WO2009010967A1

WO2009010967A1 - An agent for treatment of inflammation

Info

Publication number: WO2009010967A1
Application number: PCT/IL2008/000976
Authority: WO
Inventors: Pnina Fishman; Sara Bar-Yehuda; Shira Cohen; Avivit Ochaion; Ilan Cohn
Original assignee: Can-Fite Biopharma Ltd.
Priority date: 2007-07-15
Filing date: 2008-07-15
Publication date: 2009-01-22
Also published as: IL184620A0

Abstract

The present disclosure relates to the use of an agent for treating an individual afflicted with an inflammatory condition or disease; the agent comprising one or more members of a group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides. The agent may be used in conjugation with an anti-inflammatory drug, such as methotrexate, with an A3 adenosine receptor agonist and/or with folic acid. The inflammatory condition or disease is preferably an autoimmune disease. The present disclosure also concerns pharmaceutical compositions comprising the agent as well as methods for treatment of an inflammatory condition or disease. One agent in the context of the present disclosure may be Cremophor, e.g. Cremophor RH40, which may be used in combination with the anti-inflammatory agent, methotrexate (MTX).

Description

AN AGENT FOR TREATMENT OF INFLAMMATION

FIELD OF THE INVENTION

The present disclosure relates to agents for treatment of an inflammatory condition or disease as well as to compositions and methods useful in the treatment of inflammatory conditions or diseases.

BACKGROUND OF THE INVENTION

Polyoxyl hydrogenated castor oil (which will be referred to herein, as "PHCO") is a non-ionic solubilizer and emulsifying agent that is obtained by reacting ethylene oxide with hydrogenated castor oil. Such products are sold commercially under the trade name Cremophor by BASF, Germany. One such product is Cremophor RH 40™ (polyoxyl 40 hydrogenated castor oil (USP/NF)) obtained through reacting ethylene oxide with hydrogenated castor oil at a respective molar ratio of 40-45 to 1. Another such product is Cremophor RH 60™ which is obtained through reacting these ingredients at a ratio of 1 to 60. The main constituent of PHCO is glycerol polyethylene glycol oxystearate, which, together with fatty acid glycerol polyglycol esters, forms the hydrophobic part of the product. The hydrophilic part consists of polyethylene glycols and glycerol ethoxylate.

Cremophor RH 40™ has been used as an excipient, either by itself, or with other excipients, in pharmaceutical products. For example, use as a carrier within a soft capsule containing the active ingredient N⁶-(3-iodobenzyl)-adenosine-5'-N- methyluronamide (IB-MECA). In the case of the IB-MECA-containing formulation, Cremophor RH 40™ has been used as an excipient together with the medium chain triglyceride, Miglyol 812™ (Condea Chemie GmbH, Germany), which are triglycerides of the fractionated vegetable fatty acids C8 and ClO, comprising caprylic and capric fatty acids. SUMMARY OF THE INVENTION

In accordance with the present disclosure it has been discovered that a composition comprising (i) polyoxyl 40 hydrogenated Castor Oil (having the trade name Cremophor RH 40™) and (ii) the medium chain triglyceride (MCT) product Miglyol 812™ (the composition being referred to herein as the "PHCO composition") had a strong anti-inflammatory effect demonstrated by reduction in disease symptoms in a human clinical study. In that clinical study the PHCO composition was administered to patients in combination with methotrexate (MTX) and was also used as a carrier for IB-MECA. Many of the patients in this study also received folic acid.

Also, it was found that the PHCO composition had the effect of reducing proliferation of stimulated lymphocytes and of potentiating the anti-inflammatory effect of MTX.

It was further found that administration of the PHCO composition to animals, ameliorated inflammatory disease symptoms in these animals, both alone or when administered in combination with another agent.

Thus, without being bound by theory, it has been suggested that the antiinflammatory effect may be embodied in one or more of the components of the PHCO composition. The anti-inflammatory activity may also be a result of interaction of the PHCO composition with MTX, IB-MECA and/or folic acid.

In accordance with a first of its aspects, the present disclosure provides for the use of an agent for treating an individual afflicted with an inflammatory condition or disease; the agent comprising one or more members of the group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides.

Further, there is provided the use of an agent for the preparation of pharmaceutical composition for treating an individual afflicted with an inflammatory condition or disease; the agent comprising one or more members of the group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides.

In accordance with a further aspect, there is provided a method of treatment of an individual afflicted with an inflammatory condition or disease, comprising administering to the individual an amount of an agent effective to induce an antiinflammatory effect, the agent comprising one or more members of the group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides.

In accordance with yet a further aspect, there is provided a pharmaceutical composition for the treatment of an inflammatory condition or disease comprising as active agent an amount of one or more members of the group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides; the amount of the agent being effective to induce an anti-inflammatory effect in an individual afflicted with an inflammatory condition or disease.

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BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the effect of a composition comprising polyoxyl 40 hydrogenated castor and Miglyol 812 ("Cremophor" in the figure), MTX or the combination of the composition and MTX, on the proliferation of PHA stimulated peripheral blood mononuclear cells (PBMNC). Results are presented in terms of optical density (OD) as percent of control. Reduction beyond control denotes inhibition of proliferation.

• Fig. 2 shows the A_2A adenosine receptor (A_2AAR) and the A₃ adenosine receptor (A₃AR) level upon treatment of PHA -stimulated peripheral blood mononuclear cells (PBMNC) with a composition comprising polyoxyl 40 hydrogenated castor and Miglyol 812 (indicated as "Excipients" in the figure). Western blot analysis assay was utilized to determine protein expression level.

Fig. 3 shows the disease score in rats with an adjuvant-induced arthritis including control animals and animals treated with a PHCO composition (indicated as "Excipients" in the figure). Treatment was induced after onset of disease. The results that are shown are 6 days after onset of treatment.

Fig. 4 shows the disease score in rats with an adjuvant-induced arthritis including control animals, animals treated with MTX and animals treated with MTX and a PHCO composition (indicated as "Excipients" in the figure). Treatment was induced after onset of disease. The results that are shown are 10 days after onset of treatment.

DESCRIPTION OF NON-LIMITING EXEMPLARY EMBODIMENTS

The present disclosure concerns an agent that has been found to exhibit an antiinflammatory activity. The agent in the context of the present disclosure comprises one or more members of the group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides. Thus, in accordance with a first of its aspect, there is provided the use of the agent for treating an inflammatory condition or disease. The term "agent" is used to encompass a single component or a combination of any one of the components defined above.

In accordance with a second aspect, there is provided the use of the agent for the preparation of a pharmaceutical composition for the treatment of an inflammatory condition or disease.

In accordance with a third aspect, there is provided a method for the treatment of an inflammatory condition or disease comprising administering to an individual afflicted with an inflammatory condition or disease an amount of the agent, the amount being effective to induce an anti-inflammatory response in said individual. hi accordance with a fourth aspect, there is provided a pharmaceutical composition for the treatment of an inflammatory condition or disease, the composition comprising as active ingredient the agent as defined herein, in an amount effective to induce an anti-inflammatory response.

In accordance with one embodiment, the agent comprises a combination of a hydrophobic part and a hydrophilic part, the hydrophobic part comprises a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, and the hydrophilic part comprises a polyethylene glycol and a glycerol ethoxylate.

The agent may be obtained by reacting ethylene oxide with hydrogenated castor oil at a molar ration of ethylene oxide to hydrogenated castor oil of about 30-60 to 1. hi accordance with one embodiment, the reaction is carried out at an ethylene oxide:hydrogenated castor oil molar ratio of about 45:1.

In accordance with some other embodiments, the agent is a non-ionic agent characterized by one or more of a saponification value of between 40 to 60 and a hydroxyl value of between 50 to 75. More specifically, the agent is characterized by a saponification value of 50 to 60 and a hydroxyl value of 60 to 75.

Some preferred agents in accordance with the present teaching are known in the art by the generic trade-name Cremophor, preferably Cremophor RH grades. Some specific Cremophor RH grades include Cremophor RH40, Cremophor RH 455 and Cremophor RH 60 as provided by BASF, the details of which are included in BASF technical leaflet of May 1992 (MEl 25e, Register 14). A preferred Cremophor in accordance with the present teaching is Cremophor RH40.

In accordance with another embodiment, the agent comprises one or a combination of plant-derived medium chain triglycerides, the medium chain triglyceride being defined by a C6 to C14 fatty acid, preferably a neutral fatty acid.

In accordance with some other embodiments, the plant-derived medium chain triglyceride comprises one or more members of the group consisting of caproic acid (C6:0); caprylic acid (C8:0); capric acid (C10:0); lauric acid (C12:0) and myristic acid (C14:0).

A preferred combination of medium chain triglyceride comprises a combination of caprylic and capric triglyceride.

In accordance with some alternative embodiments, the said one or combination of plant-derived medium chain triglycerides is a fractionated Coconut oil.

Some preferred medium chain triglyceride agents in accordance with the present teaching are known in the art by the generic trade name Miglyol neutral oils. Specific Miglyol neutral oils in the context of the present disclosure include the 810, 812, 818, 829 and 840 neutral oils. A preferred Miglyol is the 812 neutral oil (as detailed in SaSoI Germany GmbH leaflet 09.04).

Based on the teaching herein, a person versed in the art may find one or more derivatives for the agents. For example, since Cremophor RH grades and Miglyol are typically used as excipients, The Handbook of Pharmaceutical Excipients (Edited by RC Rowe, PJ Sheskey, and SC Owen, Royal Pharmaceutical Society of Great Britain, London, UK) can be used to identify alternatives for the agent as defined herein and their combinations which have similar pharmacological properties to said PHCO composition, permitting to use said substance(s) for treating inflammation in an individual with or without another anti-inflammatory agent as disclosed herein. Compositions comprising such other substances, method of treatment employing such other substances as well as the use of such other substance for the preparation of antiinflammatory pharmaceutical preparations, are also encompassed by teaching herein. The agent may be administered to the individual in need of an anti-inflammatory treatment concomitant with one or more of an A₃ adenosine receptor agonist, an antiinflammatory agent and/or folic acid.

The term "A₃ adenosine receptor agonist" in the context of the present disclosure refers to any molecule capable of specifically binding to the A₃ Adenosine Receptor (A₃AR), thereby fully or partially activating said receptor. The agonist is thus a molecule that exerts its prime effect through the binding and activation of the A₃AR. This means that at the doses it is being administered it essentially binds to and activates only the A₃AR.

The characteristic of some adenosine A₃ adenosine receptor agonists and methods of their preparation are described in detail in, inter alia, US 5,688,774; US 5,773,423, US 5,573,772, US 5,443,836, US 6,048,865, WO 95/02604, WO 99/20284, WO 99/06053, WO 97/27173, US7,064,751, all of which are incorporated herein by reference.

In accordance with one preferred embodiment, the agonist is N⁶-(3-iodobenzyl)- adenosine-5'-N- methyluronamide (IB-MECA).

The anti-inflammatory agent may be any anti-inflammatory drug known in the art, particularly those exhibiting an effect similar to that induced by methotrexate (MTX). In accordance with one embodiment, the anti-inflammatory agent is an anti- folate compound.

As used herein, the term "anti-folate compound" refers to a compound having structural similarity to folate and activity as a folate antagonist against one or more folate- dependent enzymes. Examples of anti-folate compounds include, e.g., aminopterin, raltitrexed, lometrexol, multitargeted anti-folate (MTA), AQA, MTX, and analogs thereof. Aminopterin, for example, possesses a hydrogen instead of a methyl group at position N-IO compared to the structure of MTX. Raltitrexed (ZD 1694) is a selective inhibitor of thymidylate synthase. Lometrexol selectively inhibits glycinamide ribonucleotide formyltransferase, the first enzyme involved in the pathway of de novo purine synthesis. Other anti-folate compounds include, for example, trimetrexate, edetrexate, and the like (see, e.g., Takimoto, Oncologist 1 :68-81, 1996, for a listing of exemplary anti-folate compounds). A preferred anti-folate compound in accordance with the present disclosure is MTX.

The present teaching provides a solution for the treatment of an inflammatory condition or disease.

The term "treating" or "treatment" used herein refers to treating an individual suffering from an inflammatory disease or condition, in order to reduce inflammatory disease symptoms in the individual.

In accordance with one embodiment, the inflammatory condition or disease is an autoimmune disease. Thus, the term "treatment" is further intended to include both prophylactic treatment to prevent or delay the onset of an autoimmune disease (or to prevent the manifestation of clinical or subclinical, e.g., histological, symptoms thereof), as well as therapeutic suppression or alleviation of symptoms after the manifestation of autoimmune disease, by abating autoimmune attack and preventing or slowing down autoimmune tissue destruction, "abatement", "suppression" or "reduction" of autoimmune attack or reaction encompasses partial reduction or amelioration of one or more symptoms of the attack or reaction. A "substantially" increased suppressive effect (or abatement or reduction) of autoimmune reaction means a significant decrease in one or more markers or histological or clinical indicators of autoimmune reaction or disease.

The inflammatory disease or condition may be, without being limited thereto, an autoimmune disease such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, Crohn's disease, multiple sclerosis (MS), the autoimmune stage of diabetes mellitus (juvenile-onset or type I diabetes), autoimmune uveoretinitis (AUR) and others where MTX has been used. The treatment may intended to reduce disease manifestation such as the number of swollen or tender joints in rheumatoid arthritis, the amount or extent of skin lesions is psoriasis patients, etc., or symptoms associated with the disease, such reduction of pain, morning stiffness, patient disability and others.

The agent may be used in conjugation with another agent or drug. The other agent or drug may be one or a combination of an adenosine A₃ receptor agonist, folic acid or an anti-inflammatory agent. Administration "in conjunction" encompasses simultaneous and sequential administration, as well as administration in combined form or separately.

Further, the agent may be used in conjugation with two or more of the adenosine A₃ receptor agonist, the folic acid and/or the anti-inflammatory agent. For example, the agent may be used in combination with MTX and folic acid. The adenosine A₃ receptor agonist, folic acid or an anti-inflammatory agent may be administered to the individual in accordance with acceptable treatment protocols. In the case of MTX, for example, acceptable treatment protocols include weekly administration either orally or by injection, at such weekly doses of 3-30 mg.

The agent as defined herein may be formulated together with the one or combination of the adenosine A₃ receptor agonist, folic acid and/or the antiinflammatory agent, or it may be administered in a separate delivery vehicle. As indicated above, the agent is preferably administered systemically, in a formulation suitable for oral administration.

In accordance with one preferred embodiment, the agent is used for systemic treatment of an individual afflicted with an inflammatory condition or disease. According to one embodiment, the systemic treatment comprises oral administration of the agent to said individual.

The term "systemic administration" or "systemically administering" means to denote administration through a route in which said agent inflicts a systemic effect. Systemic administration my typically be orally (including enteral or intragastric administration). However, other systemic administration routes are also possible, including, but not limited to, parenteral (e.g. intravenous, intraperitoneal, sub-dermal or intramuscular), nasal (e.g. via a nasal spray), in the form of an inhaled spray, transdermal delivery. A person versed in the art of formulating ingredients for system administration will be able to design a formulation on the basis of relevant pharmacokinetic and pharmacological considerations.

The treatment may be once, twice or several times daily, once every other day, etc. As known in the art of clinical development, the treatment schedule may be determined through appropriately designed clinical studies by scientific or pharmacologic considerations. The effective amount of said agent may be determined, for example, be dose- finding clinical studies or through extrapolation from laboratory animals through a number of dose conversion formulas or by other considerations.

The agent to be used for treatment may be selected through clinical studies, of the kind exemplified herein, through in vitro studies of the kind also exemplified or through experiments in appropriate animal models of inflammatory diseases. The PHCO composition, may for example, be polyoxyl 40 hydrogenated castor oil or polyoxyl 60 hydrogenated castor oil.

The active agent may be administered within a soft shell capsule, typically enteric coated, may be administered as a drink, and in general in any suitable delivery form.

NON-LIMITING EXAMPLES Example 1: Clinical study

Methods

The clinical study was A Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study to test the safety and efficacy of CFlOl (a cGMP grade manufacture of the A3 adenosine receptor agonist IB-MECA synthesized for Can-Fite BioPharma, under good clinical practice (GMP) by Albany Molecular Research Inc, Albany, NY, USA), administered orally, added to weekly MTX administration, in patients with active RA.

Three doses of CFlOl that were tested in the study were 0.1, 1 and 4 mg in a soft-shell capsule that included, other than CFlOl also polyoxyl 45 hydrogenated castor oil (Cremophor RH 40™) and Miglyol 812. Capsules not containing CFlOl were used as control. These control capsules included 326.5 mg of polyoxyl 45 hydrogenated castor oil and 173.5 mg Miglyol 812. In the CFl 01 -containing capsules a small amount of the polyoxyl 45 hydrogenated castor oil and Miglyol 812 was substituted by this drug.

Patients were administered orally with the CFl 01 -containing or the control capsules twice daily to patients that were concomitantly treated also with MTX. The study was a 12 weeks study. Many of the patients received also folic acid. Disease activity was measured by standard measures at baseline and throughout the study. The disease activity was evaluated by ACR standard criteria laid down by the American College of Rheumatology.

Results

The percentage of patients in the control group (who received the control tablets) that had an ACR20 response (an ACR20 response means a 20% improvement in 5 out of 8 diseases parameters) was 50% as compared to 53.8%, 47.6% and 44.4% of the patients receiving 0.1, 1 and 4 mg of CFlOl, respectively. Historical placebo response rates in patients with active disease, despite receiving MTX, are at a range of 15-30%, indicating that the control capsules had an anti-inflammatory activity by themselves or upon interaction within the body with one of the other administered agents, e.g. MTX or folic acid.

The ACR20 response in the patients receiving the control capsules continuously accrued through the 12 weeks of the study with the response being 0, 11.3%, 22.6%, 38.7% and 46.8% on weeks 2, 4, 8, 12, respectively. Such a response accrual patterns is not expected to happen in a placebo group, also indicating an anti-inflammatory activity in the anti-in control capsules.

Patient reported parameters including patient global assessment, pain assessment and health assessment questionnaire disability index, also showed a continuous improvement throughout the study, a pattern not expected in a placebo response. The overall improvement seen in these parameters considerably exceeded levels reached in placebo responses. This finding also indicates that the control is active.

Example 2: In vitro studies

Materials and Methods Reaeents

RPMI, fetal bovine serum (FBS) and antibiotics for cell cultures were obtained from Beit Haemek, Haifa, Israel. Methotrexate (MTX) and phytohemagglutinin (PHA) were purchased from ABIC, Israel. Rabbit polyclonal antibodies against rat and human A₃AR as well as rat A_2AAR was purchased from Santa Cruz Biotechnology Inc., Ca, USA. 3-[4,5-Dimethylthiazol-2-yl]-2,5-dephenyltetrazolium bromide for the MTT assay was purchased from Sigma.

The POHC composition that was used was derived from control capsules used in the clinical study reported in Example 1.

Blood sample collection and separation

Blood samples were collected from healthy subjects who signed an informed consent prior to blood withdrawal. To separate PBMNC, heparanized blood (20ml) was subjected to Ficoll hypaque gradient.

Cell cultures of mitogen activated PBMNC

PBMNC (2xlO6/ml) from healthy subjects were incubated with 5μg/ml PHA in RPMI 1640 supplemented with 10% FBS. The POHC composition which included 326.5 mg of Cremophor RH 40™ and 173.5mg of Miglyol 812™ were diluted 1:5000 and added to the PHA treated cultures for the whole culture period. After 24h MTX (lμM) was added for additional 48 hours. To test the effect of excipients and MTX on cell growth MTT assay was used and performed as follows.

MTT assay

Cells and additives as described above were cultured in 96-well microtiter plates. At the end of the incubation period (72 hours total), MTT assay was used. MTT stock solution (5mg/ml) was added (1 :10) to the culture system and incubated for 4 hours. Then the culture medium was removed and MTT solvent (HCL 0.05N in isopropanol) was added to the culture in an amount equal to the original volume. Absorbance of the converted dye was measured at 570nm.

At the end of the incubation time the PBMNC 's were collected from the culture plates and protein extracts were prepared.

Western Blot Analysis of ^'A?A and A^ adenosine receptors

To assess the effect of the excipients and MTX on the expression level of A₂A and A₃ adenosine receptors, the above mentioned cells and additives were cultured in 10 cm tissue culture plates (5xlO4/ml) for 72 hours. At the end of the incubation period cell samples were rinsed with ice-cold PBS and transferred to ice-cold lysis buffer (TNN buffer, 5OmM Tris buffer pH=7.5, 15OmM NaCl, NP 40). The trypsinized cells were washed again with ice-cold PBS, harvested by centrifugation and subjected to lysis in TNN buffer. Cell debris was removed by centrifugation for 10 min at 7500xg. The supernatant was utilized for WB analysis. Protein concentrations were determined using the Bio-Rad protein assay dye reagent. Equal amounts of the sample (50μg) were separated by SDS-PAGE, using 12% polyacrylamide gels. The resolved proteins were then electroblotted onto nitrocellulose membranes (Schleicher & Schuell, Keene, NH, USA). Membranes were blocked with 1% bovine serum albumin and incubated with the relevant primary antibody (dilution 1 : 1000) for 24h at 4⁰C. Blots were then washed and incubated with the secondary antibody for Ih at room temperature. Bands were recorded using color development kit (Promega, Madison, Wl, USA).

Results

Excipients potentiate the inhibitory effect of MTX on the proliferation of PHA stimulated PBMC in vitro

As can be seen in Fig. 1, the incubation with the diluted POHC composition inhibited PBMNC proliferation in three different cultures each one of them derived from different healthy subject. Furthermore, a combined exposure of the cells to MTX and the diluted POHC composition caused a larger inhibitory effect as compared to MTX alone.

Fig.2. depicts the effect of the excipients on the expression level of the A2A and the A3 protein expression level in PHA-stimulated PBMNC. It can be noted that the excipients induced up-regulation of the A2A adenosine receptor protein expression level.

Without intending to be bound by theory, it should be noted that MTX is known to mediate its anti-inflammatory effect via the A3 and the A2A adenosine receptors. The excipients-mediated increase in the level of these two receptors may explain some of the excipient-induced anti-inflammatory effect. Example 3: In vivo studies

Methods

Adjuvant induced arthritis (AIA) model was established in rats by immunizing the animals with an emulsion contacting Mycobacterium tuberculosis in Freund's adjuvant. A PHCO composition comprising

Treatment with the PHOC composition, at a dilution of 1:500 (in PBS) was initiated upon onset of disease. The PHOC composition was administered orally, three- times daily. Each administration was of 0.5 ml.

MTX was administered IP at a dose of 0.75 mg/kg, once weekly.

The severity of the disease was measured by the observed clinical score according to acceptable measures.

Results

The clinical score results depicted in Fig. 3, show that the PHOC composition induces a marked improvement of the clinical score. The results depicted in Fig. 4 show that the combined treatment of MTX and the excipients is beneficial over MTX treatment alone.

The results show that the combined treatment of MTX and the excipients is beneficial over MTX treatment alone.

Claims

CLAIMS:

1. Use of an agent for treating an individual afflicted with an inflammatory condition or disease; the agent comprising one or more members of a group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides.

2. Use according to Claim 1, for treating an individual in combination with one or more of an A₃ adenosine receptor agonist, an anti-inflammatory agent or folic acid.

3. Use according to Claim 2, wherein the anti-inflammatory agent is methotrexate (MTX).

4. Use according to any one of Claims 1 to 3, wherein the treatment is systemic.

5. Use according to Claim 4, wherein the treatment is oral.

6. Use of an agent for the preparation of pharmaceutical composition for treating an individual afflicted with an inflammatory condition or disease; the agent comprising one or more members of the group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides.

7. Use according to Claim 6, wherein said pharmaceutical composition is intended for treatment of an individual in combination with one or more of an A₃ adenosine receptor agonist, an anti-inflammatory agent or folic acid.

8. Use according to Claim 7, wherein said anti-inflammatory agent is MTX.

9. Use according to any one of Claims 6 to 8, for the preparation of a composition for systemic administration.

10. Use according to Claim 9, for the preparation of a composition for oral administration.

11. Use according to any one of Claims 1 to 10, wherein said agent comprises a combination of a hydrophobic part and a hydrophilic part, said hydrophobic part comprises said glycerol polyethylene glycol oxystearate and said fatty acid glycerol polyglycol ester, and said hydrophilic part comprises said polyethylene glycol and said glycerol ethoxylate.

12. Use according to any one of Claims 1 to 11, wherein said agent is obtained by reacting ethylene oxide with hydrogenated castor oil at a molar ration of ethylene oxide to hydrogenated castor oil of about 30-60 to 1.

13. Use according to Claim 12, wherein said ethylene oxide :hydrogenated castor oil ration is about 45:1.

14. Use according to any one of Claims 1 to 13, wherein said agent is a non-ionic agent characterized by one or more of a saponification value of between 40 to 60 and a hydroxyl value of between 50 to 75.

15. Use according to Claim 14, wherein said agent is characterized by a saponification value of 50 to 60 and a hydroxyl value of 60 to 75.

16. Use according to any one of Claims 1 to 10, wherein said one or combination of plant-derived medium chain triglycerides comprises a C₆ to Ci₄ neutral fatty acid.

17. Use according to Claim 16, wherein said one or combination of plant-derived medium chain triglycerides comprises one or more members of the group consisting of caproic acid (C6:0); caprylic acid (C8:0); capric acid (C10:0); lauric acid (C12:0) and myristic acid (C14:0).

18. Use according to any one of Claims 1 to 10, wherein said one or combination of plant-derived medium chain triglycerides comprises fractionated Coconut oil.

19. Use according to any one of Claims 1 to 18, wherein said inflammatory condition or disease is an autoimmune disease.

20. Use according to Claim 19, wherein said autoimmune disease is selected from rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, Crohn's disease, multiple sclerosis (MS), the autoimmune stage of diabetes mellitus (juvenile-onset or type I diabetes), autoimmune uveoretinitis (AUR).

21. A method of treatment of an individual afflicted with an inflammatory condition or disease, comprising administering to the individual an amount of an agent effective to induce an anti-inflammatory effect, the agent comprising one or more members of the group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides.

22. The method of Claim 21, being for systemic treatment.

23. The method of claim 21 or 22, being for oral treatment.

24. The method of any one of Claims 21 to 23, wherein said agent is as defined in any one of Claims 11 to 18.

25. The method of any one of Claims 21 to 24, for the treatment of an autoimmune disease.

26. The method of Claim 25, wherein said autoimmune disease is selected from rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, Crohn's disease, multiple sclerosis (MS), the autoimmune stage of diabetes mellitus (juvenile-onset or type I diabetes), autoimmune uveoretinitis (AUR).

27. The method of any one of Claims 21 to 26, comprising treatment with one or more of an adenosine A₃ receptor agonist, folic acid or an anti-inflammatory agent.

28. The method of Claim 27, wherein said anti-inflammatory agent comprises MTX.

29. A pharmaceutical composition for the treatment of an inflammatory condition or disease comprising as active agent an amount of one or more members of the group consisting of: (i) a polyoxyl hydrogenated castor oil; (ii) a reaction product of ethylene oxide with hydrogenated castor oil; (iii) one or more of a glycerol polyethylene glycol oxystearate and a fatty acid glycerol polyglycol ester, combined with one or more of a polyethylene glycol and glycerol ethoxylate; (iv) one or combination of plant-derived medium chain triglycerides; the amount of the agent being effective to induce an antiinflammatory effect in an individual afflicted with an inflammatory condition or disease.

30. The pharmaceutical composition of Claim 29, comprising a physiologically acceptable carrier for systemic delivery of said active agent.

31. The pharmaceutical composition of Claim 30, wherein said carrier is for oral delivery of said active agent.

32. The pharmaceutical composition of any one of Claims 29 to 31 , wherein said agent is as defined in any one of Claims 11 to 18.

33. The pharmaceutical composition of any one of Claims 29 to 32, wherein said inflammatory condition or disease is an autoimmune disease.

34. The pharmaceutical composition of Claim 33, wherein said autoimmune disease is selected from rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, Crohn's disease, multiple sclerosis (MS), the autoimmune stage of diabetes mellitus (juvenile- onset or type I diabetes), autoimmune uveoretinitis (AUR).