|Title of Invention||
SYNTHESIS OF VARIOUS SALTS OF CROSS-LINKED POLYALLYLAMINE POLYMER BY ION EXCHANGE METATHESIS
|Abstract||The invention describe the method of preparing sevelamer Y soft salts from synthesis of cross linked polyallyl amine polymer by ion exchange process, the said method comprising suspending sevelamer hydrochloride in X molar solution of selected salt, MY or MY2 whose anion is be exchnged wherein M is an alkali an dalkali earth metal ion and Y is counter anion and the soft salts of cross linked polyallyl anine have improved phosphate absorption properties resulting in reduced damage within body and which improve patient tolerance and compliance, thereby improving the comfort level of patient and are relativly easy to manufacture.|
|Full Text||FORM - 2
THE PATENTS ACT, 1970
The Patents Rules 2003
(SECTION 10 & rule 13)
SYNTHESIS OF VARIOUS SALTS OF CROSS - LINKED POLYALLYLAMINE
POLYMER BY ION-EXCHANGE METATHESIS
We, INDIAN INSTITUTE OF TECHNOLOGY, an Indian Institute, having its office at IIT P.O, Chennai 600 036, Tamil Nadu.
The following specification describes and ascertains the nature of this invention and the manner in which it is to be performed:-
FIELD OF INVENTION:
The invention relates to phosphate binder polymer. Cross linked pollyallyl amine hydrochloride polymer, also known as sevelmer hydrochloride, is a commercially important polymer. It is completely insoluble in water and many organic solvents. In water it is known to form a viscous gel. Being an ionic polymer it is capable of functioning as an ion-exchange polymer. It has been shown to be a good phosphate binder. Commercially it is used as a drug to remove excess phosphate from the human body, especially in renal patients (patients with kidney disorders).
Diseased person with renal failure will not be able to keep the phosphate level in the blood within the normal range when consuming protein diet. Phosphate enters the body primarily through ingested protein. The phosphate level rises in the blood. This is known as hyper phosphatemia, which if untreated allows Calcium to be pulled from the bone mass producing degenerative bone disease. By ingesting phosphate binder with food intake, the phosphate anions from the ingested protein are trapped by the binder and thrown out with feces and allowing only desired amount of absorption into the blood from the intestinal tract. Initially aluminum and calcium compounds were used, but found to have undesired side effects. Then came anion exchange polymers, which are ingested with food and are designed to sequester phosphate anions during the digestive process in the intestinal tract.
An ion exchange resin or polymer is a resin or polymer carrying ionigenic groups that are capable of exchanging ions of sequestering ions. The ion exchange polymers remove and isolate varying ions and ionogenic molecules.
In prior art the polymer salt is preferably the hydrogen chloride salt and can
include low salt or reduced salt forms of polymer.
Eg. 1 The salt is present in the range 4-30% based upon weight of polymer.
Eg. 2 Sevelamer which is stored and administered as a salt in which 40% of amine groups are protonated as hydrochloride salt (18% by weight of polymer in chloride)
Eg. 3 Polyallyamine wherein 9-27% of amine groups are protonated to obtain Polyallyamine hydrochloride (4 - 12% of polymer by weight in chloride anion)
The most common and most commercially exploited is sevelamer hydrochloride.
Sevelamer hydrochloride is a salt of cross-linked polyallyl amine with hydrochloric acid. Sevelamer hydrochloride is commercially available and it is widely used as an oral drug for the removal of excess phosphate from the human body. The side effects reported for this drug are discomfort of the stomach, acidosis. Since the hydrochloride salt is a salt of a strong acid, namely hydrochloric acid, the above reported problems will exist in its usage as binder.
Cross linked polyallyl amine hydrochloride is also used as a coating material in the manufacture of ink-jet printer paper. Again due to the corrosive nature of the hydrochloric salt the shelf life of the paper is limited.
The patent applications US 5496545, US 5487888, US 4605701 and US 4528347 and others all describe method of manufacturing poly ally amine and cross-linked poly ally amine bent none draw attention to acidosis character of the sevelamer hydrochloride.
In US 6423754 describes in example 2: preparation of poly allyl amine hydrochloride to obtain granular white solid form and example 3: describes it is also cross linked with epichlorohydrin.
The US 6,926,912 deals with treating anhydrous calcium sulphate as such a poor phosphate binding, with an alkaline material, to make it an extremely effective phosphate binder. This application covers lanthanum and cerium sulphate also. This invention relates to metal sulphate material for pharmaceutical use, which metal sulphate material is selected from atleast one of calcium, lanthanion and cerium sulphate compounds treated with an alkali solution (eg. Aqueous alkaline hydroxide i.e., maybe sodium hydroxide)
US 6 600 oil are to relates to rapid method of purifying and drying of polymer hydrogel, wherein higher level water could also be dried from the hydrogel.
Compounds which are in use for phosphate binding include various ion exchange polymers. One such polymer is sevelamer hydrochloride. The disadvantages of using this are many.
Therefore there is an urgent need to develop alternative salts (“soft salts”) of cross linked polyallyl amine.
OBJECT OF INVENTION:
The first object of the invention is to obtain plurality of soft salts for absorbing
phosphate from human body.
The second object is to prepare plurality of soft salts from sevelamer hydrochloride by ion exchange process.
The third object is to find a phosphate binder which does not decompose in the body, has no side effects, can be administered in relatively low/moderate
dosages and which is effective and more effective than the products known in
The fourth object is to prepare soft salts that are superior in performance but less harmful phosphate binding polymer.
The fifth object is to prepare soft salts which are least harmful within body, and is not acidosis and is not corrosive in nature.
BRIEF DESCRIPTION OF INVENTION:
The polymer hydrochloride is known to undergo ion exchange (metathesis) with phosphate in human body. Hence it is used as a phosphate binder to remove excess phosphate from the human body. This property of sevelamer hydrochloride, namely ion-exchange property is used in the invention, to prepare several “SOFT-SALTS” of cross-linked polyallyl amine. The methodology is described in chart l.
Based on the said protocol it is attempted to synthesize several “soft-salts” of cross-linked polyallyl amine. These new salts have been characterized by IR spectroscopy and thermal analysis techniques. Conditions have been optimized to obtain the complete exchange of chloride ion from sevelamer hydrochloride. The new materials have also been studied for phosphate uptake in a quantitative manner.
DESCRIPTION OF INVENTION:
Sevelamer hydrochloride is a commercially important product. However due to the forementioned problems there is a need to develop soft salts of sevelamer. The salts prepared in this invention are potentially useful as drugs for phosphate binding properties, in place of sevelamer hydrochloride.
Compounds which have been suggested for phosphorus control include various ion exchange polymers. One such polymer is sevelamer. It has been long recognized that this polymer is not safe and causes acidosis in the body. Thus there is still a need to discover superior salt for phosphorus control in human body.
The polymer is generally rendered water- insoluble by cross linking. As phosphate binders are administrated in relatively large doses over long periods of time, metal ion release, absorption and toxicity are of prime concern.
Generally the polymer is administered in the form of a salt. Also the anionic counter ions are related to minimize adverse effects on the patient. Some of the examples of suitable counter ions are Acetate, lactate, succincte, butyrate, ascorbate, citrate, an amino acid derivable etc.,. The counter ions can be same as, or different from each other. The reaction product can contain two different type of counter ions, both of which are exchanged for phosphate being removed.
Different magnesium salts have been shown to have efficacy as phosphate binders. Eg. Magnesium carbonate - but magnesium produces laxative effects if in overdose.
Oral administration of phosphate binders include calcium or aluminium salts. Calcium combines with phosphate to form insoluble calcium phosphate, e.g.: Calcium acetate tablets. This type of therapeutics generally results in hypocalcaemia which is due to absorption of high amount of ingested calcium. So serum calcium level needs to be monitored during therapy with calcium based phosphate binders.
Another e.g.: Aluminium based phosphate binders form insoluble aluminium phosphate. However the ingested aluminium which is accumulated inside the body is toxic in nature and harmful to the patient.
So ion exchange resin was developed to overcome problems of calcium and aluminium. Anion exchange resins in the chloride form was then developed.
Thereafter class of hydrophilic anion exchange polymers with improved phosphate binding was developed.
Eg. Aliphatic amine polymers
There are lot of problems existing in the present phosphate binders used. Almost all of the patients treated with calcium based phosphate binders developed progressive cardiovascular calcification, whereas the patients treated with calcium free binder sevelamer showed no such problem. However due to the cholestrol sequestering activities of sevelamer, the low density linoprotein (LDL) Cholesterol was lower among the sevelamer -treated patients than the calcium treated patients, resulting in a major imbalance in cardiovascular risk factor.
A patient on calcium based phosphate binder also cannot take iron supplement. Calcium binds with iron and makes it unavailable for absorption by the body. Most common calcium based binders are calcium acetate and calcium carbonate. It has been found Calcium acetate is better phosphate binder than calcium carbonate. Calcium salts are very commonly used as phosphorus binders. However it is now proved that calcium acetate is more effective phosphorus binder than other calcium salts. Calcium acetate binds twice as much phosphorus as calcium carbonate. So lower dose of calcium acetate is sufficient. The higher phosphate binding /calcium absorption ratio coupled with a low dose indicates that less calcium will be absorbed when calcium acetate is used for phosphorus control. Also the calcium acetate
increases fecal excretion of phosphorous by binding the dietary and endogenous phosphorus. Therefore calcium acetate is usable for medical purposes and is proved more efficient as phosphorus binder than other calcium salts. The use of any of the calcium salts however result in hyper calcium due to absorption of high amounts of ingested calcium. Also prolonged use of aluminum salts leads to accumulation of aluminum and aluminum toxicity in the body. Thus neither calcium based nor aluminium based binders provide the desired result of phosphor control without side effects.
Therefore polymers of use are preferably of a molecular weight which enables them to reach and remain in the gastro intestinal tract for appropriate part of time to bind the predetermined amount of phosphate. The polymers should, thus, be of sufficiently high molecular weight to resist, partially or completely absorption from the gastro intestinal tract into other regions of the body. Non-cross linked polymers need atleast to be in the molecular weights in the range of 2000 to 500,000 Daltons. Cross linked polymers however are not generally characterized by molecular weight. The cross linked polymers discussed herein should be sufficiently cross linked to resist absorption from the gastro intestinal tract,
A polymeric phosphate binder has many advantages. Polymeric phosphate binder can also be co-administered with other supplements, say calcium supplement, prior to, simultaneous or subsequent to administration of polymeric phosphate binder.
Example: calcium acetate, calcium carbonate etc. The calcium supplement is both a calcium source and buffering agent. Calcium supplement can be included in polymeric phosphate binder formulations wherein then it can serve as a carrier for the binder. Example: calcium carbonate, it can serve as a hardening agent in tablet form of polymeric phosphate binder composition,
Then such a cotnpositioon provides the polymeric phosphate binders a calcium supplement and a carbonate supplement is in single dosage form.
A cross linked polymer for binding phosphate anion means a polymer comprising a polyvalent cation attached to the polymer through atleast one covalently bound anionic functional group. The polymer is essentially a Poly allylamine, the Anion may be sulfate, carboxylate, phosphate and mixture thereof and the Cation is generally aluminium, calcium, magnesium, iron and zinc.
The polymer is manufactured by:-
- forming a cross linked polymer,
- attaching atleast one anionic group to the polymer, and
- Binding atleast one polyvalent cation into anionic group attached to the polymer.
The cations are loaded onto the polymer bound anionic groups in ion exchange procedure. Calcium salts are widely used to bind intestinal phosphate and prevent absorption. The ingested calcium combines with phosphate to form insoluble calcium phosphate salts Example: calcium carbonate and calcium acetate. A Chloride is an inorganic ion, whereas an acetate is an organic ion.
A cross linked polymer for phosphate anions is prepared wherein the said polymer comprising atleast one cation bound to said polymer and wherein said cation functions as the binding site for phosphate anions and thereby capture said phosphate anions.
Many have compared the performance of known phosphate binders. E.g., Comparing Calcium acetate Vs Calcium carbonate, as oral phosphate binder,
Calcium acetate binds phosphorous more effectively than calcium carbonate while reducing the frequency of hypercalcemic events
A pharmaceutical composition product Phos Lo (R) is calcium acetate, is also popular as phosphate binder.
From the prior art it is known that sevelamer hydrochloride and calcium acetate are two of the most acceptable form of phosphate binder, but even these two have these own set of drawbacks, wherein the former one suffers from acidosis within body and latter one suffers from calcification withir body. Both the drawbacks are not appreciated since the side effect is a: harmful as the excess phosphate within body and there is an urgent need to over come the major defects in the prior art.
In the invention it is attempted to synergies the most effective remedies, eliminate the major drawbacks of prior art and also retain the essential strength of binding in the phosphate binder, so envisaged in the invention. As such in the invention it is attempted to achieve a set of soft salts, of which sevelamer acetate is the most preferred in which neither hydrochloride nor calcium problem would arise.
The salt prepared as per the invention is non-toxic in nature i.e., when ingested in therapeutically effective amounts neither the polymers nor any of the ions released into the body upon ion exchange are harmful as already established in the literatures. The ingested polymers do not dissolve to form potentially harmful by products but remain intact to transport bound phosphate out of the body.
The invention relates to the unexpected discovery that soft salts of cross linked polyallyl amine have improved phosphate absorption properties resulting in reduced damage within body and which improve patient tolerance
and compliance, thereby improving the comfort level of patient and are relatively easy to manufacture.
Typical experimental procedure for the synthesis of sevelamer Y salts where in Y is the counter anion:
In a typical experiment 20 grams of sevelamer hydrochloride was suspended in 500mL of X molar solution (X vary from 0.05 to 1.0) of the appropriate salt who anion is to be exchanged. The mixture was stirred using a magnetic stirrer at room temperature (30 -35°C) for 24h. During this swelling, of the polymer to a transparent viscous gel was observed. The mixture was filtered under suction and the solid obtained was washed with lOOmL of water (10 x lOOmL) to remove the excess salt solution. The product was dried in a vacuum (approximately 5 - 10mm Hg) oven at 60 - 7O°C to constant weight. The product was characterized by IR spectroscopy and thermal analysis.
Sevelamer Acetate : A suspension of 2Og of sevelamer hydrochloride salt in soomL of 1.0 molar solution of sodium acetate (prepared from analar grade sodium acetate) was stirred at room temperature for 24I1 using a magnetic stirrer. The resulting thick gel was filtered and washed with lOOmL of distilled water (10 x 100 mL). The product was dried in a vacuum oven at 60 - 7O°C to a constant weight. The weight of the product obtained was 20gram, nearly quantitative mass balance. The product was characterized by IR spectroscopy which showed the characteristic carboxylate stretching frequency bands. It was also characterized by thermal analysis.
Sevelamer citrate : A suspension of 2Og of sevelamer hydrochloride salt
in soomL of 1.0 molar solution of trisodium citrate (prepared from analar grade trisodium citrate) was stirred at room temperature for 24)1 using a magnetic stirrer. The resulting thick get was filtered and washed with lOOOmL of distilled water (10 x 100 mL). The product was dried in a vacuum
oven at 60 -7O°C to a constant. The weight of the product obtained was 16 gram. The product was characterized by IR spectroscopy which showed the characteristic carboxylate stretching frequency bands. It was also characterized by thermal analysis.
Sevelamer lactate :- A suspension of 2Og of sevelamer hydrochloride salt in soomL of 1.0 molar solution of sodium lactate (prepared from 60% weight solution lactate) was stirred at room temperature for 24I1 using a magnetic stirrer. The resulting thick gel was filtered and washed with lOOOmL of distilled water (10 x 100 mL). The product was dried in a vacuum oven at 60-7O°C to a constant weight. The weight of the product obtained was 18 gram. The product was characterized by IR spectroscopy which showed the characteristic carboxylate stretching frequency bands. It was also characterized by thermal analysis.
Estimation of chloride released during the ion - exchange reactions :-
When sevelamer hydrochloride is exchanged with other salts such as a sodium citrate it release chloride ion. The amount of chloride ion released during the exchange process was estimated in the filtrate from the above experiments using standard argentometric titrations. The results are presented in Table 1. The amount of chloride released during the exchange reaction is given in milliequivalent per gram of the sevelamer hydrochloride salt taken.
Phosphate binding studies:
1.0 gram of the sevelamer salt was suspended in 100ml of 1.0M sodium dihydrogen phosphate and the mixture was stirred at room temperature for 18 - 24I1. The solid was filtered and the phosphate in the filtrate was estimated after appropriate dilution using standard EDTA titrimetric analysis. From the difference in the phosphate concentration before and after exchange reaction
the phosphate uptake was calculated. The results are listed in Table 2. The phosphate uptake is reported in milliequivalent per gram of the sevelamer salt taken.
It is to be noted that estimate of phosphate uptake is definitely equal to or higher in the salts, prepared in the invention, than in comparison to sevelamer hydrochloride available in for prior art. This means the dosage shall not be increased to the patient, there by making it further easy on the patient. The soft salts thereby achieve the characteristic of being safe within the body ans also dosage shall remain same if not reduced selectively which may be possible as reflected in Table 2.
|Indian Patent Application Number||262/CHE/2006|
|PG Journal Number||15/2010|
|Date of Filing||20-Feb-2006|
|Name of Patentee||INDIAN INSTITUTE OF TECHNOLOGY, MADRAS AND MADRAS INSTITUTE OF NEPHROLOGY|
|Applicant Address||IIT P.O., CHENNAI 600 036,|
|PCT International Classification Number||A61K31/785|
|PCT International Application Number||N/A|
|PCT International Filing date|