WO2010136839A1

WO2010136839A1 - Use of deferoxamine and related compounds in targeted delivery forms to treat an inflammatory bowel disease

Info

Publication number: WO2010136839A1
Application number: PCT/IB2009/005776
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2009-05-29
Filing date: 2009-05-29
Publication date: 2010-12-02

Abstract

The invention refers to the use of deferoxamine or salt or analog thereof in a targeted delivery dosage form which is suited for the treatment of inflammatory bowel disease.

Description

USE OF DEFEROXAMINE AND RELATED COMPOUNDS IN TARGETED DELIVERY FORMS TO TREAT AN INFLAMMATORY BOWEL DISEASE

FIELD OF THE INVENTION

The invention relates to the use of deferoxamine or similar hydroxamate siderophores in a targeted pharmaceutical form for the delivery thereof on an inflamed intestinal tract, characterized in that said delivery shall substantially by-pass or avoid the gastric tract. BACKGROUND OF THE INVENTION

Inflammatory bowel disease, or IBD, is a collective term that mclude^Crohn's disease

(CD), ulcerative colitis (UC) and intestinal disorders such as collagenous, lymphocytic, ischaemic, active, indeterminate, and diversion colitis, as well as Behcet's syndrome, proctitis, and proctosigmoiditis. The irritable bowel syndrome, alias spastic colitis, or functional bowel disease, also shares several aspects of the mentioned IBD.

Reactive oxygen species (ROS) may be pathogenic in the gastro-intestinal (GI) tract. In fact, oral iron supplements exacerbate the condition in anemic patients, since iron increases the hydroxyl radicals production by Fenton chemistry.

In fact, the iron-chelator desferoxamine has provided beneficial effects. The study of

Rampton DS et al. (Aliment Pharmacol Ther. 2000; 14:1163-8) on in vitro colonic biopsies of healthy and UC subjects via chemiluminescence is a positive confirmation.

An precise, direct correlation between chemiluminescence and the inflammatory levels in GI is given elsewhere (Oldenburg et al. Clin Chim Acta 2001 ; 310(2): 151 -6.).

The potentiality of deferoxamine in ulcerative colitis is nevertheless controversial.

Good evidences have been obtained in dextran sulfate-induced colitis (Damiani et al., J

Gastroenterol Hepatol. 2007; 22(11):1846-51), in cysteamine-induced duodenal ulcera

(Anderson et al., 5^th hit Symp Cell/Tissue Injury & Cyto/Organo-protection; Focus on GI Tract; Sept. 17-19, 2008, Yalta, Ukraine), and in dinitro-benzene-sulfonate, DNBS- induced model of colitis (Sturniolo et al., World J Gastroenterol 2005; 11(28):4396-99).

Instead, deferoxamine has proven to be ineffective in the acetic acid model of UC

(Keshavarzian et al., Gut 1990; 31:786-90). This could confirm that said drug works in ulcerate intestinal epithelium wherein a metal-catalyzed oxidative stress is a causative co-factor, or where the presence of iron contributes to the overall immune-activation. Moreover, the works of Jun et al. (Exper MoI Med. 2005; 37(4) -.297-31; Life Sciences, 2007; 80(5):436-45; J Cell Biochem. 2007; 102(6): 1442-57) have pointing out that DFO may trigger a mucosal adaptive immunity by the up-regulation of IL-8.

In any case deferoxamine has not been yet introduced into clinical practice of in IBD. This could be also due to the discouraging occurrence of the iron-deficiency anemia in these patients; or to the limited efficacy of the drug by the oral route, proven by the failure to treat the acute iron overload (Jackson et al., Clin Tox, 1995, 33(4), 325-9).

When undertaking this issue, we found a previously unknown issue relevant to the administration and disposition of deferoxamine on gastro-duodenal tract, which has to be solved if the therapeutic switch of this drug to IBD therapy is desired.

The examples found in patent literature have been directed to improve the use of deferoxamine in the treatment of iron overload condition, with a purported amelioration of the parenteral delivery of this iron chelator in such patients, typically thalassemics.

Indeed, the present invention whish to establish a proper use of deferoxamine in matching the medical need arising from an inflammatory gastrointestinal condition. SUMMARY

The applicant has found that hydroxamate sidereofoxes, particularly deferoxiamine, may be effectively administered to an IBD patient if stomach is substantially by-passed, so that the degradation of said hydroxamate is avoided. Accordingly, the invention relates to the use of composition for the targeted release of deferoxamine and analogs and salts thereof for the treatment of IBD.

In one aspect, the invention relates to an oral pharmaceutical composition for the treatment of an IBD patient which comprises an controlled release unit dosage of deferoxamine and analogs and salts thereof which avoid the contact thereof with gastric environment while releasing the drug onto the lower ileum and colorectal tracts.

In another aspect, the invention relates to a rectal pharmaceutical composition for the treatment of IBD patient which comprises a topical unit dosage of deferoxamine and analogs and salts thereof for the above cited purpose.

The invention further relates to method of treatment of IBD with the cited means. These and other aspects will be further illustrated in the foregoing disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the results of the HPLC analysis of deferoxamine mesylate before (A) and after (B) a test simulating a model of gastric juice.

Fig. 2 shows the estimated release of desferoxamine mesylate, Desferal™ (calculated as % of the initial dose) within the GI tracts from the Comp. Ex. 1 and Examples 1-5.

Fig. 3 shows the structures of deferoxamines, i.e. deferoxamine B and close analogs.

Fig. 4 shows the structures of deferoxamine analogs, i.e. hydroxamate with citric acid and cyclic diglycine backbones.

Fig. 5 shows the structures of miscellaneous hydroxamate, deferoxamine analogs. DETAILED DESCRIPTION OF THE INVENTION

The expression "deferoxamine and analogs and salts thereof as used herein include several hydroxamate chelator, preferentially hexadentate, of microbial origin.

The term "deferoxamine" alias desferoxamine, or desferoxamine, is a collective term which include closely related "close analogs" of deferoxamine - which is generally intended as deferoxamine B - namely: deferoxamine A, deferoxamine C, deferoxamine D₁ and D₂, deferoxamine E₅ deferoxamine G, and deferoxamine H.

The preferred deferoxamine for the present invention is deferoxamine B, meaning N- [5 -(3 - [(5-aminopentyl)- hydroxycarbamoyl] -propionamido) pentyl] -3 -([5 -(N- hydroxyacetamido)-pentyl] -carbamoyl)-propionohydroxamic acid. A suitable source of deferoxamine is deferoxamine mesylate from Novartis (Desferal™) and its generic equivalents, such as from Teva Group BPC Div. at Biogal Pharmaceutical Works Ltd (Debrcen, Hungary); Excella GmbH (Feucht, Germany); Diaspa Strides Italia SrI (Corana, Italy); Navinta LLC (Andhra Pradesh, India). In a preferred embodiment, DFX is deferoxamine mesylate (CAS 138-14-7; MW 656.8) as specified in Ph. Eur. 5.5 and USP 30. If desired, a 97% purity deferoxamine obtained by further purification processes (e.g. US Pat. 6,858,414) can be applied.

In alternative to mesylate, a variety of salt of desferoxamine or analog thereof can be used, e.g., hydrochloride, sulfonate, sulfate, adipate, n-decanesulfonate, and embonate. Other desferoxamine analogs are disclosed in U.S.PatNos. 5,367,113 and 5,322,961. The expression "deferoxamine or analog" include substances from microbial strain producing poly(hydroxamic acid)-containing siderophores, such as: a) hydroxamates with citric acid backbone, e.g. schizokinen, arthrobactin, aerobactin, acinetoferrin, nannochelins, and rhizobactin-1021; b) hydroxamates with cyclic diglycine backbone, e.g. coprogen, desacetylcoprogen, neocoprogen I, neocoprogen II, and N^α-dimethyl coprogen; c) hydroxamates with unrelated structures such as ornibactin, ferrichrome, rhodotulic, dimerumic acid, fusigenin, triacetylfusarinine, exochelins, and the like. The abbreviation "DFX" will be used hereinafter as a collective acronym to include deferoxamine and salts and analogs thereof as previously mentioned.

In the present invention, it has been found that DFX can be partially digested (hence inactivated) by the acid and the enzymes secreted in the gastro-duodenal tract. Also, in this tract DFX could have a better (unwanted) systemic availability for the acidic pHH may produce an undissociated, more absorbable form. This and other considerations has led to the need of improving the use of DFX by a targeted release dosage form thereof.

In general, the term "targeted release" as used herein includes "controlled release" by the oral route as well as "rectal release" formulations, i.e., dosage form that allow the release of DFX onto the intestinal tract while substantially avoiding the contact with the stomach and the permanence within the gastric environment. Delayed release, extended release, and pulsatile release forms and their combinations, are types of controlled release, oral dosage forms.

"Delayed release", as used herein, refers to an oral dosage form that releases DFX at a time other than promptly after administration. "Extended release", as used herein, refers to an oral dosage form that allows at least a twofold reduction in DFX dosing frequency as compared to that DFX presented as a conventional oral dosage form (e.g. prompt drug-releasing, oral dosage form). "Pulsatile release dosage form", as used herein, refers to an oral dosage form is characterized by a lag time (no release lapse) followed by the rapid release of DFX.

The terms "controlled release", "sustained release", "extended release" and "pulsatile release" could be considered as synonyms in the context of the present invention. The expression "substantially avoiding the contact with stomach" means that the targeted release forms of invention will deliver in stomach less than around 25% w/w of the total DFX dose, more preferably less than 15%, even more preferably less than 10%.

Convenient modes of targeted release of DFX to treat IBD are controlled/pulsatile release compositions such as enteric coated tablets, capsules, powder or granules; as well as rectal compositions such as cream, ointment, gel, foam, suppository, or enema.

When the active agent is administered orally via a tablet, capsule or granules, preferably the dosage form will have an enteric coat which dissolves after the stomach, so that the active agent is predominantly delivered to the intestinal tract. In an embodiment of the present invention, a pH-dependent controlled release of DFX is applied. E.g., Eudragit™ S is used for colon delivery as it dissolves at pH greater than 7.0. The premature release of DFX may be solved by the use of Eudragit™ FS.

In another embodiment, a bacteria-dependent controlled delivery of DFX is applied, wherein colonic bacteria are used to degrade the substrate. Bacteria are estimated at about 10^π per g with around 400 species (mostly anaerobic) within the colon. Natural polysaccharides can be used, as well as their chemically modified derivatives alone or mixed with hydrophobic polymers to avoid premature drug release. This polymer shows good film forming properties, resistant to pancreatic enzymes but they will undergo degradation due to bacterial enzyme. In another embodiment of the present invention, a pulsatile drug delivery (i.e. time- dependent controlled delivery) of DFX is applied. Pulsatile release undergo a lag-time of no release, followed by a rapid and complete release of DFX. A lag-time of 5 hours is usually considered sufficient since small intestine transit is about 3-4 hours.

Pulsatile drug delivery for the present invention can be made of single-unit delivery, or multiple (pellet) unit delivery.

Single-unit pulsatile delivery include capsular delivery as well as pulsatile delivery by osmosis, by erosion or solublization of coating, and by rupture of membrane.

Capsular delivery will comprise an insoluble capsule body housing DFX and a plug.

After a predetermined lag-time plug is removed because it undergoes swelling, erosion or dissolution, e.g. Pulsincap . A water insoluble body containing DFX herein closed with an insoluble but permeable and swellable hydrogel (plug). Upon contact with gut fluid, the plug swells pushing itself out of the capsule. Position and dimensions of plug with control lag-time. Plug material include insoluble but permeable polymer (e.g. polymethacrylates); erodible compressed polymer (e.g. hydroxypropyl methyl cellulose (HMPC), PVA, polyethylene oxide); congealed melted polymer (e.g. glyceryl monoleate); enzymatic-controlled erodible polymer (e.g. pectin). Capsular deliver with poor gastric resistance may be further enteric coated (Saeger & Virley. Pulsincap™

Mac226). For faster release, effervescent or disintegrating agents can be added.

Pulsatile delivery by osmosis such as the Port™ system comprises a gelatin shell filled with DFX also having an insoluble lipidic plug. The shell is coated with semipermeable membrane (e.g. cellulose acetate) then plugged with insoluble plug. When the system comes in contact with water, this moves across semi-permeable membrane and exert a pressure which remove the plug after a lag-time. A variant thereof is based on DFX released through orifice of a semi-permeable capsule supported by an expending osmotic layer after barrier layer is dissolved (as in U.S. Pat. No. 5,318,558).

Pulsatile delivery by erosion or dissolution of coating are made with a reservoir device comprising DFX coated with a barrier layer, which is eroded or dissolved after a lag period with the prompt release of DFX. An example is the "Time Clock" system (Wilding IR, Davis SS, Pozzi F, Furlani P, Gazzaniga A. Int J Pharm. 1994;111 :99-102) comprising the active coated with lipid barriers such as carnauba wax and beeswax along with surfactants like polyoxyethylene sorbitan monooleate. Noteworthy, the lag time is independent of gastrointestinal motility, pH, enzyme and gastric residence time.

Another example is the Chronotropic™ system (Gazzaniga A, Iamartino P, Maffione G, Sangalli ME. Int J Pharm. 1994;2(108):77-83) that will comprise the active coated with a hydrophilic swellable polymer, e.g. HPMC for a delayed release. The lag-time depend by the coat thickness and HPMC viscosity in both tablet and capsule forms.

In three-layered tablet, two pulsed release will be obtained from two DFX layers separated by a gellable polymer barrier, e.g HPMC, methacrylic/acrylic polymers or polyalcohols (see Gazzaniga A. et al., J Contr ReI. 2001;73:103-10). Pulsatile delivery by rupture of membrane will be based on rupturable kind of coating. The release of the DFX the core will occur when the surrounding polymeric membrane is broken by an inbuilt pressure. The effervescent excipients produces gas or osmotic agent causing swelling until rupture of coating (see Gazzaniga A. et al., Proceed Int Control ReI Bioact Mater, 1999;26:887-8). For example, citric acid and sodium bicarbonate incorporated in tablet core are then coated with ethyl cellulose. The lag time is controlled by composition of the external polymeric (swelling) membrane, e.g., croscarmellose sodium starch glycollate or low substituted hydroxy propyl cellulose. When this is eroded, the contact with water will produce the CO₂ gas, the resulting pressure cause the membrane to break and the prompt release of the active, DFX. (Krδgel I, Bodmeier R. Int J Pharm. 1999;187:175-184).

In an embodiment a capsule is enteric coated will contain a plurality of enteric coated granules containing the active agent. These coated granules are insoluble in intestinal fluids below pH 7 but are soluble in colonic intestinal fluids. Such a capsule is described, e.g., in U.S. Pat. No. 5,401,512 and WO-A-9214452.

Suitable materials for forming the enteric coat, include, e.g. enteric coating polymers, such as, e.g. HPMC-phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, acrylic acid copolymers, and methacrylic acid copolymers. A suitable methacrylic acid copolymer is Eudragit™ L-30-D 55 aqueous copolymer dispersion supplied as an aqueous dispersion with 30 % w/w solids.

A variety pf pH-independent polymers can be used, including polyvinylpyrrolidone (PVP), copovidone, polyethylene glycols, polyvinylalcohol-polyethylene glycol copolymer, polyvinyl acetate, poly(ethylacrylate, methyl methacrylate) 2:1, poly(ethyl acrylate, methyl methacrylate, trymethylammonio ethyl methacrylate chloride) 1:2:0.2, poly(ethyl acrylate, methyl methacrylate, trymethylammonioethyl methacrylate chloride) 1:2:0.1, ethers of cellulose (alkylcelluloses) such as HMPC, hydroxylpropylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, carboxymethyl cellulose, their derivatives and mixtures thereof.

Alternatively the release control may be ensured by congealed lipid, i.e. wax and fats excipients, alone or in combination with the aforementioned polymers. A not limitative list of such excipients includes stearates, glyceryl esters, waxes (carnauba, cethyl esters, microcrystalline), alone or mixtures thererof.

In another embodiment of the invention, cores may be a multi-layer tablet designed to ensure a pulsatile drug. In the case of a bi-layered tablet, this target can be achieved by fractioning the dose into two parts, i.e., the immediate release fraction in a layer comprising disintegrants, the modified release fraction in a layer comprising excipients that exert the release control. Alternatively different active principles can be included each in one separate layer of the tablet.

Multiparticulate systems are reservoir type of devices with a coating that either ruptures or changes its permeability. They show various advantages over single dosage, including short and reproducible gastric residence time, flexibility to blend pellets with different composition or release pattern, amenable to capsule and tablets, Disadvantages include: multiple manufacturing steps, low drug load, and incomplete release.

The enteric coating optionally comprises further materials such as plasticizers, colorants, antifoam agents, and anti-adherents. The enteric coated granule optionally comprises subcoat layer(s) situated between the base particle and the active ingredient layer, or the active ingredient layer and the enteric coating. The subcoat layer serves to minimize contact between DFX contained in a layer and an enteric coating comprising acid groups, such as methacrylic acid copolymer. Suitable materials to form the subcoat layer include starch, gelatine, sugars, natural and synthetic gums such as acacia, alginates, cellulose derivatives, PVP and PVP-PVA copolymers, polyethylene glycol, and waxes. The subcoat layer may further comprise a plasticizers, such as polyethylene glycol, propylene glycol, triethyl citrate, triacitin, diethyl phthalate, tributyl sebecate, or combinations thereof. The enteric coated granule may be contacted with a hydrophobic material such as talc, magnesium stearate, or fumed silica to form a hydrophobic layer on the surface of the enteric coated granule. The hydrophobic layer reduces agglomeration or reduces static during the handling of the enteric coated granules.

In another embodiment, the enteric coated granule comprises: a coated particle and an enteric coating encapsulating the coated particle. In another embodiment, the enteric coated granule comprises: a coated particle comprising a base particle, a subcoat disposed on the base particle, and a DFX layer disposed on the subcoat; and an enteric coating encapsulating the coated particle. In another embodiment, the enteric coated granule comprises: a coated particle; a subcoat disposed on the coated particle; and an enteric coating encapsulating the coated particle. In another embodiment, the enteric coated granule comprises: a coated particle comprising a base particle, a first subcoat disposed on the base particle, and a DFX layer disposed on the subcoat; a second subcoat disposed on the coated particle; and an enteric coating encapsulating the coated particle. In another embodiment, the enteric coated granule comprises a coated particle in which base particle comprises DFX and a second active ingredient; and an enteric coating encapsulating the coated particle. The enteric coated granule may comprise a first subcoat situated between the base particle and the active ingredient layer; and/or a second subcoat situated between the coated particle and the enteric coating.

DFX may be administered orally in controlled release unit dosage form; for example, containing 1 to 2000 mg,morally conveniently 10 to 500 mg, such as 60 to 250 mg, and such as 150 to 300 mg of active ingredient per unit dosage form.

Typical enema formulations comprise an effective amount of DFX dissolved or dispersed in a suitable aqueous flowable carrier vehicle. The carrier vehicle is preferably thickened with natural or synthetic thickeners such as gums, acrylates or modified celluloses. The formulation can also comprise an effective amount of a lubricant such as a natural or synthetic fat or oil or lecithin. 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 formulations can be delivered from a preloaded syringe pressurised container to release a foam onto the colon. An exemplary enema foam suitable for the present invention is Asacol™ Foam Enema, as in the electronic Medicines Compendium (eMC) released by Procter & Gamble Pharmaceuticals UK Ltd.

Suppositories may be formulated according to methods known in the art, e.g. those described in the Pharmaceutical Codex 12" Ed., the Pharmaceutical Press, 170-6 or Remington's Pharmaceutical Sciences 18th Ed., Mack Publishing Co, 1609-14. A suitable rectal dose will be in the range of from 0.01 to 20 mg/Kg, preferably in the range of 0.1 to 10 mg/Kg, most preferably in the range of 0.5 to 1 mg/Kg.

Further embodiments of the present invention comprise one or more additional therapeutic such as, e.g., an immunosuppressive such as azathioprine, methotrexate, cyclosporine, octreotide, FIL506, rapamycin, and mycophenolate mofetil, an antiinflammatory such as 5-ASA₅ sulfasalazine and olsalazine; a steroid including cortico- and glucocorticosteroids such as prednisolone, hydrocortisone, methylprednisolone, dexamethasone and ACTH; an immunomodulatory agent PVAC, anti-CD40 ligand, anti-CD40, natalizumab, anti- VCAMI and anti-ICAMl; a cytokine such as IL-10; and a TNF antagonist such as infliximab, etanercept, adalimumab, and CDP870.

Another embodiment include therapuetic antibiotic such as metronidazole, imipenem, vancomycin, ciprofloxacin; or local anesthetic such as lidocaine, and carbocaine.

Another embodiments of the present invention comprise one or more non-therapeutic biologically active ingredient having a proved lenitive effect on the intestinal tract, including ω 3 -fatty acid such as DHA, EPA; short-chain fatty acids (SCFA) such as acetate, butyrate, and propionate; curcumin; superoxide dismutase (SOD); and the like.

In a further embodiment is provided a method for the treatment of a subject with IBD.

In a method of this embodiment, DFX may be taken once, twice, three times a day. The dosages of DFX may vary from 10 mg through to 1 g per day, more typically 20 mg to 500 mg per day, still more typically 100 mg to 250 mg per day.

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

Usually, DFX 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 DFX are administered over a period of from 60 days to 120 days. After relief or symptoms is achieved, administration of the DFX 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 Comparative Example 1 - Bimodal release tablets

Tablets are made by separately mixing deferoxamine mesylate with: (A) melted fat and carbohydrates (hydrogenated palm oil, lactose) and, (B) magnesium stearate, corn starch, lactose at room temperature. The mixtures are cooled, granulated using a standard granulator, the resulting granules are then compressed. Process details are given in the Example 1 of US2005031686 .

Ingredient mg/unit Fast-dissolving tablet layer (A) Deferoxamine mesylate 150

Hydrogenated palm oil 100

Lactose 200

Slow-dissolving tablet layer (B) Deferoxamine mesylate 150

Lactose 100 Magnesium stearate 50

Pre-dried corn starch 100

Example 1 — Single-enteric coated tablets

The core tablet made by direct compression of deferoxamine, cellulose and calcium phosphate is sprayed with a shellac aqueous suspension comprising antiadhesives (talc, lactose, microcrystalline silica, magnesium stearate) and plasticizers (PVP, glyceride fatty acids). Process details are given in the Example 1 of US2005186278.

Ingredient mg/unit

Core tablet Calcium phosphate 50

Microcrystalline cellulose 25

Deferoxamine mesylate 50

Coating Shellac 3.5

Magnesium stearate 5

Silicon dioxide 0.9

Talc 1

Lactose 0.2 Acetyl monoglycerides 0.2

Hydroxypropyl methyl cellulose 1.7 Polyvinylpyrrolidone 0.1

Example 2 - Double-enteric coated tablets A core tablet is made by direct compression of deferoxamine mesylate, lactose, microcrystalline cellulose, PVP and magnesium stearate, then the core are fluid-bed subcoated with HMPC 2% aqeeuous solution conprising PEG as plasticizer. Tablets are further coated with a suspension of cellulose acetate phthalate and diethylphthalate as plasticizer. Process details are given in the Example 1 of EP 0572942. Ingredient mg/unit

Core tablet Deferoxamine mesylate 300

Lactose 15

Microcrystalline cellulose 1

Polyvinylpyrrolidone 0.5 Magnesium steaxate 10

Subcoating Hydroxypropyl methyl cellulose 8

PEG-400 2

External coating Cellulose acetate phthalate 6

Diethylphthalate 1.2 Examples 3 - High performance, gastro-resistant capsules

HMPC hard capsule (Shionogi Qualicaps SA, Madrid, Spain) with 2% κ-carrageenan are filled with Deferoxamine mesylate (300 mg). The capsules are sprayed with hydroxypropylcellulose to improve adhesion of the next spry of Eudragit L 30 D-55 suspension with plasticizers. Process details are given by Degussa, Pharma Polymers 01/2005, "Enteric Coating of Hard Gelatin Capsules with Eudragit™ L 30 D-55". Example 4 - Enemas

Enemas are obtained by dissolving deferoxamine mesylate in water, then adding parabes, sodium EDTA, sodium metabisulphite, and methyl cellulose under continuous stirring with distilled water, up to a final volume of 1500 ml. The solution is well mixed by shaking and packaged as 100 ml doses in Wheaton enema bottles. Ingredient mg/unit

Deferoxamine mesylate 100

Methylhydroxybenzoate 25

Propylhydroxybenzoate 12.5

Sodium EDTA 10

Sodium metabisulphite 15

Methyl cellulose 500

Distilled water q.b. to 100 ml

Preparative Example - Deferoxamine adipate A solution of deferoxamine base is obtained by passing an aqueous solution of the mesylate salt over Dowex-1™ anion exchange resin (in OH^" form) and concentrating the solution at 10 % w/v. The deferoxamine base solution is added dropwise to suspension of equimolar adipic acid, then stirred for 10 min. and dried under vacuum. Example 5 - Suppositories Suppositories are obtained by melting hydrogenated coco-glycerides Witepsol™ W 45 (Sasol GmbH, Germany) in a water bath. Deferoxamine adipate is thereto added under stirring, then a combination of PEG 4000 and PEG 1250 (1:3 w/w) is warmed in water batch, this admixture is poured into the melted fat, well incorporated and mixed before being poured into disposable suppository molds. Reference: Puranajoti, et al.. Morton Grove Pharmaceuticals (Morton Grove, IL, USA). Ingredient mg/unit

Deferoxamine adipate 200

Hydrogenated coco-glycerides 250 PEG 4000 / PEG 1250 1 :3 200 Additional Examples 1-2 - Formulation of deferoxamine analogs

Similar formulation are conceived with the use of other hydroxamate siderophore, For example, HMPC hard capsule (Shionogi Qualicaps SA, Madrid, Spain) with 2% K- carrageenan are filled with DFX analogs such as exochelin, e.g. from Mycobacterium smegmatis as obtained in Biochem J. 1995; 305(l):187-96; or coprogen, e.g. from Pilobolus spp. as obtained in J Am Chem Soc, 1953; 75 (23), 6064-5. In vitro assay Ex. 1 - Pharmacokinetic profiles of the targeted release forms

The release profile of the Examples shall be tested, e.g., according to the method of Chuong et al, Dissolution Technologies, 2008, 7-14, a 3-steps process herein applied to the targeted delivery forms of desferoxamine as per previous examples. The first step is in gastric fluid, i.e. an acidic dissolution stage, 500 ml of 2 g/1 NaCl, pH adjusted to 1.4 with HCl for 2 h.

In step 2, 245 ml of 0.09 M Na₃PO₄-12 H₂O is added to bring the dissolution medium pH from 1.4 to 6.0 to simulate small intestinal fluid. Dissolution is continued at 100 rpm for 4 h. Step 3 (buffer stage 2) is carried out in simulated large intestinal fluid by the addition of 100 ml of 0.3 M NaOH or 87 ml of 0.05 M Na₃PO₄- 12 H₂O to raise medium pH to 7.3, for an additional 8 h of dissolution test.

For rectal formulations such as enema and suppository, the dissolution test is to be carried out by a reversed sequence: first is step 3, followed by step 2, then step 1. After each dissolution step, the deferoxamine concentration released (dissolved) in the three solution simulating the GI tracts can be duly quantified by the absorbance either at 230 nm, or at 428 nm following the addition OfFeCl₃ at 20% to 80% molar excess. In vitro assay Ex. 2 - Behaviour in simulated gastric juice

A solution of 500 mg of deferoxamine mesylate from Desferal™ in 500 ml of 2 g/1 NaCl, is adjusted to pH 1.4 with HCl and added with BC Pepsin 1:10000 (Biocatalyst Ltd, Parck Nantgarw, Wales, UK), then kept a 37 °C for 3 hours in a rotatory shaker.

The solution is neutralized with 1.2% w/v sodium bicarbonate and centrifugated for the subsequent HPLC analysis. The HPLC method use an Inertsil™ ODS-3V column

(5μm, 150x4.6 mm ID); as eluent: i-propanol / 10.5 mM (NH₄)₂HPO₄+ 1.0 mM EDTA + 5.6mM C₇H₁₅-SO₃Na; the pH is kept to 2.8 by H₃PO₄ = 8/1; the flow rate is: 0.9 ml/min; the column temperature: 4O⁰C; injection vol. 20 μl; with detection at 230 nm.

Chromatograms show deferoxamine, which peak is at around 15 min., before (A) and after (B) the assay. The newer peaks shall be unidentified degradation products.

Claims

1. The use of a targeted release dosage form of deferoxamine and analog and salt thereof ("DFX") in therapeutically effective amount to treat a patient with inflammatory bowel disease ("IBD"), characterized in that the release of said DFX in stomach and the contact with gastric fluids is substantially prevented.

2. The use according to claim 1 wherein said DFX is deferoxamine mesylate.

3. The use according to claim 1 wherein said DFX is other-than-mesylate salt.

4. The use according to claim 1 wherein said DFX is a hydroxamates with citric acid backbone, a hydroxamates with cyclic diglycine backbone, or another hydroxamate siderephore with hexadentate structure.

5. The use according to one or more claims 1 to 4 wherein said dosage form is an oral, controlled release formulation.

6. The use according to one or more claims 1 to 4 wherein said dosage form is a rectal formulation.

7. A targeted release pharmaceutical composition to deliver a therapeutically effective amount of deferoxamine and analog and salt thereof (DFX) for the use in treatment a patient with an inflammatory bowel disease (IBD), characterized in that the release of DFX in stomach and the contact with gastric fluids is substantially prevented.

8. A pharmaceutical composition according to claim 7 providing the oral pulsatile release of a DFX to an patient suffering from IBD.

9. The composition according to claim 8 in form of tablet, bead, granule, or capsule.

10. The composition for the treatment of IDB in a patient in need thereof comprising a therapeutically effective amount of a pharmaceutical composition according to one or more claims 7 to 9 together with a pharmaceutically acceptable carrier.

11. The composition according to claim 10 wherein said IBD is Crohn's disease.

12. The composition according to claim 10 wherein said IBD is ulcerative colitis.

13. The composition according to claim 10 wherein said IBD is selected from the group consisting of collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, proctitis, proctosigmoiditis, and indeterminate colitis.

14. The composition according to claim 10 wherein said IBD is irritable bowel syndrome.

15. The pharmaceutical composition according to claim 7 providing the rectal release of a DFX.

16. The composition according to claim 15 wherein said IBD is Crohn's disease.

17. The composition according to claim 15 wherein said IBD is selected from the group consisting of proctitis, and proctosigmoiditis,

18. The composition according to claim 15 in form of cream, ointment, gel, foam, suppository, or enema.

19. A pharmaceutical composition for the treatment of IDB in a patient in need of thereof, comprising a therapeutically effective amount of a pharmaceutical composition according to one or more claims from 7 to 18 together with a pharmaceutically acceptable carrier.

20. A method of treating IDB in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to claim 7 together with a pharmaceutically acceptable carrier.

21. The method according to claim 20 wherein DFX is administered to an IBP patient with iron-deficient anemia in conjunction with iron supplementation, provided that in case of oral iron supplements, the DFX are administered at least 6 hours after or 3 hours before said supplements.