EP0530242A1 - Compounds - Google Patents
CompoundsInfo
- Publication number
- EP0530242A1 EP0530242A1 EP91909433A EP91909433A EP0530242A1 EP 0530242 A1 EP0530242 A1 EP 0530242A1 EP 91909433 A EP91909433 A EP 91909433A EP 91909433 A EP91909433 A EP 91909433A EP 0530242 A1 EP0530242 A1 EP 0530242A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- polymer
- alkyl
- substitute sheet
- polymers
- nitrogen atom
- 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.)
- Withdrawn
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
- C08F8/32—Introducing nitrogen atoms or nitrogen-containing groups by reaction with amines
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/44—Preparation of metal salts or ammonium salts
Definitions
- the present invention relates to novel anion exchange polymers, processes for their preparation, pharmaceutical compositions containing them and their use in the lowering of plasma cholesterol levels in humans.
- Coronary Heart Disease is one of the most serious health problems of contemporary society.
- Worldwide epidemiological studies have shown that the incidence of CHD is related to a number of independent risk factors, in particular, for example, high concentrations of serum cholesterol (hypercholesterolaemia) .
- serum cholesterol hypercholesterolaemia
- Such adverse factors lead to atherosclerosis, and ultimately, in severe cases, intermittent claudication, cerebrovascular insufficiency, thrombosis and cardiac arrest.
- ion exchange polymers can be used as sequestering agents to bind bile acids and salts in the intestinal tract, forming complexes which are then excreted in the faeces. This sequestering leads to a decrease in the amount of bile acids returning to the liver via enterohepatic circulation.
- the synthesis of replacement bile acids from hepatic cholesterol depletes hepatic cholesterol, regulates hepatic LDL receptors and consequently reduces plasma cholesterol levels.
- Such sequestering polymers have been recognised as useful for the treatment of hypercholesterolaemia and it is now proven that reducing serum cholesterol with bile acid sequestrants has a beneficial effect on protecting against the occurrence of coronary heart disease.
- SUBSTITUTE SHEET One particular agent which is currently used to lower serum cholesterol levels in humans by binding bile acids in the intestinal tract is cholestyramine.
- Cholestyramine is a cross-linked anion exchange polystyrene polymer bearing an ionisable trimethylammonium group bound to the polymer backbone.
- this agent is associated with a number of undesirable side-effects, for example, it is unpalatable and must be taken in high doses and causes, in some cases, bloating, constipation and other gut side- effects.
- its ability to bind bile acids is inefficient with respect to the amounts of resin which it is necessary to use (up to 36 g per person per day) .
- the present invention therefore provides in a first aspect, cross-linked polymers of structure (I)
- a, b, c and d indicate the relative molar percentages of the units present in the polymer, (a) and (b) together being from about 25 to about 99.5 molar percent, and (c) being from about 0.5 to about 8 molar percent;
- X is a cross-linking unit
- X 1 is a comonomer unit
- R and R' are the same or different and are each hydrogen or C 1 _ alkyl
- R 1 and R 2 are the same or different and are each C 1 _ 4 alkyl, and R 3 is C 1 _ 20 alkyl or C- L _ 20 aralkyl; or R 1 is C _ 4 alkyl and R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R 1 to R 3 together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms;
- SUBSTITUTE SHEET R 1 ' and R 2 ' are the same or different and are each
- R 3 is C 1 _ 20 alkyl or C 1 _ 20 aralk y 1 or R 1 ' is C 1 _ 4 alkyl and R 2 ' and R 3 ' together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R 1 ' to R 3 ' together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms;
- n and n' are the same or different and are each 1 to 20;
- p is a number indicating the degree of polymerisation of the polymer
- Y ⁇ is a physiologically acceptable counter ion.
- (a) plus (b) is from about 25 to about 99.5 molar percent; preferably from about 60 to about 99.5 molar percent.
- (c) is from about 0.5 to about 8 molar percent; preferably from about 0.5 to about 5.0 molar percent.
- X is a cross-linking unit i.e. a unit which provides a random distribution of cross-links between chains of polymers.
- SUBSTITUTE SHEET Preferred such units include, for example, divinylbenzene, alkylene glycol bis methacrylates of structure (i)
- z is l to 4, preferably z is 1.
- m is 2 to 6, preferably m is 2.
- X 1 is a comonomer unit.
- X 1 is styrene, an alkyl alkylate of structure (ii) or an alkylstyrene of structure (iii)
- R and d are as described for structure (I) and R 4 is C 1 _ 0 alkyl.
- R is preferably methyl and R 4 is preferably C 6 _ 12 alkyl.
- R 1 to R 3 or R 1 ' to R 3 ' together with the nitrogen atom to which they are attached form an unsaturated ring optionally containing one or more further heteroatoms.
- Suitable examples of such rings unsaturated 5 or 6 membered rings such as imidazolyl and pyridyl. More suitably, R 1 or R 1 is C 1 _ 4 alkyl and R 2 and R 3 or R 2 ' and R 3 together with the nitrogen atom to which they are attached form a saturated ring optionally containing one or more further heteroatoms.
- saturated rings include, for example, morpholino, piperidino and piperazino rings, and in addition, bicyclic rings i.e. those in which the R 1 or
- R J group forms a bridge between the two nitrogen atoms of a saturated ring e.g.
- R 1 and R 2 or R 1 and R 2 ' are the same or different and are each C 1 _ alkyl; more preferably R 1 and
- R 2 or R 1' and R are the same and are each C 1-4 alkyl, in particular methyl; and R 3 or R 3 ' is C 1 _ 20 alkyl or C 1 _ 0 aralkyl, preferably C 1 _ 0 alkyl, most preferably ⁇ l -" .2 --- ⁇ - r ⁇ ' - P rt i cu l ar C 12 alkyl.
- n is 1 to 20; preferably n is 8 to 20; most preferably n is 8 to 12.
- n' is 1 to 20; preferably n' is 8 to 20; most preferably n' is 8 to 12.
- p is a number indicating the degree of polymerisation of the polymer. Owing to the three dimensional cross- linkage, precise figures cannot be given for p, but in any case will be greater than 1,000.
- Y ⁇ is a physiologically acceptable counter ion such as a bicarbonate, carbonate, formate, acetate, sulphonate, propionate, malonate, succinate, maleate, tartrate, citrate, maleate, fumarate, ascorbate, sulphate, phosphate, halide or glucuronate; or the anion of an a ino acid such as aspartic or glutamic acid.
- Y ⁇ is a sulphate, phosphate or halide ion; more preferably a halide ion, in particular a chloride ion.
- C 1-4 alkyl and C 1 _ 20 alkyl groups as herein defined include both straight and branched alkyl groups.
- the polymers of the present invention are also characterised by their total exchange capacity i.e. the theoretical maximum capacity of the resin if each counter ion were to be exchanged with bile acid.
- the total exchange capacity is defined in terms of the number of milliequivalent ⁇ of counter ion per gram of dry weight of polymer.
- Suitable total exchange capacities are in the range of, for example where the counter ion Y ⁇ is chlorine,
- SUBSTITUTE SHEET from about 1.5 to about 5.0 meq Cl ⁇ per gram of resin.
- Preferred within this range are polymers having a total exchange capacity of between 2 and 3 meq Cl ⁇ /gram of resin.
- bile acid when used herein shall be taken to include bile acids, bile salts and conjugates thereof.
- the polymers of the present invention can be prepared by processes analogous to those known in the art.
- the present invention therefore provides, in a further aspect, a process for preparing the polymers of structure (I) which comprises reaction of a polymer of structure (II)
- R- are as described for structure (I)
- Suitable groups Z displaceable by an amine will be apparent to those skilled in the art and include for example halogen, such as bromine.
- the reaction between a polymer of structure (II) and a compound of structure R 1 R 2 R 3 N and a compound of structure R 1, R 2 'R 3 'N can be carried out in a suitable solvent at elevated temperature.
- suitable solvents include for example, a C j ⁇ al a ol such as ethanol, N-methyl- pyrrolidone, dimethylformamide, tetrahydrof ran, nitro- ethane or sulpholane.
- the reaction is carried out in methanol at a temperature of about 40° for a period of up to 24 hours or until the reaction is complete.
- the intermediate polymers of structure (II) can be prepared from readily available materials by methods known to those skilled in the art.
- polymers of structure (II) in which X is a cross-link of structure (i) in which 2 is 1 and is 2, and Z is bromine and R is methyl can be prepared by reaction of the appropriate bromo alkyl methacrylate, ethylene glycol bis methacrylate, and, optionally, for example, a C 1 _ 20 alkyl alkacrylate (if a comonomer unit X 1 is desired in the final polymer) in an aqueous suspension comprising polyvinyl alcohol in the presence of an initiator at elevated temperature.
- chloro or bromo alkyl methacrylates can be prepared by reaction of the corresponding chloro- or bromoalkanol and methacrylic anhydride in the presence of 4-dimethylaminopyridine (DMAP) in a suitable solvent such as pyridine, or by reaction of the corresponding chloro or bromo alkanol with methacryloyl chloride in the presence of a base in a suitable solvent -
- DMAP 4-dimethylaminopyridine
- SUBSTITUTE SHEET suitable combinations of bases and solvents include, for example sodium bicarbonate in petroleum spirit as a solvent and pyridine as a base in toluene as solvent (cf. method described in Polymer (1987) , _l__, 325-331, and Br.Polymer J. (1984) 16, 39-45) .
- the polymers of structure (I) have been found to bind bile acids both in in vitro and in in vivo models. As indicated earlier it is recognised that removal of bile acids from the intestinal tract in this way lowers serum cholesterol levels and also has a beneficial effect on protecting against atherosclerosis and its dependent clinical conditions.
- the present invention therefore provides in a further aspect, polymers of structure (I) for use in therapy, in particular for the lowering of serum cholesterol levels in mammals, including humans.
- the polymers of structure (I) are expected to be of use in protecting against atherosclerosis and its sequelae, and for example, in the treatment of pruritus and diarrhoea.
- polymers of structure (I) When used in therapy polymers of structure (I) are in general administered in a pharmaceutical composition.
- a pharmaceutical composition comprising a polymer of structure (I) in association with a pharmaceutically acceptable carrier.
- compositions of the present invention can be prepared by techniques well known to those skilled in the art of pharmacy.
- polymers are preferably administered as formulations in admixture with one or more conventional pharmaceutical excipients which are physically and chemically compatible with the polymer, which are non- toxic, are without deleterious side-effects but which confer appropriate properties on the dosage form.
- aqueous pharmaceutically acceptable carriers such as water itself or aqueous dilute ethanol, propylene glycol, polyethylene glycol or glycerol or sorbitol solutions are preferred.
- Such formulations can also include preservatives and flavouring and sweetening agents such as sucrose, fructose, invert sugar, cocoa, citric acid, ascorbic acid, fruit juices etc.
- preservatives and flavouring and sweetening agents such as sucrose, fructose, invert sugar, cocoa, citric acid, ascorbic acid, fruit juices etc.
- digestible oil or fat based carriers should be avoided or minimised as they contribute to the condition sought to be alleviated by use of the polymers. They are also subject to absorption by the polymers during prolonged contact, thus reducing the capacity of the polymer to absorb bile acids after administration.
- the polymers can also be prepared as 'concentrates' , for dilution prior to administration, and as formulations suitable for direct oral administration. They can be administered orally ad libitum, on a relatively continuous basis for example by dispersing the polymer in water, drinks or food, for example in a granule presentation suitable for admixture with water or other drink to provide a palatable drinking suspension.
- the polymers are administered in tablet form or in gelatin capsules containing solid particulate polymer or a non-aqueous suspension of solid polymer
- SUBSTITUTE SHEET containing a suitable suspending agent.
- suitable excipients for such formulations will be apparent to those skilled in the art and include, for example, for tablets and capsules, lactose, microcrystalline cellulose, magnesium, stearate, povidone, sodium starch, glycollate and starches; and for suspensions in capsules, polyethylene glycol, propylene glycol and colloidal silicone dioxide. If desired these dosage forms in addition optionally comprise suitable flavouring agents. Alternatively, a chewable tablet or granule presentation incorporating suitable flavouring and similar agents may be used.
- the polymer is administered in unit dosage form, each dosage unit containing preferably from 0.5 g to 1.5 g of polymer.
- the daily dosage regimen for an adult patient may be, for example, a total daily oral dose of between 1 and 10 g, preferably 1-5 g, the compound being administered 1 to 4 times a day.
- the compound is administered for a period of continuous therapy of one month or more sufficient to achieve the required reduction in serum cholesterol levels.
- polymers of the present invention can be co-administered (together or sequentially) with further active ingredients such as HMGCoA reductase inhibitors and other hypocholesterolaemic agents, and other drugs for the treatment of cardiovascular diseases.
- SUBSTITUTE SHEET was determined by elemental analysis and/or potentiometric titration of chloride ion. Figures quoted are expressed as milli equivalents of exchangeable chloride ion per gram of dry resin weight; and the percent cross-linking values given are based on the ratios of the starting monomers used in the polymerisation stage.
- a chewable tablet composition can be prepared from the following : mg/tablet
- a food additive composition for example, a sachet for reconstitution or mixing with food, is prepared by incorporating into a powder formulation compound of structure (I) (250 mg) , sodium carboxymethylcellulose (50 mg) , sucrose (2400 mg) and flavours (50 mg) .
- the lower the % dissociation the more efficient the polymer can be expected to be in extracting bile acids in vivo.
- Test compound 150 mg is equilibrated with 5mM sodium glycocholate (30 ml) in Krebs' buffer. The compound is separated by centrifugation and the total bound determined by subtraction of the amount in the supernatant from the total bile acid used. Dissociation is measured by resuspending the compound in Krebs' buffer, shaking and sampling the mixture through a filter at several time points up to 20 minutes. Radioactivity and hence bile acid dissociated is determined in the filtrate.
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Abstract
Polymères de polyméthacrylate et leur utilisation thérapeutique comme agents de réduction du taux de cholestérol.Polymethacrylate polymers and their therapeutic use as cholesterol lowering agents.
Description
COMPOUNDS
The present invention relates to novel anion exchange polymers, processes for their preparation, pharmaceutical compositions containing them and their use in the lowering of plasma cholesterol levels in humans.
Coronary Heart Disease (CHD) is one of the most serious health problems of contemporary society. Worldwide epidemiological studies have shown that the incidence of CHD is related to a number of independent risk factors, in particular, for example, high concentrations of serum cholesterol (hypercholesterolaemia) . Such adverse factors lead to atherosclerosis, and ultimately, in severe cases, intermittent claudication, cerebrovascular insufficiency, thrombosis and cardiac arrest.
It is known that ion exchange polymers can be used as sequestering agents to bind bile acids and salts in the intestinal tract, forming complexes which are then excreted in the faeces. This sequestering leads to a decrease in the amount of bile acids returning to the liver via enterohepatic circulation. The synthesis of replacement bile acids from hepatic cholesterol depletes hepatic cholesterol, regulates hepatic LDL receptors and consequently reduces plasma cholesterol levels. Such sequestering polymers have been recognised as useful for the treatment of hypercholesterolaemia and it is now proven that reducing serum cholesterol with bile acid sequestrants has a beneficial effect on protecting against the occurrence of coronary heart disease.
SUBSTITUTE SHEET
One particular agent which is currently used to lower serum cholesterol levels in humans by binding bile acids in the intestinal tract is cholestyramine. Cholestyramine is a cross-linked anion exchange polystyrene polymer bearing an ionisable trimethylammonium group bound to the polymer backbone. However, the use of this agent is associated with a number of undesirable side-effects, for example, it is unpalatable and must be taken in high doses and causes, in some cases, bloating, constipation and other gut side- effects. Furthermore, its ability to bind bile acids is inefficient with respect to the amounts of resin which it is necessary to use (up to 36 g per person per day) .
In addition, other polymers have been disclosed in the art as sequestering agents, in particular US 3787474 discloses the use of polymers derived from acrylic monomers of structure RCH=CHR1A in which R is methyl or ethyl, R1 is hydrogen or methyl and A is for example, C02(CH )2N(R3) R4X in which R3 is methyl or ethyl, and R4 is hydrogen, methyl or ethyl and X is Cl~, Br~, I~ or CH3SO3- cross-linked with methyl bisacrylamide or ethylene glycol bis methacrylate; US 4393145 discloses further polymers derived from acrylic monomers cross-linked through divinyl benzene (10 to 12%) , and SE 7906129 discloses acrylic polymers cross-linked by 10-12% of a divinyl cross-linking monomer. However, despite these disclosures, no such acrylic polymers are available for human use and there remains a need for effective bile acid sequestering agents which do not have the disadvantages associated with agents currently in use.
The present invention therefore provides in a first aspect, cross-linked polymers of structure (I)
SUBSTITUTE SHEET
in which
a, b, c and d indicate the relative molar percentages of the units present in the polymer, (a) and (b) together being from about 25 to about 99.5 molar percent, and (c) being from about 0.5 to about 8 molar percent;
X is a cross-linking unit;
X1 is a comonomer unit;
R and R' are the same or different and are each hydrogen or C1_ alkyl;
R1 and R2 are the same or different and are each C1_4alkyl, and R3 is C1_20alkyl or C-L_20aralkyl; or R1 is C _4alkyl and R2 and R3 together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R1 to R3 together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms;
SUBSTITUTE SHEET
R1' and R2' are the same or different and are each
C1-4alkyl, and R3 is C1_20alkyl or C1_20 aralky1 or R1' is C1_4alkyl and R2' and R3' together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R1' to R3' together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms;
n and n' are the same or different and are each 1 to 20;
p is a number indicating the degree of polymerisation of the polymer; and
Y~ is a physiologically acceptable counter ion.
Suitably, (a) plus (b) is from about 25 to about 99.5 molar percent; preferably from about 60 to about 99.5 molar percent.
Suitably, (c) is from about 0.5 to about 8 molar percent; preferably from about 0.5 to about 5.0 molar percent.
Suitably, X is a cross-linking unit i.e. a unit which provides a random distribution of cross-links between chains of polymers.
SUBSTITUTE SHEET
Preferred such units include, for example, divinylbenzene, alkylene glycol bis methacrylates of structure (i)
in which m is 2 to 6, z is 1 to 4 and (c) comprises from about 0.5 to about 8 molar percent of said polymer; and trismethacrylates of structure (ii)
Suitably, z is l to 4, preferably z is 1. Suitably, m is 2 to 6, preferably m is 2.
Suitably X1 is a comonomer unit. Preferably X1 is styrene, an alkyl alkylate of structure (ii) or an alkylstyrene of structure (iii)
SUBSTITUTE SHEET
in which R and d are as described for structure (I) and R4 is C1_ 0alkyl. In such comonomers groups R is preferably methyl and R4 is preferably C6_12alkyl.
Suitably R1 to R3 or R1' to R3' together with the nitrogen atom to which they are attached form an unsaturated ring optionally containing one or more further heteroatoms. Suitable examples of such rings unsaturated 5 or 6 membered rings such as imidazolyl and pyridyl. More suitably, R1 or R1 is C1_4alkyl and R2 and R3 or R2' and R3 together with the nitrogen atom to which they are attached form a saturated ring optionally containing one or more further heteroatoms. Suitable examples of saturated rings include, for example, morpholino, piperidino and piperazino rings, and in addition, bicyclic rings i.e. those in which the R1 or
RJ group forms a bridge between the two nitrogen atoms of a saturated ring e.g.
diazabicyclo [2.2.2] octane rings of structure Θ -N N.
Preferably, R1 and R2 or R1 and R2' are the same or different and are each C1_ alkyl; more preferably R1 and
R2 or R1' and R are the same and are each C1-4alkyl, in particular methyl; and R3 or R3' is C1_20alkyl or C1_ 0aralkyl, preferably C1_ 0alkyl, most preferably ~l-".2---~-r~ ' - P rticular C 12alkyl.
SUBSTITUTE SHEET
Suitably, n is 1 to 20; preferably n is 8 to 20; most preferably n is 8 to 12.
Suitably, n' is 1 to 20; preferably n' is 8 to 20; most preferably n' is 8 to 12.
p is a number indicating the degree of polymerisation of the polymer. Owing to the three dimensional cross- linkage, precise figures cannot be given for p, but in any case will be greater than 1,000.
Suitably Y~ is a physiologically acceptable counter ion such as a bicarbonate, carbonate, formate, acetate, sulphonate, propionate, malonate, succinate, maleate, tartrate, citrate, maleate, fumarate, ascorbate, sulphate, phosphate, halide or glucuronate; or the anion of an a ino acid such as aspartic or glutamic acid. Preferably Y~ is a sulphate, phosphate or halide ion; more preferably a halide ion, in particular a chloride ion.
It is to be noted that C1-4alkyl and C1_20alkyl groups as herein defined include both straight and branched alkyl groups.
The polymers of the present invention are also characterised by their total exchange capacity i.e. the theoretical maximum capacity of the resin if each counter ion were to be exchanged with bile acid. In this specification the total exchange capacity is defined in terms of the number of milliequivalentε of counter ion per gram of dry weight of polymer.
Suitable total exchange capacities are in the range of, for example where the counter ion Y~ is chlorine,
SUBSTITUTE SHEET
from about 1.5 to about 5.0 meq Cl~ per gram of resin. Preferred within this range are polymers having a total exchange capacity of between 2 and 3 meq Cl~/gram of resin.
It is to be noted that the term 'bile acid' when used herein shall be taken to include bile acids, bile salts and conjugates thereof.
The polymers of the present invention can be prepared by processes analogous to those known in the art. The present invention therefore provides, in a further aspect, a process for preparing the polymers of structure (I) which comprises reaction of a polymer of structure (II)
in which a, b, c, d, p, R, R' , X, X1, n and n' are as described for structure (I) , and Z is a group displaceable by an amine, with a compound of structure R1R2R3N, in which R1 to R3 are as described for structure (I) ; and a compound of structure R1 R2 R3'N in which R1' to
R- are as described for structure (I)
Suitable groups Z displaceable by an amine will be apparent to those skilled in the art and include for example halogen, such as bromine.
SUBSTITUTESHEET
The reaction between a polymer of structure (II) and a compound of structure R1R2R3N and a compound of structure R1,R2'R3'N can be carried out in a suitable solvent at elevated temperature. Suitable solvents include for example, a Cj^al a ol such as ethanol, N-methyl- pyrrolidone, dimethylformamide, tetrahydrof ran, nitro- ethane or sulpholane. Preferably the reaction is carried out in methanol at a temperature of about 40° for a period of up to 24 hours or until the reaction is complete.
The intermediate polymers of structure (II) can be prepared from readily available materials by methods known to those skilled in the art. For example polymers of structure (II) in which X is a cross-link of structure (i) in which 2 is 1 and is 2, and Z is bromine and R is methyl can be prepared by reaction of the appropriate bromo alkyl methacrylate, ethylene glycol bis methacrylate, and, optionally, for example, a C1_20alkyl alkacrylate (if a comonomer unit X1 is desired in the final polymer) in an aqueous suspension comprising polyvinyl alcohol in the presence of an initiator at elevated temperature. Suitable initiators will be apparent to those skilled in the art and include, for example azobisisobutyronitrile benzoyl peroxide and WAKO V601 (Trade name - Me02C(CH3)CN=NC(CH3)2C02Me) .
The starting monomers can be prepared by methods apparent to those skilled in the art. For example, chloro or bromo alkyl methacrylates can be prepared by reaction of the corresponding chloro- or bromoalkanol and methacrylic anhydride in the presence of 4-dimethylaminopyridine (DMAP) in a suitable solvent such as pyridine, or by reaction of the corresponding chloro or bromo alkanol with methacryloyl chloride in the presence of a base in a suitable solvent -
SUBSTITUTE SHEET
suitable combinations of bases and solvents include, for example sodium bicarbonate in petroleum spirit as a solvent and pyridine as a base in toluene as solvent (cf. method described in Polymer (1987) , _l__, 325-331, and Br.Polymer J. (1984) 16, 39-45) .
The polymers of structure (I) have been found to bind bile acids both in in vitro and in in vivo models. As indicated earlier it is recognised that removal of bile acids from the intestinal tract in this way lowers serum cholesterol levels and also has a beneficial effect on protecting against atherosclerosis and its dependent clinical conditions. The present invention therefore provides in a further aspect, polymers of structure (I) for use in therapy, in particular for the lowering of serum cholesterol levels in mammals, including humans. In addition the polymers of structure (I) are expected to be of use in protecting against atherosclerosis and its sequelae, and for example, in the treatment of pruritus and diarrhoea.
When used in therapy polymers of structure (I) are in general administered in a pharmaceutical composition.
in a still further aspect of the present invention there is therefore provided a pharmaceutical composition comprising a polymer of structure (I) in association with a pharmaceutically acceptable carrier.
The compositions of the present invention can be prepared by techniques well known to those skilled in the art of pharmacy.
SUBSTITUTE SHEET
The polymers are preferably administered as formulations in admixture with one or more conventional pharmaceutical excipients which are physically and chemically compatible with the polymer, which are non- toxic, are without deleterious side-effects but which confer appropriate properties on the dosage form.
In general, for liquid formulations, aqueous pharmaceutically acceptable carriers such as water itself or aqueous dilute ethanol, propylene glycol, polyethylene glycol or glycerol or sorbitol solutions are preferred. Such formulations can also include preservatives and flavouring and sweetening agents such as sucrose, fructose, invert sugar, cocoa, citric acid, ascorbic acid, fruit juices etc. In general, digestible oil or fat based carriers should be avoided or minimised as they contribute to the condition sought to be alleviated by use of the polymers. They are also subject to absorption by the polymers during prolonged contact, thus reducing the capacity of the polymer to absorb bile acids after administration.
The polymers can also be prepared as 'concentrates' , for dilution prior to administration, and as formulations suitable for direct oral administration. They can be administered orally ad libitum, on a relatively continuous basis for example by dispersing the polymer in water, drinks or food, for example in a granule presentation suitable for admixture with water or other drink to provide a palatable drinking suspension.
Preferably, the polymers are administered in tablet form or in gelatin capsules containing solid particulate polymer or a non-aqueous suspension of solid polymer
SUBSTITUTE SHEET
containing a suitable suspending agent. Suitable excipients for such formulations will be apparent to those skilled in the art and include, for example, for tablets and capsules, lactose, microcrystalline cellulose, magnesium, stearate, povidone, sodium starch, glycollate and starches; and for suspensions in capsules, polyethylene glycol, propylene glycol and colloidal silicone dioxide. If desired these dosage forms in addition optionally comprise suitable flavouring agents. Alternatively, a chewable tablet or granule presentation incorporating suitable flavouring and similar agents may be used.
Preferably the polymer is administered in unit dosage form, each dosage unit containing preferably from 0.5 g to 1.5 g of polymer.
The daily dosage regimen for an adult patient may be, for example, a total daily oral dose of between 1 and 10 g, preferably 1-5 g, the compound being administered 1 to 4 times a day. Suitably the compound is administered for a period of continuous therapy of one month or more sufficient to achieve the required reduction in serum cholesterol levels.
in addition the polymers of the present invention can be co-administered (together or sequentially) with further active ingredients such as HMGCoA reductase inhibitors and other hypocholesterolaemic agents, and other drugs for the treatment of cardiovascular diseases.
The following data and examples indicate the properties and preparation of the polymers of the present invention. Temperatures are recorded in degrees celsius. The exchange capacity of the ammonium substituted polymers
SUBSTITUTE SHEET
was determined by elemental analysis and/or potentiometric titration of chloride ion. Figures quoted are expressed as milli equivalents of exchangeable chloride ion per gram of dry resin weight; and the percent cross-linking values given are based on the ratios of the starting monomers used in the polymerisation stage.
SUBSTITUTE SHEET
EXAMPLE 1
(a) A suspension of 11-bromoundecanol (lOOg) and 4-dimethylaminopyridine (DMAP) (lg) in methacrylic
5 anhydride (60 ml) and pyridine (37ml) was stirred for 48 hours at room temperature. Water (400ml) was added and the aqueous phase brought to pH 3 using dilute hydrochloric acid. The aqueous phase was extracted with hexane (3 x 300ml) , water (200ml) , saturated sodium hydrogen 0 carbonate solution (2 x 400ml) and finally water (200ml) . After drying (MgS04) , the solution was concentrated in vacuo to give a clear oil (108g) . This was subjected to column chromatography on silica gel with hexane as eluent, to give 11-bromoundecyl methacrylate as a clear oil 5 (70.8g; 56% yield) .
(b) 11-Bromoundecyl methacrylate (49.5g), ethylene glycol bismethacrylate (0.5g) and azobisisobutyronitrile (AIBN) (0.5g) were mixed to give a suspension and added to 0 a solution of poly(vinyl alcohol) (M.W. 125,000) (l.Og) in distilled water (500ml) . The mixture was then stirred at 80°C under an atmosphere of nitrogen at such a rate as to maintain the monomers in suspension. After 7 hours the stirring was stopped and the mixture poured into distilled 5 water. The resin formed was washed by decantation with cold and hot water, filtered, and washed with acetone and diethyl ether. Drying under reduced pressure gave an approximately 1.6 molar % cross-linked 11-bromoundecyl methacrylate co-polymer containing 3.1 meq Br/g (44.9g). 0
(c) The above 1.6 molar % cross-linked 11-bromo- undecyl methacrylate co-polymer (lOg) was suspended in dimethylformamide (lOOml) , N,N-dimethyldodecylamine (3.3g) added, and the reaction mixture heated at 70°C for 24 ;
SUBSTITUTE SHEET
hours. The polymer was filtered and washed with dimethyl- formamide, methanol, diethyl ether and dried under vacuum to give cross-linked ll-bromoundecyl methacrylate [ll-N,N- dimethyl-N-dodecylammonioundecyl methacrylate]chloride co-polymer containing 2.2 meq Br/g (12.46g).
(d) The above co-polymer (lOg) was suspended in dimethylformamide (100ml) , 33% trimethylamine in ethanol (75ml) added, and the reaction mixture heated at 70°C for 26 hours. Additional 33% trimethylamine in ethanol
(50ml) was added at 6h. After cooling the mixture was passed through a 53 micron sieve and the retained beads were washed with methanol. Anion exchange was accomplished by stirring the polymer in aqueous 2N HClr ethanol (250ml:250ml) and then allowing to stand overnight. The polymer was then filtered and washed with aqueous 2N HCl, water, methanol and diethyl ether and finally dried under vacuum to give cross-linked [11-N,N- dimethyl-N-dodecylammonioundecyl methacrylate]chloride- [ll-N,N,N-trimethylammonioundecyl methacrylate]chloride co-polymer beads (9.65g), (exchange capacity = 2.3 meq Cl"/g) .
EXAMPLE 2
(a) Methacrylic anhydride (336ml) was added to a solution of 8-bromooctanol (508.9g) and pyridine (186ml) in hexane (1.5/) with cooling to 10°C in an ice-bath. After stirring at 10°C for 1 hour, 4-dimethylaminopyridine (5g) was added and the reaction was stirred for 72 hours at room temperature. The reaction mixture was washed with 2N HCl (1/) and then the aqueous phase was washed with hexane (500ml) . The combined organic extracts were washed with 2N HCl (2 x 500ml) , water, saturated sodium
SUBSTITUTE SHEET
hydrogen carbonate solution (2 x 500ml) , water ( 11) , dried (MgS0 ) and concentrated in vacuo to give a clear oil. This oil was subjected to column chromatography on silica gel with a hexane:dichloromethane gradient as eluent, to give 8-bromooctyl methacrylate as a clear oil (230.2g, 37%) .
(b) 8-Bromooctyl methacrylate (24.75g), ll-bromo¬ undecyl methacrylate (24.75g) and ethylene glycol bismethacrylate (0.5g) were copolymerised as in Example
1(b) to give, after washing, an approximately 1.5 molar % cross-linked 8-bromooctyl methacrylate ll-bromoundecyl methacrylate co-polymer containing 3.3 meq Br/g (45.5g).
(c) The above cross-linked 8-bromooctyl methacrylate ll-bromoundecyl methacrylate co-polymer (20g) was suspended in dimethylformamide (180ml) , 33% trimethyl¬ amine in ethanol (80ml) added, and the reaction mixture heated at 70°C for 30 hours. Additional 33% trimethyl- amine in ethanol (100ml) was added at 24h. Anion exchange and washing as in Example 1(d) gave [8-N,N,N-trimethyl- ammonioocty1 methacrylate]chloride[11-N,N,N-trimethy1- ammonioundecyl methacrylate]chloride co-polymer beads (20.3g), exchange capacity = 3.16 meq Cl~/G) .
SUBSTITUTE SHEET
Example A
A chewable tablet composition can be prepared from the following : mg/tablet
Compound of structure (I) : 1250
Silicon dioxide 15
Microcrystalline cellulose 280
Sorbitol 445
Lactose 450
Sweetener 5
Peppermint 30
Magnesium Stearate 25
2500mg
Example B
A food additive composition, for example, a sachet for reconstitution or mixing with food, is prepared by incorporating into a powder formulation compound of structure (I) (250 mg) , sodium carboxymethylcellulose (50 mg) , sucrose (2400 mg) and flavours (50 mg) .
SUBSTITUTE SHEET
DATA
In vitro Dissociation assay
The following assay provides a measure of affinity of the polymers of the invention for the bile acid, glycocholate (GC) based on the amount of GC bound at a subsaturating concentration of 5mM (t=0) , and an estimate of the rate at which this bile acid dissociates into a large volume of buffer. The results are obtained as initial amounts of GC bound (t=0) and amounts remaining bound after 2 minutes in buffer (t=2min) ; from these figures the % dissociation i.e. the proportion of bound GC dissociated from the polymer after 2 minutes can be obtained. The lower the % dissociation the more efficient the polymer can be expected to be in extracting bile acids in vivo.
Method
Test compound (150 mg) is equilibrated with 5mM sodium glycocholate (30 ml) in Krebs' buffer. The compound is separated by centrifugation and the total bound determined by subtraction of the amount in the supernatant from the total bile acid used. Dissociation is measured by resuspending the compound in Krebs' buffer, shaking and sampling the mixture through a filter at several time points up to 20 minutes. Radioactivity and hence bile acid dissociated is determined in the filtrate.
SUBSTITUTE SHEET
Claims
1. A polymer of structure (I)
in which
a, b, c and d indicate the relative molar percentages of the units present in the polymer, (a) and (b) together being from about 25 to about 99.5 molar percent, and (c) being from about 0.5 to about 8 molar percent;
X is a cross-linking unit;
XI is a comonomer unit;
R and R' are the same or different and are each hydrogen or C1_4alkyl;
R1 and R2 are the same or different and are each C1_ alkyl, and R3 is C1_2oalkyl or C1_20 aralkyl; or R1 is C1_4alkyl and R2 and R3 together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms;
SUBSTITUTE SHEET or R1 to R3 together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms;
R1' and R2' are the same or different and are each
C1_4alkyl, and R3' is C1_20alkyl or C1_20aralkyl; or R1' is C1_4alkyl and R2' and R3' together with the nitrogen atom to which they are attached form a saturated ring, optionally containing one or more further heteroatoms; or R1' to R3 together with the nitrogen atom to which they are attached form an unsaturated ring, optionally containing one or more further heteroatoms;
n and n' are the same or different and are each l to 20;
p is a number indicating the degree of polymerisation of the polymer; and
γ~ is a physiologically acceptable counter ion.
2. A polymer of structure (I) as claimed in claim 1 for use in therapy.
3. A polymer of structure (I) as claimed in claim 1 for use in the lowering of serum cholesterol levels.
4. A pharmaceutical composition comprising a polymer of structure (I) as claimed in claim 1, in association with a pharmaceutically acceptable carrier.
SUBSTITUTE SHEET
5. A process for preparing a polymer as claimed in claim 1 which comprises reaction of a polymer of structure
(II)
in which a, b, c, d, p, R, R', X, X1, n and n' are as described for structure (I) , and Z is a group displaceable by an amine, with a compound of structure R1R R3N, in which R1 to R3 are as described for structure (I) ; and a compound of structure R1 R2 R3 N in which R1' to
R- are as described for structure (I) .
SUBSTITUTE SHEET
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB909011332A GB9011332D0 (en) | 1990-05-21 | 1990-05-21 | Compounds |
GB9011332 | 1990-05-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0530242A1 true EP0530242A1 (en) | 1993-03-10 |
Family
ID=10676309
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP91909433A Withdrawn EP0530242A1 (en) | 1990-05-21 | 1991-05-20 | Compounds |
Country Status (5)
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---|---|
EP (1) | EP0530242A1 (en) |
JP (1) | JPH05506880A (en) |
AU (1) | AU7867491A (en) |
GB (1) | GB9011332D0 (en) |
WO (1) | WO1991018027A2 (en) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5800809A (en) * | 1992-01-14 | 1998-09-01 | Hisamitsu Pharmaceutical Co, Inc | Non-crosslinked acrylic polymers and non-crosslinked anion exchange resins |
ES2149537T3 (en) * | 1992-01-14 | 2000-11-01 | Hisamitsu Pharmaceutical Co | INTERCHANGE RESIN OF UNLINKED ANIONS AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME. |
US5556619A (en) * | 1992-08-20 | 1996-09-17 | The Du Pont Merck Pharmaceutical Company | Crosslinked polymeric ammonium salts |
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 |
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 |
US6129910A (en) * | 1993-06-02 | 2000-10-10 | Geltex Pharmaceuticals, Inc. | Water-insoluble noncrosslinked bile acid sequestrants |
US5607669A (en) * | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
MX9602812A (en) * | 1994-01-18 | 1997-06-28 | Du Pont | Crosslinked polymeric ammonium salts. |
TW474813B (en) * | 1994-06-10 | 2002-02-01 | Geltex Pharma Inc | Alkylated composition for removing bile salts from a patient |
US6203785B1 (en) | 1996-12-30 | 2001-03-20 | Geltex Pharmaceuticals, Inc. | Poly(diallylamine)-based bile acid sequestrants |
FR2757866B1 (en) * | 1996-12-30 | 2004-12-17 | Catalyse | POLYMERS COMPRISING QUATERNARY AMMONIUM GROUPS, THEIR USE FOR THE MANUFACTURE OF AN ANTIBACTERIAL PROPERTY MATERIAL AND THEIR PREPARATION METHODS |
US5925379A (en) * | 1997-03-27 | 1999-07-20 | Geltex Pharmaceuticals, Inc. | Interpenetrating polymer networks for sequestration of bile acids |
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 |
JP2006052236A (en) * | 2002-07-30 | 2006-02-23 | Yukio Nagasaki | New compound having cholesterol-reducing activity |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2843573A (en) * | 1955-03-21 | 1958-07-15 | Rohm & Haas | New quaternary ammonium compounds in which the nitrogen atom carries an alkoxymethyl group |
BE756035A (en) * | 1969-09-12 | 1971-03-11 | Inveresk Res Int | POLYMERS BRIDGES |
US4393145A (en) * | 1979-05-01 | 1983-07-12 | Etablissement Texcontor | Anionic ion exchange resins with cholesterol-decreasing properties |
FR2528435B1 (en) * | 1982-06-09 | 1986-10-03 | Inst Francais Du Petrole | NITROGEN ADDITIVES FOR USE AS DISORDERS TO REDUCE THE POINT OF MEDIUM HYDROCARBON DISTILLATES AND COMPOSITIONS OF MEDIUM HYDROCARBON DISTILLATES CONTAINING THE ADDITIVES |
-
1990
- 1990-05-21 GB GB909011332A patent/GB9011332D0/en active Pending
-
1991
- 1991-05-20 JP JP91509109A patent/JPH05506880A/en active Pending
- 1991-05-20 EP EP91909433A patent/EP0530242A1/en not_active Withdrawn
- 1991-05-20 WO PCT/GB1991/000788 patent/WO1991018027A2/en not_active Application Discontinuation
- 1991-05-20 AU AU78674/91A patent/AU7867491A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO9118027A2 * |
Also Published As
Publication number | Publication date |
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WO1991018027A2 (en) | 1991-11-28 |
AU7867491A (en) | 1991-12-10 |
JPH05506880A (en) | 1993-10-07 |
GB9011332D0 (en) | 1990-07-11 |
WO1991018027A3 (en) | 1992-01-09 |
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