica for the preparation of a medicament |
| JP4010585B2 (en) * | 1996-10-15 | 2007-11-21 | 久光製薬株式会社 | Tablets containing anion exchange resin |
| US6203785B1 (en) | 1996-12-30 | 2001-03-20 | Geltex Pharmaceuticals, Inc. | Poly(diallylamine)-based bile acid sequestrants |
| US6423754B1 (en) | 1997-06-18 | 2002-07-23 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with polyallylamine polymers |
| US6726905B1 (en) | 1997-11-05 | 2004-04-27 | Genzyme Corporation | Poly (diallylamines)-based phosphate binders |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR206115A1 (en) * | 1973-06-11 | 1976-06-30 | Merck & Co Inc | PROCEDURE TO PREPARE A NON-BRANCHED AND NON-CROSSLINK LINEAR POLYMER |
| US4027009A (en) * | 1973-06-11 | 1977-05-31 | Merck & Co., Inc. | Compositions and methods for depressing blood serum cholesterol |
-
1978
- 1978-01-30 FI FI780296A patent/FI67483C/en not_active IP Right Cessation
- 1978-02-01 DK DK46578A patent/DK46578A/en not_active Application Discontinuation
- 1978-02-02 SE SE7801242A patent/SE433170B/en unknown
- 1978-02-02 NL NL7801240A patent/NL7801240A/en not_active Application Discontinuation
- 1978-02-02 NO NO780367A patent/NO148838C/en unknown
- 1978-02-06 PH PH20753A patent/PH15263A/en unknown
- 1978-02-06 IL IL53978A patent/IL53978A/en unknown
- 1978-02-06 GR GR55356A patent/GR66100B/el unknown
- 1978-02-07 NZ NZ186399A patent/NZ186399A/en unknown
- 1978-02-08 CA CA296,622A patent/CA1109395A/en not_active Expired
- 1978-02-08 AT AT0087978A patent/AT363173B/en not_active IP Right Cessation
- 1978-02-08 AU AU33099/78A patent/AU518127B2/en not_active Expired
- 1978-02-09 HU HU78ME2145A patent/HU177685B/en unknown
- 1978-02-10 ES ES466892A patent/ES466892A1/en not_active Expired
- 1978-02-10 IT IT7848013A patent/IT7848013A0/en unknown
- 1978-02-14 CH CH162578A patent/CH636012A5/en not_active IP Right Cessation
- 1978-02-14 BE BE185141A patent/BE863930A/en not_active IP Right Cessation
- 1978-02-15 PL PL1978204642A patent/PL122299B1/en unknown
- 1978-02-15 FR FR7804268A patent/FR2381079A1/en active Granted
- 1978-02-15 LU LU79071A patent/LU79071A1/en unknown
- 1978-02-15 GB GB6014/78A patent/GB1567294A/en not_active Expired
- 1978-02-16 IE IE332/78A patent/IE46408B1/en unknown
- 1978-02-16 ZA ZA00780913A patent/ZA78913B/en unknown
- 1978-02-16 PT PT67663A patent/PT67663B/en unknown
- 1978-02-16 DE DE19782806707 patent/DE2806707A1/en not_active Withdrawn
- 1978-02-17 JP JP1666278A patent/JPS53102958A/en active Pending
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