GB1567294A - Pharmaceutical compositions - Google Patents
Pharmaceutical compositions Download PDFInfo
- Publication number
- GB1567294A GB1567294A GB6014/78A GB601478A GB1567294A GB 1567294 A GB1567294 A GB 1567294A GB 6014/78 A GB6014/78 A GB 6014/78A GB 601478 A GB601478 A GB 601478A GB 1567294 A GB1567294 A GB 1567294A
- Authority
- GB
- United Kingdom
- Prior art keywords
- adsorbate
- poly
- dichloride
- composition
- fumed silica
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
A pharmacologically acceptable bile acid sequestering agent composition which after the prolonged action of moist air does not stick and is free-flowing, contains an essentially uniform adsorbate of a quaternary ionic polymer on a finely divided, water-insoluble, solid, pharmacologically acceptable aggregate having a large surface-to-mass ratio. The composition is prepared by mixing the component in aqueous solution, evaporating the water and drying the adsorbate thus formed. The composition described can be used for the reduction of cholesterol in the blood.
Description
(54) PHARMACEUTICAL COMPOSITIONS
(71) We, MERCK & CO. INC., a corporation duly organized and existing under the laws of the State of New Jersey, United States of America, of Rahway,
New Jersey, Unites States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:- Certain ionene polymers, and in particular poly - [Imethyl - (3 - trimethyl ammoniopropyl)iminioitrimethylene dichloride], are highly efficient as bile-acid sequestrants. Poly - [imethyl - (3 - trimethyl - ammonio?ropyl)iminiol- trimethylene dichloride] is however extremely hygroscopic and, when exposed to air, even at relatively low humidities, rapidly deliquesces to form initially a sticky unworkable product, and finally a solution of the polymer. This hygroscopic characteristic has presented a formidable problem in the formation of poly [(methyl - (3 - trimethylammoniopropyl)iminioStrimethylene dichloride] and, even when such formulation, e.g. by encapsulation of tableting, is conducted under anhydrous conditions, the resulting tablets and capsules rapidly absorb water under normal atmospheric conditions (the coatings of such capsules being permeable to water) to produce unsatisfactory adhesive caking products.
Compositions comprising substantially uniform pulverulent mixtures of poly [Imethyl - (3 - trimethylammoniopropyl)iminioltrimethylene dichloride] with various pharmacologically acceptable solid carriers, such as powdered silica, starch, talc, cellulose and kaolin, when prepared by thoroughly dry-mixing the components (as in a ball mill) under substantially anhydrous conditions, are adhesive in character, and ordinarily become sticky and cake after relatively short exposure to air at 25% relative humidity.
A method of preparing substantially non-adhesive, powdered poly [Imethyl - (3 - trimethylammoniopropyl)iminioltrimethylene dichloride] adsorbate compositions, which remain free-flowing and non-caking, even after prolonged contact with moist air of relative humidity greater than 35% and in some cases up to 76%, has now been discovered and the present invention is based on that discovery. The invention is applicable generally to ionene quaternary polymers of the following formula:
C113 Z el N -W (2n+2+V) nS 2CE2 2N (CH3)3 CE12CH2CH2N (C173)3 Formula I n herein called "ionene quaternary polymers of Formula I". In Formula I, n is the number of repeating units in the polymer; Y is a univalent or multivalent pharmacologically acceptable anion; a is the anionic charge on Y; m is the reciprocal of a; W is propyl, hydroxypropyl, allyl, alkoxypropyl (e.g. ethoxypropyl or methoxypropyl), halopropyl (e.g. chloropropyl, bromopropyl or iodopropyl), or primary, secondary, tertiary or quaternary ammoniopropyl, (e.g. unsubstituted ammoniopropyl, alkylammoniopropyl such as methylammoniopropyl, dialkylammoniopropyl such as dimethylammoniopropyl, or trialkylammoniopropyl such as trimethylammoniopropyl); Z is allyl, N- trimethylammoniopropyl - Nmethyl- 3 -- aminopropyl, N- trimethylmethylammoniumpropyl- N,N dimethyl - 3 ammoniopropyl, halopropyl (e.g. chloropropyl, bromopropyl or iodopropyl), or primary, secondary, tertiary or quaternary ammoniopropyl, (e.g.
unsubstituted ammoniopropyl, alkylammoniopropyl such as methylammoniopropyl, dialkylammoniopropyl such as dimethylammoniopropyl, or trialkylammoniopropyl such as trimethylammoniopropyl) and V is the number of positively charged nitrogens (N+) in the W and Z groupings.
In accordance with the present invention, a non-adhesive free-flowing pharmacologically acceptable bile acid sequestrant composition comprising a hygroscopic ionene quaternary polymer having the formula I set forth herein, is prepared by forming a substantially uniform suspension of a fumed silica or a silica aerogel in an aqueous solution of the ionene quaternary polymer, evaporating off water from the resulting suspension, and drying the adsorbate thus produced. It is preferred to use approximately equal weights, on a dry basis, of fumed silicon dioxide and the ionene quaternary polymer, which is preferably poly - [(methyl (3 - trimethylammoniopropyl)iminioltrimethylene dichloride], although substantially non-adhesive adsorbate compositions are prepared when the weight ratio is about 40 parts fumed silica to 60 parts polymer; fumed silica-polymer adsorbates containing up to 75% fumed silica are likewise both non-adhesive and effective as bile-acid sequestrants, but they are not ordinarily used because of their increased proportion of fumed silica material.
It should be noted that fumed silicon dioxides are prepared by burning silicon tetrachloride in a flame of hydrogen and oxygen to produce primary spherical particles which, while still semi-molten, fuse into clusters of such particles called aggregates; these aggregates, during further cooling and collecting, become physically entangled to form agglomerates. The latter, upon dispersion in an aqueous solution, can disentangle to reform aggregates. Fumed silicon dioxides so prepared, are supplied in the form of a light fluffy, amorphous pure white, non-toxic, pharmacologically acceptable powder, approved by FDA for use as a direct food additive, under the trade mark Cab-O-Sil, by Cabot Corporation, 125 High Street, Boston, Massachusetts. A similar non-toxic, FDA-approved, micron-sized synthetic silica is supplied under the trade mark Syloid silica aerogels and xerogels by W. R. Grace and Co., Davison Chemical Division,
Charles and Baltimore Streets, Baltimore, Maryland. These aerogels and xerogels are prepared by the reaction of sulfuric acid and sodium silicate. The aerogels are highly porous solids formed by replacement of liquid in a gel by gas so that there is little shrinkage. The xerogels are porous solids formed from a gel by drying with unhindered shrinkage.
The process in accordance with the invention is conveniently conducted by first forming a substantially uniform suspension of fumed silica in approximately ten to fifty times its weight of water, and slowly adding to this suspension, with rapid stirring, an aqueous solution of the ionene quaternary polymer, which preferably contains about 5% of the polymer, e.g. poly - [(methyl - (3 - trimethylammoniopropyl) - iminioltrimethylene dichloride]. The rate of addition is usually adjusted so as to be complete in from 5 to 15 minutes, and the resulting milky suspension is stirred vigorously for a short time, e.g. 5 to 15 minutes. The suspension is then evaporated to dryness under reduced pressure with stirring at a temperature within the range 250C to 400C; the temperature should not exceed 500C during this evaporation step, since some discoloration of the polymer can occur above this temperature. The residual powdered silica-polymer adsorbate composition is then dried in vacuo at a temperature of 25"C to 400 C.
It is a preferred feature of the present invention that it is not necessary to use isolated solid polymer for preparing the aqueous solution. Instead, the aqueous polymerization reaction solution can itself be used in this procedure thereby avoiding the isolation, drying and storage of the ionene quaternary polymer. This is advantageous when the polymer, like poly - [(methyl - (3 trimethylammoniopropyl)iminioltrimethylene dichloride], is highly hygroscopic.
This preferred method thus results in the direct product, from the aqueous polymerization reaction solution, of the desired adsorbate composition in a nonadhesive form adapted for pharmaceutical formulation.
In the adsorbate compositions of the present invention, 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, in which the polymer component, although intimately associated with the fumed silica, is present in the form of discrete granules. As might be expected 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. It is indeed surprising that, in spite of their greater hygroscopicity, the adsorbate compositions of the present invention remain completely non-adhesive, non-caking and free-flowing after two days' exposure to moist air at 76% relative humidity, whereas the compositions obtained by dry-mixing the same components become adhesive and cake even after a few hours exposure to moist air of 35% relative humidity.
Effective lowering of cholesterol blood levels can be obtained by the oral administration of remarkably small dosages of the adsorbate compositions of this invention. This enables a flexibility of formulation previously unavailable. The compositions of the present invention 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 or synthetic gums. The compositions 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 X" by weight of the polymer-silica adsorb ate - composition, e.g. poly - [fmethyl - (3 trimethylammoniopropyl)iminioltrimethylene dichloride] - fumed - silica adsorbate composition, the remainder being additives such as carriers, flavorings, excipients, and flow agents. In such a unit dose, the active polymer may make up from 100 milligrams to up to 10 grams in powder packets.
For convenience of administration, it is preferred to use tablets or capsules containing 300600 milligrams of adsorbate compositions comprising equal amounts of fumed silica and the ionene quaternary polymer, e.g. poly - [(methyl (3 - trimethylammoniopropyl)iminiol trimethylene dichloride]. Such unit dosage compositions would thus provide about 150300 milligrams of the polymer; a capsule or tablet containing 600 milligrams of adsorbent composition taken four times per day would thus provide a daily dosage of 1.2 grams of the polymer. Multiple dosages, e.g., two or three tablets or capsules can of course be taken at one time if desired. In the case of tablets, a plastic film can be applied, if desired, to seal the tablets from moisture, and to mask the taste of the polymer in well known ways.
An enteric coating such as fats, fatty acids, waxes and mixtures thereof, shellac, ammoniated shellac, and cellulose acid phthalates, may also be applied by well known and accepted techniques.
The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.
EXAMPLE 1
A mixture of about forty grams of fumed silicon dioxide and 1100 ml of water is stirred vigorously until a thin, lump-free, substantially uniform suspension is obtained. This suspension is stirred while slowly adding to it a solution of forty grams of anhydrous poly - [(methyl - (3 - trimethylammoniopropyl)iminioltri- methylene dichloride] in 300 ml of water. The resulting suspension is evaporated to dryness under reduced pressure, and the residual adsorbate is dried in vacuo for a period of about 15 hours and milled to give about 85 grams of a white, fluffy, freeflowing, non-caking powder containing about 5% of adsorbed moisture.
EXAMPLE 2
A mixture of 122.61 mg of fumed silicon dioxide is suspended in 5 ml of water using a high speed stirrer. A solution containing 121.1 mg anhydrous weight of poly - [{methyl - (3 - trimethylammoniopropyl)iminioltrimethylene dichloride] in 3 ml of water is added slowly while agitation is continued. The resulting milky suspension is evaporated to dryness in vacuo, and the residue adsorbate is further dried in vacuo to give a fumed silica - poly - [(methyl - (3 - trimethyl ammoniopropyl)iminio}trimethylene dichloride] composition in the form of a fluffy white free-flowing non-caking powdery adsorbate which, upon exposure to laboratory atmosphere (relative humidity approximately 35 vE) for a period of 15 hours, fully retains its free-flowing and non-caking characteristics.
EXAMPLE 3
A mixture of 1.34 g of fumed silicon dioxide is suspended in 60 ml of water using a high speed stirrer. A solution containing 1.34 g anhydrous weight of poly [(methyl - (3 - trimethylammoniopropyl)iminiojtrimethylene dichloride] in 30 ml. of water is added slowly while agitation is continued. The resulting milky suspension is stirred vigorously for approximately half an hour, and then evaporated to dryness in vacuo, and the residual adsorbate is further dried in vacuo to give approximately 2.5 g. of a fumed silica-poly-[lmethyl - (3 - trimethyl ammoniopropyl)iminio}trimethylene dichloride] 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 - trimethylammon opropyl)iminioUtrimethylene dichloride] utilized as the bile acid sequestrant 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 the specifications of our copending applications Nos. 24486/75(1,470,538), 15642/76(1,525,762 and 43741/77(1,539,006).
WHAT WE CLAIM IS:
1. A method of preparing a non-adhesive free-flowing pharmacologically acceptable bile acid sequestrant composition comprising a hygroscopic ionene quaternary polymer, having the formula I set forth herein, that comprises forming a substantially uniform suspension of a fumed silica or a silica aerogel in an aqueous solution of the ionene quaternary polymer, evaporating off water from the resulting suspension, and drying the adsorbate thus produced.
2. A method as claimed in Claim 1, in which the ionene polymer is poly[{methyl - (3 - trimethylammoniopropyl)iminioltrimethylene dichloride] and the solid aggregate is fumed silica.
3. A method as claimed in Claim 2, in which there is initially formed a substantially uniform suspension of fumed silica in approximately 10 to 50 times its weight of water, an aqueous solution of poly[{methyl - (3 - trimethyl ammoniopropyl)iminioltrimethylene dichloridei is slowly added to this suspension with rapid stirring, and the water is evaporated from the resulting suspension under reduced pressure while stirring and maintaining the temperature of the mixture at 25--40"C to produce a composition comprising approximately equal weights of poly - [(methyl - (3 - trimethylammoniopropyl)iminio}trimethylene dichloride] and fumed silica.
4. A method as claimed in Claim 3, in which the initial suspension contains one part by weight of fumed silica in approximately 25 parts by weight of water and the dilute solution of poly - [f methyl - (3 - trimethylammoniopropyl)iminioj- trimethylene dichloride] contains one part of it in about eight parts by weight of water.
5. A method as claimed in any one of Claims 1 to 4, including the further step of milling the resulting adsorbate after drying it.
6. A bile acid sequestrant composition that is non-adhesive and free-flowing after prolonged exposure to moist air and that comprises a substantially uniform adsorbate of an ionene quaternary polymer, having the formula I set forth herein, on a fumed silica or silica aerogel.
7. A sequestrant composition as claimed in Claim 6 comprising a substantially uniform adsorbate film of polyjimethyl - (3 - trimethylammoniopropyl)iminioltri- methylene dichloride] on fumed silica.
8. A composition as claimed in Claim 7 containing approximately equal weights of poly - [(methyl - (3 - trimethylammoniopropyl)iminioltrimethylene dichloride] and fumed silica.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (10)
1. A method of preparing a non-adhesive free-flowing pharmacologically acceptable bile acid sequestrant composition comprising a hygroscopic ionene quaternary polymer, having the formula I set forth herein, that comprises forming a substantially uniform suspension of a fumed silica or a silica aerogel in an aqueous solution of the ionene quaternary polymer, evaporating off water from the resulting suspension, and drying the adsorbate thus produced.
2. A method as claimed in Claim 1, in which the ionene polymer is poly[{methyl - (3 - trimethylammoniopropyl)iminioltrimethylene dichloride] and the solid aggregate is fumed silica.
3. A method as claimed in Claim 2, in which there is initially formed a substantially uniform suspension of fumed silica in approximately 10 to 50 times its weight of water, an aqueous solution of poly[{methyl - (3 - trimethyl ammoniopropyl)iminioltrimethylene dichloridei is slowly added to this suspension with rapid stirring, and the water is evaporated from the resulting suspension under reduced pressure while stirring and maintaining the temperature of the mixture at 25--40"C to produce a composition comprising approximately equal weights of poly - [(methyl - (3 - trimethylammoniopropyl)iminio}trimethylene dichloride] and fumed silica.
4. A method as claimed in Claim 3, in which the initial suspension contains one part by weight of fumed silica in approximately 25 parts by weight of water and the dilute solution of poly - [f methyl - (3 - trimethylammoniopropyl)iminioj- trimethylene dichloride] contains one part of it in about eight parts by weight of water.
5. A method as claimed in any one of Claims 1 to 4, including the further step of milling the resulting adsorbate after drying it.
6. A bile acid sequestrant composition that is non-adhesive and free-flowing after prolonged exposure to moist air and that comprises a substantially uniform adsorbate of an ionene quaternary polymer, having the formula I set forth herein, on a fumed silica or silica aerogel.
7. A sequestrant composition as claimed in Claim 6 comprising a substantially uniform adsorbate film of polyjimethyl - (3 - trimethylammoniopropyl)iminioltri- methylene dichloride] on fumed silica.
8. A composition as claimed in Claim 7 containing approximately equal weights of poly - [(methyl - (3 - trimethylammoniopropyl)iminioltrimethylene dichloride] and fumed silica.
9. A tablet or capsule comprising a composition as claimed in Claim 7 or 8 in
amount such that it contains from 150 to 300 milligrams of poly - [{methyl-(3 trimethylammoniopropyl)iminio}trimethylene dichloride].
10. A composition as claimed in Claim 6 substantially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76949177A | 1977-02-17 | 1977-02-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1567294A true GB1567294A (en) | 1980-05-14 |
Family
ID=25085598
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB6014/78A Expired GB1567294A (en) | 1977-02-17 | 1978-02-15 | Pharmaceutical compositions |
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) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5607669A (en) * | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
| US5618530A (en) * | 1994-06-10 | 1997-04-08 | Geltex Pharmaceuticals, Inc. | Hydrophobic 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 |
| US5679717A (en) * | 1994-06-10 | 1997-10-21 | Geltex Pharmaceuticals, Inc. | Method for removing bile salts from a patient with alkylated amine polymers |
| US5703188A (en) * | 1993-06-02 | 1997-12-30 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
| US5900475A (en) * | 1994-06-10 | 1999-05-04 | Geltex Pharmaceuticals, Inc. | Hydrophobic sequestrant for cholesterol depletion |
| 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 |
| 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 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4027009A (en) * | 1973-06-11 | 1977-05-31 | Merck & Co., Inc. | Compositions and methods for depressing blood serum cholesterol |
| AR206115A1 (en) * | 1973-06-11 | 1976-06-30 | Merck & Co Inc | PROCEDURE TO PREPARE A NON-BRANCHED AND NON-CROSSLINK LINEAR POLYMER |
-
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 NO NO780367A patent/NO148838C/en unknown
- 1978-02-02 NL NL7801240A patent/NL7801240A/en not_active Application Discontinuation
- 1978-02-02 SE SE7801242A patent/SE433170B/en unknown
- 1978-02-06 IL IL53978A patent/IL53978A/en unknown
- 1978-02-06 PH PH20753A patent/PH15263A/en unknown
- 1978-02-06 GR GR55356A patent/GR66100B/el unknown
- 1978-02-07 NZ NZ186399A patent/NZ186399A/en unknown
- 1978-02-08 AT AT0087978A patent/AT363173B/en not_active IP Right Cessation
- 1978-02-08 CA CA296,622A patent/CA1109395A/en not_active Expired
- 1978-02-08 AU AU33099/78A patent/AU518127B2/en not_active Expired
- 1978-02-09 HU HU78ME2145A patent/HU177685B/en unknown
- 1978-02-10 IT IT7848013A patent/IT7848013A0/en unknown
- 1978-02-10 ES ES466892A patent/ES466892A1/en not_active Expired
- 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 FR FR7804268A patent/FR2381079A1/en active Granted
- 1978-02-15 PL PL1978204642A patent/PL122299B1/en unknown
- 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
Cited By (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840766A (en) * | 1993-06-02 | 1998-11-24 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
| US6129910A (en) * | 1993-06-02 | 2000-10-10 | Geltex Pharmaceuticals, Inc. | Water-insoluble noncrosslinked bile acid sequestrants |
| US5624963A (en) * | 1993-06-02 | 1997-04-29 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
| US6060517A (en) * | 1993-06-02 | 2000-05-09 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
| 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 |
| US5703188A (en) * | 1993-06-02 | 1997-12-30 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
| US5981693A (en) * | 1994-06-10 | 1999-11-09 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
| US5618530A (en) * | 1994-06-10 | 1997-04-08 | Geltex Pharmaceuticals, Inc. | Hydrophobic amine polymer sequestrant and method of cholesterol depletion |
| US5917007A (en) * | 1994-06-10 | 1999-06-29 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and alkylated compositions therefor |
| US5919832A (en) * | 1994-06-10 | 1999-07-06 | Geltex Pharmaceuticals Inc. | Amine polymer sequestrant and method of cholesterol depletion |
| US5693675A (en) * | 1994-06-10 | 1997-12-02 | Geltex Pharmaceuticals Inc. | Alkylated amine polymers |
| US5969090A (en) * | 1994-06-10 | 1999-10-19 | Geltex Pharmaceuticals, Inc. | Hydrophobic sequestrant for cholesterol depletion |
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| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |