WO2010133906A2

WO2010133906A2 - Use of specific chelating polymers in medicaments for the treatment of inflammatory bowel disease

Info

Publication number: WO2010133906A2
Application number: PCT/IB2009/005631
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2009-05-18
Filing date: 2009-05-18
Publication date: 2010-11-25
Also published as: WO2010133906A3

Abstract

The invention relates to the use of chelating polymers with affinity for group-Ill cations, preferably poly-hydroxamic acid or poly-iminodiacetic acid, in the manufacturing of a medicament for the treatment of inflammatory bowel disease (IBD).

Description

USE OF SPECIFIC CHELATING POLYMERS IN MEDICAMENTS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE

FIELD OF THE INVENTION

This invention relates to the use of chelating polymers having high affinity for the group-Ill cations in the manufacturing of a medicament for the treatment of an inflammatory bowel disease (IBD). BACKGROUND OF THE INVENTION

Inflammatory bowel disease (IBD) is a collective term describing non-cancerous, pathological conditions of the gastrointestinal tract. A common IBD is ulcerative colitis, a unspecifϊc inflammatory disease of poorly understood aetiology, a mucosal lesion which involves the rectum and extended for a variable length of colon. Crohn's disease is an acute or chronic granulomatous disease affecting any part of the alimentary tract but is mainly found in the terminal ileum, large intestine or both with multiple lesions and normal intestine intervening between them. Irritable bowel syndrome shares several of the above mentioned IBD features.

IBD is considered a 2-stage process, with an initiation and a maintenance phase. It is unclear whether the initiation phase is associated with microflora changes, however there is evidence of bacterial involvement in the maintenance phase suggesting the association between the enteric microflora and the disease. The bacterial flora of the healthy gut is very stable and in symbiosis with the host. If this symbiotic relationship is disturbed, by for example altering the balance of the organisms, physical damage of the gut may result. Indeed, the chronic manifestation of IBD well correlates with an aberrant mucosal immune response to the microbiota of the gastrointestinal (GI) tract in genetically susceptible individuals. For example Lodes MJ et al. (J Clin Invest. 2004; 113(9): 1296-306) have found that bacterial flagellin, which activate innate immunity via Toll-like receptor 5 (TLR5), is a dominant antigen in Crohn's disease and contribute to the pathogenesis of IBD. As a confirmation, both active Crohn's disease and ulcerative colitis can be diagnosed and monitored based on the biostructure of the fecal flora, as reported by Swidsinski A et al. Inflamm Bowel Dis. 2008; 14(2):147-161. The pathogenesis of IBD is therefore sustained by the actions of bacterial enzymes, that progressively degrade the mucus glycoprotein, thereby causing the disruption of the colonic mucosal barrier. As consequence, the viscoelastic gel secreted by mucosa with to protect the GI mucosal surface against mechanical shear, micro-organisms, and antigens and toxins thereof, is readily depleted.

Several efforts have been made to apply hydrocolloids and hydrophilic polymers to restore the mucous integrity. EP-0351987 disclosed the use of a polyacrylate, preferably Carbomer™, to treat IBD either by oral or rectal administration. US 4,917,890 discloses a treatment of ulcerative colitis with the polysaccharide from aloe extract. WO 9401436 disclosed a treatment of irritable bowel syndrome with classic anion-binding polymers with xanthan gum. WO 9916454 disclosed a combination of hydrocolloids such as xanthan gum and hydroxypropylmethyl cellulose (HPMC) for IBD.

However, such polymers partially fail to match a sound therapeutic purpose since a simple coating effects on the damaged mucosa do not improve the pro-inflammatory condition nor the iper-proliferative environment existing in the gut of an IBD patients.

In fact, the bacterial over-growth with the concomitant overload of transition metals in gut mucosa shall synergistic enhance the IBD. The excess of multivalent, hard cations seems a disease enhancer, both by direct pro-inflammatory action and by sustaining the pro-pathogenic microflora. For example, Lerner A (Ann N Y Acad Sci. 2007; 1107:329-45) speculated that aluminum is a potential environmental factor in inducting Crohn's disease. Others have reported the beneficial effect of chelation therapy, namely Rampton DS et al. (Aliment Pharmacol Ther. 2000; 14: 1163-8).

The present invention aim to improve this approach by the use of polymers originally conceived for metal recovery and decontamination of water and other industrial fluids. SUMMARY

It has been surprisingly found that a chelating polymer specific for group III cations, particularly a polymer comprising hydroxamic acid or imidodiacetic acid groups, is effective in the treatment of inflammatory bowel disease (IBD). Therefore, the invention relates to a medicament comprising said chelating polymer in therapeutic effective amount to treat an inflammatory bowel disease (IBD).

More particularly, the invention relates to medicament for oral or rectal administration comprising a chelating polymer selective on group-Ill cations for the treatment of IBD. The invention also relates to a method of treating IBD by said medicaments. DETAILED DESCRIPTION

The expression "chelating polymer specific for group III cations" herein means a linear, branched, or cross-linked, hydrophobic or hydrophilic, gellable, powdered or solid-state macromolecules composed of repeating units comprising chelating (anionic) groups owning a particular affinity for the group III cations.

The expression "group III cations" include Al³⁺, Co²⁺, Cr³⁺, Fe^2+/3+, Mn²⁺, Ni²⁺, Zn²⁺, i.e. the metal cations which are precipitated as oxide/hydroxide when the pH is raised above 7, preferably at pH around 9.

Therefore, preferred active ingredient for the present invention are chelating polymers with poly-hydroxamic acid and poly-iminodiacetic acid structure, either prepared by known methods or available from commercial vendors.

In a preferred embodiment, a poly-hydroxamic acid is used as chelating polymer. These are generally obtained by "post-modification" of polymers comprising carboxylic groups or synthones thereof, which are partially or totally converted into hydroxamate groups (CONHOH) by the reaction of activated carboxylate form with hydroxylamine as such or in a protected form.

The polymers useful in the present invention have between about 2 and 95% of the total number of functional groups appended to the polymer chain of a CONHOH type. Preferably from about 10 to 65% of the groups are functional hydroxamic or groups and most preferably between about 15 and 55%.

Suitable poly-hydroxamic acids can be obtained from natural polymers containing carboxy groups, e.g. hydroxamated collagen mimetics (Kinberger GA, Inorg Chem.

2006; 45(3):961-3), hydroxamated pectin (Yang SJ, Agric Food Chem. 2004,

30;52(13):4270-3), hydroxamated (poly) iV-acryloyl-β -alanine (WO/1986/000891), and so on. Hybrid natural and synthetic poly-hydroxamic acids are included, e.g., poly(methyl acrylate)-grafted sago starch (Lutfor MR et al. J Appl Polym Science. 200I₅ 79(7): 1256-64).

Post-modification can be carried out on natural polymer-containing OH groups, e.g. succynilated polysaccharides or with other linkers bearing carboxy groups, or synthones thereof.

Examplary such polymers include hydroxamated chitosan succinate (Aiedeh K Eur J Pharm Sci 2001; 13(2): 159-68); hydroxamated chitosan α-ketoglutaric acid (Ding P. J Hazard Mater. 2007; 146(l-2):58-64); glycine hydroxamate guaran crosslinked with epichlorohydrin. (Ahuja M, et al. Carbohydrate Polym, 1997; 33(1), 57-62). By this method, a variety of poly-hydroxamic acids from natural or semi-synthetic OH- polymers, including cellulose and derivatives thereof, can be obtained.

Further poly-hydroxamic acids may be obtained by the post-modification of synthetic polymers with COOH groups, or synthones thereof. Examples include those from JV- acryloxysuccinimide, acryloyl chloride, and (2-hydroxyethyl)acrylate polymer (Pradeep K. et al. Biomacromolecules, 2005, 6 (6):2946-53); from poly(methyl methacrylate-co- methacrylic acid) (Skarja GA₅ Biomaterials. 2009, 30(10): 1890-7); from n- butylmethacrylate and vinyl co-polymer (Nakayama Y, Biomed Mater Res B Appl Biomater. 2007;80(l):260-7); from acrylonitrile-divinylbenzene polymer (Selvi et al. J Appl Polym Scien. 2004; 92(2) 847-55); from poly(styrene-co-maleic acid) (Mendez R, et al. Eur Polym J. 1996; 32(4), 515-21); poly(styrene-p-hydroxamic acids) (Agrawal YK, et al. React Funct Polym. 1999; 39(2), 155-64); from methylmethacrylate- divinylbenzene copolymer (A. Varadharaj, J Chem Tech Biotech. 1996, 67(2):149-52).

Other suitable poly-hydroxamic acids may be produced by post-modification of a COO-activated polyacrylate, as in US 4,352,871 or Sangita P. J Macromol Scien. Pure Appl Chem. 2006, 43(4-5):735-47. Preferred such starting polyacrylates are crosslinked polyacrylates as supplied by Noveon-Lubriol, i.e. Carbopol 934, 934P, 940, 97 IP, 7 IG, 974P₅ 980, 981, 1342, and 5984 EP₅ Carbomer 1342, Pemulen TR-I₅ and TR-2.

Post-modification is generally performed by the reaction of hydroxylamine in neutral or alkaline conditions. The high nucleophilic reactivity of hydroxylamine allow the reaction with "classic" activated carboxylates such as acylsuccinimide, acylimidazoles, acyl chlorides, and carbodiimide-activated acyl groups or other coupling agents; as well as with alkyl esters (COOR), and even with the low reactive amides (CONH₂).

The reaction of a protected or unprotected hydroxylamine can be carried out with homopolymers or co-polymers of acrylamide, methacrylamide, alkylacrylamide, thioacrylamide, alkylthioacrylamide, hydroxyalkylacrylates with monomers such as acrylic acid, methacrylic acid, other alkyl acrylic acids, their esters and salts. Suitable co-monomers would include but are not limited to methylacrylate, sodium acrylate, maleic anhydride, vinyl acetate, vinyl pyrrolidone, butadiene, styrene, acrylonitrile and the like. Polymers wherein one or more hydrogens of the amide group are substituted with alkyl, cycloalkyl, allyl, aryl and the like can also be utilized to form the polymers having the amide groups for reaction with a hydroxylamine. The polyacrylamide can be hydrolyzed, partially hydrolyzed or unhydrolyzed.

These and other variants of chelating polymers with hydroxamic groups can be found in referenced article and elsewhere, e.g. in U. S. Pat. 4536296 which made use of thiohydroxylarnin to prepare the poly-thiohydroxylamic acids, also included therein.

In another preferred embodiment, a poly-iminodiacetic acid is used as chelating polymer.

The poly-iminodiacetic acid are obtained by post-modification of suitable natural and synthetic polymers and resins. The post-modification with iminodiacetic acid is carried out on reactive moieties, preferably an epoxy group such as a glycidyl group, e.g. as per Caykara T et al. Mater Scien Engin. C, 2009; 29:20-4, who obtained a poly(glycidyl methacrylate) microbeads surface-modified with iminodiacetic acid (IDA).

Poly-iminodiacetic acid resins are commercially available. Preferred such chelating polymers include: Amberlite™ IRC748I (sodium form) from Rohm & Haas, now Dow Corp.; Diaion™ CRI l (sodium form) from Mitsubishi Chemical Corp.; Lewatit™ TP 207 (sodium form) a IDA-styrene-divinylbenzene from Lanxess Deutschland GmbH; Chelex 100 (sodium form) a cross-linked IDA-polystyrene from Sigma- Aldrich (catalog No. C7901 Sigma); IDA-agarose cross-linked polystyrene from Sigma- Aldrich (catalog No. 14758 Sigma); IDA-coupled Sepharose™ Fast Flow from GE Healthcare (USA); and Dionex ProPac IMAC-10™ a 4% beaded IDA-agarose from Dionex Corp. (USA). As in above example, the IDA group can be attached to simple linker such as a glycidyl group, as well as longer linker such as the 1,4-butanediol diglycidyl ether.

The afore said chelating polymer can be used in acidic form or as suitable salts. Suitable salts may be derived from any organic or inorganic acid or base of mono or polyvalent ion. Inorganic salts include sodium, potassium, calcium, and magnesium. Organic amine salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.

Convenient modes of administration to deliver .the chelating polymers are rectal compositions such as enemas and suppositories, and oral compositions such as enteric coated tablets, capsules, sachets, powder or granules.

Typical enema formulations comprise an effective amount of chelating polymer dispersed in a suitable aqueous flowable carrier vehicle. The carrier vehicle may need to be thickened with thickeners such as gums, acrylates (e.g. Carbomers™) or modified celluloses. The formulation can also comprise an effective amount of a lubricant such as a natural or synthetic fat or oil, e.g. a tris-fatty acid glycerate or lecithin. Nontoxic nonionic surfactants can also be included as wetting agents and dispersants. Unit dosages of enema formulations can be administered from prefilled bags or syringes. The carrier vehicle may also comprise an effective amount of a foaming agent such as n- butane, propane or i-butane. Such formulations can be delivered from a preloaded syringe pressurised container, so that the vehicle is delivered to the colon as a foam, which inhibits its escape from the target site.

In an embodiment, a chelating polymer is administered rectally as liquid enemas. The carrier vehicle is preferably thickened and also comprises an effective amount of a lubricant. Unit dosages of enema formulations can be administered from prefilled bags or syringes. Generally the pH of the enema should be between 4.5 to 5.5 for better patient acceptability.

When the chelating polymer is administered orally via a tablet, capsule or granules, the dosage form may have or not an enteric coating. In the latter case it is released from in the lower intestinal tract, e.g., in the ileum and in the colon of the patient. Largely used polymer for enteric coating include cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP)₅ hydroxypropyl methylcellulose phthalate, and methacrylic acid ester copolymers with acidic ionizable groups of the Eudragit™ series.

In general a suitable dose of chelating polymer will be in the range of from 0.1 to 50 mg/Kg, preferably in the range of 1 to 25 mg/Kg.

More particularly, the medicament of the present invention is in unit dosage form comprising from 200 mg to 3 g of chelating polymer per unit dose, more preferably from 250 mg to 1000 mg of chelating polymer per unit dose.

In a further embodiment is provided a method for the treatment of a subject with IBD. In a method of this embodiment, chelating polymer may be taken once, twice, three times a day. The dosages of a chelating polymer may vary from 10 mg through to 5 g per day, more typically 100 mg to 500 mg per day.

In another embodiment, a chelating polymer is administered to an iron-deficient anemic, IBD patient in conjunction with iron supplements, either from parenteral or oral routes. In this case, the chelating polymer of invention will be administered at least 6 hours after or 3 hours before iron supplements.

Usually, chelating polymer are administered once a daily. As a general rule for long term therapy the dosage may commence at a low level, such as daily and may be elevated to a higher dosage, such as twice or three times daily if required. Administration is typically over a period of from 30 days to 60 days or more. More typically, a method of the invention results in relief of symptoms when the chelating polymers are administered over a period of from 60 days to 120 days. After relief or symptoms is achieved, administration of the chelating polymers may be ceased, tapered, or reduced to lower maintenance dosages for an indefinite period. . The invention is elucidated by way of the following, non-restrictive examples.

EXAMPLES Examples 1-5 - Preparations of the medicaments

Medicaments according to the invention are herein illustrated, wherein the expression "chelating polymer" means poly-hydroxamic acid or poly-iminodiacetic acid, in free form or as acceptable salt, in particular of the types illustrated in the description. Example 1 - Tablets

Composition (10,000 tablets)

Chelating polymer (*) 200O g

Lactose 1000 g

Potato starch 352 g

Gelatin 8 g

Talc 6O g

Magnesium stearate 1O g

Silica (highly disperse) 2O g

Ethanol q.b.

The chelating polymer is mixed with the lactose and 292 g of potato starch, and the mix is moistened with hydroalcholoic gelatin solution and granulated. After drying, the remainder of potato starch, magnesium stearate, talc and silica are admixed, and the mix is compressed to tablets of 350 mg each, each comprising 200 mg of chelating polymer. Example 2 - Coated tablets

Composition (1,000 tablets)

Chelating polymer (*) 40O g

Lactose 100 g

Maize starch 7O g

Talc 8.5 g

Magnesium stearate 1.5 g

Hydroxypropylmethylcellulose 2.36 g

Shellac 0.64 g

Water and acetone q.b. The chelating polymer, the lactose and 40 g of maize starch are mixed and moistened and granulated with a warmed paste prepared from 15 g of maize starch and water. The granules are dried, and the remainder of maize starch, talc and magnesium stearate are added and mixed to granules. The mix is compressed to give tablets, then coated with a solution of HPMC and shellac in acetone/water. The final weight of coated tablets is 580 mg, each comprising 400 mg of chelating polymer. Example 3 - Suppositories Composition (1,000 suppositories)

Chelating polymer (*) 500 g

Hydrogenated coco-glycerides 680 g

Caproyl monoglycerides 18 g

EDTA 2 g

Hydrogenated coco-glycerides (Witepsol™ W45, Sasol GmbH) and monoglycerides are melted in a water bath. Then EDTA and the chelating polymer are incorporated and mixed well before pouring into disposable suppository molds to afford 1.2 g suppositories, each comprising 500 mg of chelating polymer.

(*) A poly-hydroxamic acid / poly-iminodiacetic acid as exemplified in Description. Example 4 - Hard gelatine capsules Composition (100 capsules) Chelating polymer (* *) 7O g Lactose 25 g

Microcrystalline cellulose 3 g Magnesium stearate 1 g

The cellulose and lactose are sieved at mesh width of 0.9 mm and mixed for 10 minutes. The mix is added with the chelating polymer (**) IDA-coupled Sepharose™ Fast Flow (GE Healthcare Life Science) previously dried under vacuum and then mixed for 10 min. Magnesium stearate is added with 3' further mixing, an the resulting mix is dispensed into hard gelatin capsules, each comprising 700 mg of chelating polymer. Case study #1

A 39-year old woman with a history of IBS presented the typical symptoms of abdominal pain, severe constipation, and a bowel movement almost every day, with some period of relapse with one episode every two days. She had an experience with probiotics supplemention that provided a temporary relief, although not definitive.

The capsules in accordance as described in Example 4 were recommended twice a day along with the elimination of dairy and wheat.. At the end of the two week course thereof, the patient achieved a better control of symptoms associated with IBS Example 5 - Enemas Composition (15 enema bottles)

Chelating polymer (**) 9 g

Methylhydroxybenzoate 25 mg

Propylhydroxybenzoate 12.5 mg

Disodium EDTA 30 mg

Sodium metabisulphite 300 mg

Methyl cellulose 7.5 g

Distilled water q.b. The chelating polymer (**) IDA-coupled Sepharose™ (GE Healthcare Life Science) is previously crushed, then dispersed in water. Parabes, sodium EDTA, sodium metabisulphite, methyl cellulose along with distilled water are added under stirring to a final volume of 1500 ml. The solution is well mixed by shaking and packaged as 100 ml doses in Wheaton enema bottles, each comprising 600 mg of chelating polymer. Case study #2

A 54-year old woman had suffered from ulcerative colitis for about five years. Initially her symptoms have been controlled with daily mesalazine and short course of hydrocortisone suppositories during exacerbations. The symptoms improved while taking the enemas; however, there was recurrence on discontinuation. To help control symptoms, oral prednisone was added to the treatment. However, corticosteroid signs such as increased blood pressure, mood swings and weight gain with localized fat deposition had led the patient to ask for an alternative medication.

Hence, the previous prescription were suspended, and the enemas in accordance as described in Example 5 administered every night for two weeks. Transiently the patient developed muscular aches and pains, and backache and a dry skin, i.e. typical features of systemic steroid withdrawal. At the end of the two week course thereof, the patient achieved a reasonable control of symptoms, maintained with the periodic administration (less than once per week) of the enemas.

Claims

1. Use of a chelating polymer with affinity for group-Ill cations in the manufacturing of a medicament for the treatment of inflammatory bowel disease (IBD).

2. Use according to claim 1 characterised in that the a linear, branched, or cross-linked, hydrophobic or hydrophilic, gellable, powdered or solid-state poly-hydroxamic acid in unit dosage form and comprises from 250 mg to 1000 mg per unit dose.

3. Use according to claim 1 characterised in that the a linear, branched, or cross-linked, hydrophobic or hydrophilic, gellable, powdered or solid-state poly-iminodiacetic acid in unit dosage form and comprises from 250 mg to 1000 mg per unit dose.

4. Medicament for the treatment of a IBD patient characterized in that it comprises a chelating polymer with affinity for the group-Ill cations, said chelating polymer being a poly-hydroxamic acid or a poly-iminodiacetic acid.

5. Medicament according to claim 6 wherein the IBD is ulcerative colitis or Crohn's disease.

6. Medicament according to claim 6 wherein the IBD is irritable bowel syndrome

7. Medicament according to one or more claim from 4 and 6 which comprises from 250 mg to 1000 mg of a poly-hydroxamic acid per unit dose.

8. Medicament according to one or more claim from 4 and 6 which comprises from 250 mg to 1000 mg of a poly-iminodiacetic acid per unit dose.

9. A method for the treatment of IBD including administering to said mammal a medicament comprising an effective amount of a chelating polymer according to one or more of the previous claims.