SE2050286A1 - Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof - Google Patents

Abstract

A substance comprising a carrier exhibiting at least one scavenger structure,said scavenger structure comprising a nucleophilic centre complying with the formula X1(-R”-)(-R’)mHn (formula I)whereina) X1 is a single-bonded heteroatom selected amongst N, O and S and exhibits a free electron pair,b) m is 0 or 1 and n is 1 or 2 with the sum of m plus n being 2 for X1 = N and 1 for X1 = S and O,c) -R”- is a bivalent organic group providing attachment to the carrier via one of its free valences and direct attachment to the heteroatom X1 at the other one of its free valences, andd) R’- is a monovalent organic group directly attached to the heteroatom X1 via its free valencefor use as a medicament for blocking or inhibiting semicarbazide sensitive amine oxidase (SSAO), preferably blocking or inhibiting SSAO expressed and produced by vascular smooth muscle cells and/or endothelial cells and/or soluble SSAO.

Description

USE OF SUBSTANCE AND PHARMACEUTICAL COMPOSITION THEREOF,AND MEDICAL TREATMENTS OR USES THEREOF TECHNICAL FIELD The present invention relates to the use of a pharrnaceutical composition comprising asubstance for prevention and treatment, as Well as a method of prevention and treatmentpulmonary inflammation diabetes-related complications comprising administering said pharrnaceutical composition.

BACKGROUND TECHNOLOGY Semicarbize amine oxidase (SSAO or VAP-1) is an enzyme expressed for example byendothelial cells and smooth muscle cells in blood vessels. SSAO is norrnally found inintracellular granulae. The enzyme translocates to the cell membrane upon activation andcan be solubilized by proteolytic cleavage from the membrane. SSAO exerts dualfunctions including leukocyte recruitment and also functions as ectoenzyme by theoxidation and conversion of primary amines to aldehydes, hydrogen peroxide and ammonium.

There are SSAO inhibitors but some have shown to be toxic or are not very efficient.

In WO 2009108100, inter alia carbazate-functionalized polyvinyl alcohol (PVAC) andrelated substances Was used to treat inflammatory conditions caused by various antigens.The inventors later discovered that the same substances had an antibacterial effect in thatthey affected the adhesion of the bacteria to surfaces and/or the growth of the bacteria.Thus, the substances may thus also be used to prevent and treat bacterial-induced infection.

SUMMARY oF THE INVENTIONThe aim of the present invention is to provide an efficient medicament and method ofblocking or inhibiting SSAO and thereby preventing and/or treating complications caused by the expression of SSAO.

In a first aspect the present invention relates to a substance according to claim 1.

In a second aspect the present invention relates to a pharrnaceutical compositioncomprising the substance according to the present invention and pharrnaceuticallyacceptable adjuvants for use as a medicament for blocking or inhibiting semicarbazidesensitive amine oxidase (SSAO), preferably blocking or inhibiting SSAO expressed andproduced by smooth muscle cells and/or endothelial cells in blood vessels and/or soluble SSAO.

In a third aspect the present invention relates to a method blocking or inhibiting SSAOpreferably expressed by smooth muscle cells and/or endothelial cells in blood vesselsand/or soluble SSAO in a subject in need thereof comprising administering a first dose ordosage of the substance according to the present invention or administering a first dose or dosage of the pharrnaceutical composition according to the present invention.

A fourth aspect of the present invention relates to the use of the substance or thepharrnaceutical composition according to the present invention as an immunomodulating agent or an immunomodulating composition.

All embodiments disclosed herein are applicable to all aspects unless stated otherwise.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 graph illustrating the effect of the substance of the present invention.

DETAILED DESCRIPTION OF THE INVENTIONThe present disclosure is generally directed to substance or composition for used in ormethods of preventing and treating complications associated With diabetes and pulmonary inflammation.

Definitions:"Administration" or "administering", as used herein, refers to providing, contacting,and/or delivering a compound or compounds by any appropriate route to achieve the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular,intraarterial, intrasynovial, intrastemal, intrathecal, intralesional or intracranial injection),transderrnal, topical, buccal, rectal, vaginal, nasal, ophthalmic, via inhalation, and implants.

"Co-administered", as used herein, refers to simultaneous or sequential administration ofmultiple compounds or agents. A first compound or agent may be administered before,concurrently With, or after administration of a second compound or agent. The firstcompound or agent and the second compound or agent may be simultaneously orsequentially administered on the same day, or may be sequentially administered Within 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 Week, 2 Weeks, 3 Weeks or one month ofeach other. Suitably, compounds or agents are co-administered during the period in Whicheach of the compounds or agents are exerting at least some physiological effect and/or has remaining eff1cacy.

"Contacting", as used herein as in "contacting a cell," refers to contacting a cell directly orindirectly in vitro, ex vivo, or in vivo (i.e. Within a subject, such as a mammal, includinghumans, mice, rats, rabbits, cats, and dogs). Contacting a cell, Which also includes"reacting" a cell, can occur as a result of administration to a subject. Contactingencompasses administration to a cell, tissue, mammal, subject, patient, or human. Further,contacting a cell includes adding an agent to a cell culture. Other suitable methods mayinclude introducing or administering an agent to a cell, tissue, mammal, subject, or patient using appropriate procedures and routes of administration as defined herein.

"Effective amount", as used herein, refers to a dosage of compounds or compositionseffective for eliciting a desired effect. This term as used herein may also refer to anamount effective at bringing about a desired in vivo effect in an animal, mammal, or human, such as reducing proliferation of a cancer cell or treating cancer.

"Pharmaceutically acceptable", as used herein, pertains to compounds, materials,compositions, and/or dosage forms Which are, Within the scope of sound medicaljudgment, suitable for use in contact With the tissues of a subject (e.g. human) Without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must alsobe "acceptable" in the sense of being compatible with the other ingredients of the forrnulation.

"Subj ect", as used herein, is intended to include human and non-human animals. Inembodiments, the subject is a human. Exemplary human subj ects include a human patienthaving a disorder, e.g., cancer. The term "non-human animals" includes all vertebrates,eg., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals (such as sheep, dogs, cats, cows, pigs, etc.), and rodents (such as mice, rats, hamsters, guinea pigs, etc.).

"Susceptibility," as used herein regarding a cancer cell, refers to the degree to which acancer cell is affected by a chemotherapeutic agent. The cancer cell may not be affectedat all, it may have its growth or proliferation slowed or halted without its being killed, orit may be killed. Susceptibility also refers to the degree a population of cancer cells, suchas a tumour, is affected by a chemotherapeutic agent. "Increasing the susceptibility" of acancer cell to a chemotherapeutic following contact or treatment with an agent, e.g., aninhibitor of an enzyme or an inhibitor of a protein-protein interaction, indicates that thecell is more affected by the chemotherapeutic agent than a corresponding cancer cell that has not been exposed to the agent.

"Treat" or "treating", as used herein, the term a subject having a disorder refers toadministering a regimen to the subject, e. g., the administration of a platinum-basedtherapeutic and/or another agent, such that at least one symptom of the disorder is healed,alleviated, relieved, altered, remedied, ameliorated, or improved. Treating includesadministering an amount effective to alleviate, relieve, alter, remedy, ameliorate, improveor affect the disorder or the symptoms of the disorder. The treatment may inhibit deterioration or worsening of a symptom of a disorder.

The present inventors have surprisingly found that administration of the present substanceor the present pharrnaceutical composition has an inhibitory effect on SSAO. As shown inthe examples (Example 2) the present substance block or inhibit SSAO and thereby the complications caused by the expression of SSAO may be prevented, inhibited or treated (Treatment of retinopathy, Example 3). The present Substance has also a treating effectfor diabetes related complications such as retinopathy (Example 3). Hence by presentingsupporting data (Example 3) in combination With a confirrned mechanism (Inhibition ofSSA, Example 2) it is evident that the present invention relates to a substance,composition and method Which may be used to prevent or treat any SSAO related condition or complication.

SSAO is an enzyme found in for example in endothelial cells and smooth muscle cells forexample in blood vessels and is believed to be involved in the cause or progression of forexample diabetes related complications, congestive heart failure, neuropathy,nephropathy, retinopathy, acute respiratory distress syndrome (ARDS), vascular damage, carotid plaque and varicosities.

Also, as compared to smaller agents, the molecular size of the substance according to thepresent invention effect pharmacokinetic and distribution prof1les in a Way that may beadvantageous for certain indications Where a prolonged and directed effect is needed.

Other potential benefits include excellent in vivo tolerance and low manufacturing costs.

First main aspect- A substance for use as a medicament A substance comprising a carrier Which exhibits a plurality of a scavenger structure, saidscavenger structure comprising a nucleophilic centre complying With the forrnulaX1(-R° °-)(-R°)mHn (forrnula I) Wherein a) X1 is a single-bonded heteroatom selected amongst N, O and S and exhibits a freeelectron pair, b) m is 0 or l and n is l or 2 With the sum ofm plus n being 2 for X1 = N and l for X1 = Sand O, c)-R° ”-is a bivalent organic group providing attachment to the carrier via one of its freevalences and direct attachment to the heteroatom X1 at the other one of its free valences,and d) R°-is a monovalent organic group directly attached to the heteroatom X1 via its freevalence for use as a medicament for blocking or inhibiting semicarbazide sensitive amine oxidase (SSAO), preferably blocking or inhibiting SSAO expressed and produced by vascular smooth muscle cells and endothelial cells and/or soluble SSAO.

The substance blocks or inhibits SSAO and thereby prevents or treats any indication orcomplication related to the expression of SSAO. As disclosed above a non-limiting list ofsuch indications or complications are diabetes related complications, neuropathy,nephropathy, retinopathy, pulmonary inflammation such as pneumonia, acute respiratorydistress syndrome (ARDS), vascular damage, carotid plaque and Varicosities. In oneembodiment the substance is used as a medicament for preventing or treating pulmonarysevere acute respiratory syndrome preferably as complication after viral infectionincluding CoVid-l9 infection and/or acute respiratory distress syndrome (ARDS). Inanother embodiment the substance is used as a medicament for preventing or treating congestive heart failure.

According to an embodiment of the present substance, either one or both of the organicgroups R”-and-R” ”-, With preference for -R” ”-, comprise a structure of the forrnula:-CH2(X4)0fl(C=X3)n=(X2)mfl- (forrnula II) Wherein a) each of m”, n” and o” is 0 or l, With preference for m” being l With further preferencefor either one or both of n” and o” also being l, b) each of X2 , X3, and X4, is selected amongst NH and a heteroatom S or O, Withpreference for either one or both of X2 and X4 being selected amongst NH and O Withfurther preference for X3 being selected amongst NH, O and S, c) the left free Valence provides binding to a monovalent alkyl group R* -or to the carriervia at least a bivalent alkylene group -R**-, each of Which two groups comprises themethylene group-CHz-shown in forrnula II, and d) the right free Valence binds directly to the first heteroatom X1.

The scavenger structure comprises a first nucleophilic centre Which preferably is capableof participating in an addition reaction With the carbonyl group (C=O) of an aldehydegroup, or a carbazide group-and/or With a C,C-multiple bond to Which one or more electron-WithdraWing substituents preferably are directly attached.

Preferred scavenger structures thus have a nucleophilic centre Which contain the firstheteroatom X1 together With a structure complying With forrnula II. According to oneembodiment of the present invention, the nucleophilic center is or is part of a groupselected amongst:a) amino groups preferably primary or secondary amino groupsb) hydrazide groups such as -NH-NHg, e.g. as part of a-CONHNH; group, asemicarbazide group such as-NHCONHNHQ, a carbazate group such as-OCONHNHz, a thiosemicarbazide group such as-NHCSNHNHQ, athiocarbazate group such as-OCSNHNH; (forrnation of hydrazone,semicarbazone, thiocarbazone linkages/ groups, etc When undergoingaddition/ elimination reactions With an aldehyde group)c) aminooxy groups, such as-ONHg, etc (forrnation oxime linkages/ groups, etcWhen undergoing addition/ elimination reactions With an aldehyde group),d) a thiol group e.g.-SH (Michael addition products are forrned When the thiolgroup reacts With a C,C-double bond. The product may undergo keto-enoltautomerisation When the double bond is ot,ß to a keto-or aldehyde-carbonyl, see above).

These scavenger structures are believed to be effective When it comes to binding or interact With SSAO and thereby blocking or inhibiting SSAO.

According to a still further embodiment of the substance, the carrier is a macromolecularcarrier and/or is Water-soluble or Water-insoluble and preferably exhibits polymerstructure. The carrier may be Water-insoluble and define a support and/or the substance isattached to a Water-insoluble support. In a preferred embodiment the carrier is a Water-soluble polymer preferably polyvinyl alcohol. By using a Water soluble carrier thesubstance is easier dissolved making it easier to prepare and it is also believed to increasethe efficiency of the substance When administered. Polyvinyl alcohol makes it also possible to provide several scavenger structures per carrier.

According to another embodiment, the substance has a scavenger structure capable ofundergoing an addition reaction With a carbonyl group of an aldehyde group, or a carbazide group and/or With a carbon-carbon multiple bond to Which is directly attached a carbonyl group, such as a semicarbazide group or an aldehyde group.

In one embodiment, the substance is carbazate-functionalized polyVinyl alcohol or a semicarbazide-functionalized polyVinyl alcohol.

The substance is preferably soluble in aqueous liquids such as water, body fluids, such asblood, serum, plasma, urine, lymph, lachrymal fluid, intestinal juice, gastric juice, saliVa, synovial fluid, etc.

The selection of suitable carriers depends on the requirements of a particular use. Thetypical carrier is selected amongst macromolecular compounds, i.e. is a compound whichhas a molecular weight of 2 2000 dalton, preferably 2 10000 dalton or 2 50000 dalton,and preferably exhibits a polymeric structure, i.e. is a polymer which may be ahomopolymer, copolymer or a chemical adduct between two or more polymers ofdifferent polymeric structure. In a preferred embodiment the carrier has a molecularweight of 10.000-30.000dalton. Other suitable carriers may have molecular weights S2000 dalton and exhibit polymeric structure as indicated by the possibility of the lownumbers of monomeric units discussed below, e.g. 2 20 and 5 100. The term “adductpolymer” in this context means a product formed by reacting two polymers exhibitingmutually groups capable of forrning coValent bonds that link the two polymers togetherupon reaction of the two mutually groups with each other. See for instance WO2009108100 (IPR-Systems AB) and references cited therein. Suitable macromolecularcarriers may thus be selected amongst synthetic polymers (= man-made polymers),biopolymers (nature-made polymers such as polysaccharides, polypeptides, proteins, etc)and biosynthetic polymers where “biosynthetic polymer” refers to a macromolecularcarrier or compound exhibiting both a synthetic polymeric structure and a biopolymeric structure.

The scaVenger structure including the first, the optional second nucleophilic centre andthe various heteroatoms discussed for the scavenger structures are typically part of oneand the same organic group/substituent attached to the macromolecular carrier. In certainvariants different parts of a scavenger structure may be part of different groups/substituents attached to the carrier and/or part of the carrier.

Sizes/molecular weights of suitable carrier polymers will among others depend on theactual application/use of the composition/method of the invention. Thus suitablepolymeric carriers with respect to a particular polymeric structure and/or size may varywithin a wide interval. Thus as a rule the number of monomeric subunits (mean value) ofa polymer present in the carrier may be 2 20 or 2 100 or 2 200 or 2 300 or 2 500 or 21000 or 2 2000 or 2 20 000 or 2 50 000 and/or S 50 000 or S 20 000 or S 2000 or S 1000or S 500 or S 300 or S 200, or S 100 (with the proviso that 2-limit always is lower than aS-limit when these values are combined to define intervals). Preferred numbers ofmonomeric units may in some cases be found in the interval of 200 - 600. In a preferredembodiment the carrier is a water soluble polymer, preferably polyvinyl alcohol, having a molecular weight of l0.000-30.000dalton.

Suitable numbers of scavenger structures or nucleophilic centres per monomeric unit of apolymer of the carrier will also depend on the use, the scavenger structure, etc, and maythus be found within a wide interval, such as S 80%, preferably S 50%, S40% or S 30%with lower limits being preferably 0.0l% or 0. 1% or 1% or 5% or 10% or 15% where100% corresponds to one scavenger structure or nucleophilic centre per monomeric unit.For scavenger structures containing two or more nucleophilic centres the number ofnucleophilic centres per monomeric unit may exceed 100%, such as 2 100% or 2 125% or2 150%. In a preferred embodiment the number of scavenger structures per carrier is 15- 50%, more preferably 20-40%.The substance according to the present invention may be synthesized according to well-known protocols, for instance of the kinds given in WO 2009108100 (IPR-Systems AB) and references cited therein which are hereby incorporated by reference.

All variants, embodiments and examples of the f1rst main aspect can be combined with the second and third main aspects unless expressly stated otherwise.

Second main aspect- Pharmaceutical composition According to a second aspect, there is provided a pharrnaceutical composition for use as a medicament in the prevention or treatment of diabetes related conditions or for use as a medicament for blocking or inhibiting SSAO, comprising the Substance according to the present invention and pharrnaceutically acceptable adjuvants.

The pharrnaceutical forrnulation or composition according to the present invention mayconveniently be presented in unit dosage forrn and may be prepared by any methodsknown in the art of pharrnacy. Such methods include the step of bringing into associationthe active compound(s) with the carrier which constitutes one or more accessoryingredients. In general, the forrnulations are prepared by uniforrnly and intimatelybringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary, shaping the product.

The pharrnaceutical composition may be in the form of liquids, solutions, suspensions,emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills,ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.

Pharmaceutical composition suitable for oral administration (e.g. by ingestion) may bepresented as discrete units such as capsules, cachets or tablets, each containing apredeterrnined amount of the active compound; as a powder or granules; as a solution orsuspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.

A tablet may be made by conventional means, e. g., compression or molding, optionallywith one or more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowing form such as apowder or granules, optionally mixed with one or more binders (e. g. povidone, gelatin,acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); f1llers or diluents (e. g.lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g.magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linkedpovidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing orwetting agents (e.g. sodium lauryl sulfate); and preservatives (e. g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be ftod soas to provide slow or controlled release of the active compound therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to provide the desiredrelease profile. Tablets may optionally be provided With an enteric coating, to provide release in parts of the gut other than the stomach.

Pharmaceutical composition suitable for parenteral administration (e. g. by injection,including cutaneous, subcutaneous, intramuscular, intravenous and intraderrnal), includeaqueous and nonaqueous isotonic, pyrogen-free, sterile injection solutions Which maycontain antioxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes Whichrender the forrnulation isotonic With the blood of the intended recipient; and aqueous andnon-aqueous sterile suspensions Which may include suspending agents and thickeningagents, and liposomes or other microparticulate systems Which are designed to target thecompound to blood components or one or more organs. Examples of suitable isotonicvehicles for use in such forrnulations include Sodium Chloride Injection, Ringer'sSolution, or Lactated Ringer's Injection. The forrnulations may be presented in unit-doseor multi-dose sealed containers, for example, ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of the sterile liquidcarrier, for example Water for inj ections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterile poWders, granules, andtablets. Forrnulations may be in the form of liposomes or other microparticulate systemsWhich are designed to target the active compound to blood components or one or more organs.

Pharmaceutical composition suitable for topical administration (e. g. transderrnal,intranasal, ocular, buccal, and sublingual) is preferably forrnulated as an ointment, cream,suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil. Altematively, aforrnulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated With active compounds and optionally one or more excipients or diluents.

Pharmaceutical composition suitable for topical administration in the mouth includelozenges comprising the active compound in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.

Pharrnaceutical composition suitable for topical administration to the eye also include eyedrops Wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

Pharrnaceutical composition suitable for nasal administration, Wherein the carrier is asolid, include a coarse powder having a particle size, for example, in the range of about20 to about 500 microns Which is administered in the manner in Which snuff is taken, i.e.by rapid inhalation through the nasal passage from a container of the poWder held closeup to the nose. Suitable forrnulations Wherein the carrier is a liquid for administration as,for example, nasal spray, nasal drops, or by aerosol administration by nebulizer, include aqueous or oily solutions of the active compound.

Pharrnaceutical composition suitable for administration by inhalation include thosepresented as an aerosol spray from a pressurized pack, With the use of a suitablepropellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases. Further forrnulations suitablefor inhalation include those presented as a nebulizer. In one embodiment the composition is suitable for administration done by inhalation including the use of a nebulizer.

Pharrnaceutical composition suitable for topical administration via the skin includeointments, creams, and emulsions. When forrnulated in an ointment, the active compoundmay optionally be employed With either a paraff1nic or a Water-miscible ointment base.Altematively, the active compounds may be forrnulated in a cream With an oil-in-Watercream base. If desired, the aqueous phase of the cream base may include, for example, atleast about 30% W/W of a polyhydric alcohol, i.e., an alcohol having tWo or morehydroxyl groups such as propylene glycol, butane-l,3-diol, mannitol, sorbitol, glyceroland polyethylene glycol and mixtures thereof. The topical forrnulations may desirablyinclude a compound Which enhances absorption or penetration of the active compoundthrough the skin or other affected areas. Examples of such derrnal penetration enhancers include dimethylsulfoxide and related analogues.

When forrnulated as a topical emulsion, the oily phase may optionally comprise merelyan emulsifier (otherwise knoWn as an emulgent), or it may comprise a mixture of at leastone emulsifier With a fat or an oil or With both a fat and an oil. Preferably, a hydrophilicemulsifier is included together With a lipophilic emulsifier Which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, the emulsif1er(s) With or Withoutstabilizer(s) make up the so-called emulsifying Wax, and the Wax together With the oiland/or fat make up the so-called emulsifying ointment base Which forrns the oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilizers include TWeen 60, Span 80, cetostearylalcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice ofsuitable oils or fats for the formulation is based on achieving the desired cosmeticproperties, since the solubility of the active compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus, the cream shouldpreferably be a non-greasy, non-staining and Washable product With suitable consistencyto avoid leakage from tubes or other containers. Straight or branched chain, mono-ordibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters knoWn as Crodamol CAP maybe used, the last three being preferred esters. These may be used alone or in combinationdepending on the properties required. Altematively, high melting point lipids such as White soft paraffin and/or liquid paraffin or other mineral oils can be used.

Pharmaceutical composition suitable for rectal administration may be presented as a suppository With a suitable base comprising, for example, cocoa butter or a salicylate.

Pharmaceutical composition suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are knoWn in the art to be appropriate.

In one embodiment the substance is as a pharrnaceutical composition in Which the substance is: a) in dry form, for instance as free particles,b) in dissolved form, typically in an aqueous liquid medium, orc) in suspended/dispersed form, i.e. as Water-insoluble particles suspended in an aqueous liquid medium.

The term “dissolved” in this context means that the substance is present as a solute. Thesubstance particles comprise substance in a pure form or diluted With some solid material.Useful concentrations of the substance in forrnulations according to (b) can be found Within a broad interval.

The composition may in addition to the substance contain buffers, salts, etc required forenabling acceptable conditions in vívo for the patient and for the reaction of the substanceWith the cancer. These constituents may be co-forrnulated With the substance in pharrnaceutical composition.

In one embodiment the pharrnaceutical composition is suitable for parenteral administration, preferably for intravenous administration.

In one embodiment the concentration of the substance in the pharrnaceutical compositionaccording to the present invention is 20-500 ug/ml, preferably 30-150ug/ml, morepreferably 40-120ug/ml.

All variants, embodiments and examples of the second main aspect can be combined With the first and third main aspects unless expressly stated otherwise.

Third main aspect- Method of blocking or inhibiting semicarbazide sensitive amine oxidase 1 SSAO)This aspect relates to a method of blocking or inhibiting SSAO by using the present substance or pharrnaceutical composition (defined above under the first and second mainaspects) Which may be done for prevention or treatment of diabetes relatedcomplications, congestive heart failure, pulmonary inflammation, vascular damage, carotid plaque and varicosities.

The Substance or the pharrnaceutical composition disclosed herein is administered to asubject or a patient in need thereof. The patient may be an animal or a human. Theadministration Ways or routes may vary according to the specific cancer or medical situation and are part of the knowledge of a medical practitioner.

The administration of the first dose may be done locally or systemically or incombination. Preferred administration of the first dose is as disclosed above. Consideringthat SSAO is found in the blood vessels the preferred administration is intraVenousadministration. For the treatment of diabetes related conditions a preferred Way of administration is subcutaneous since that is a common administration of insulin.

In a preferred embodiment the administration is done by parenteral administrationpreferably intraVenous injection, intramuscular or subcutaneous injection. Example 3shows the effect of improving the eyesight after parenteral administration (subcutaneous) of the present substance.

In another preferred embodiment the administration is done by oral administration.

In another preferred embodiment the administration is done by inhalation including theuse of a nebulizer. This is specifically preferred for subj ects suffering from pulmonaryinflammation, pulmonary severe acute respiratory syndrome (SARS) preferably as complication after Viral infection including CoVid-19 infection and/or acute respiratory distress syndrome (ARDS).

In one embodiment the first dose or dosage is 0.005 to l5mg/kg Weight of the subject,preferably 0.05 to 5mg/kg Weight of the subject, more preferably 0.5 to 3 mg/kg Weight ofthe subject. In another embodiment the first dose or dosage is administrated 1-3 times/7days, preferably 1-2 times/7 days, more preferably 1 times/7days. A second dose ordosage is preferably 0.005 to l5mg/kg Weight of the subject, preferably 0.05 to 5mg/kgWeight of the subject, more preferably 0.5 to 3 mg/kg Weight of the subject. In oneembodiment the second dose or dosage is the same as the first dose or dosage. The seconddose or dosage is administrated after a first treatment time of the first dose or dosage. The first treatment time is preferably 7 days or longer, or 14 days or longer.

As seen in Example 2 the present Substance (PVAC) Was highly efficient and doses below20 ug/ml serum are predicted to by suitable in an vivo situation Which corresponds to a dose of 60 mg in adult patient.

In one embodiment the subject suffers from acute pulmonary inflammation and Whereinthe first dose or dosage is administrated 1-3 times/1 day, preferably 1 times/1 day during1-7 days or preferably until respiratory improvement occurs, Where after a first dose or dosage is administrated 1-2 times/7 days.

The substance blocks or inhibits SSAO and thereby prevents or treats any indication orcomplication related to the expression of SSAO. As disclosed above a non-limiting list ofsuch indications or complications are diabetes related complications, neuropathy,nephropathy, retinopathy, pulmonary inflammation such as pneumonia, acute respiratorydistress syndrome (ARDS), vascular damage, carotid plaque and varicosities. In oneembodiment the method is for preventing or treating pulmonary severe acute respiratorysyndrome preferably as complication after viral infection including Covid-19 infectionand/or acute respiratory distress syndrome (ARDS). In one embodiment the method is oris part of an immunotherapy. In another embodiment the method is for preventing or treating congestive heart failure.

All variants, embodiments and examples of the third main aspect can be combined With the first and second main aspects unless expressly stated otherwise.

Fourth main aspect- Use as an immunomodulating agent or composition As described above the present substance or pharrnaceutical composition may be used as an immunomodulating agent or composition.

This may be done by administrating the substance or composition as disclosed herein.Preferably the use is done by administrating a first dose locally or systemically or incombination. Preferred administration of the first dose is as disclosed above. Consideringthat SSAO is found in the blood vessels the preferred administration is intravenous administration. For the treatment of diabetes related conditions a preferred Way of administration is subcutaneous since that is a common administration of insulin.

In one embodiment the first dose is 0.005 to 15mg/kg Weight of the subject, preferably0.05 to 5mg/kg Weight of the subject, more preferably 0,5 to 3 mg/kg Weight of thesubject. In another embodiment the administration is done 2-3 times/7 days, preferably 2 times/7 days.

The substance blocks or inhibits SSAO and thereby prevents or treats any indication orcomplication related to the expression of SSAO. As disclosed above a non-limiting list ofsuch indications or complications diabetes related complications, neuropathy,nephropathy, retinopathy, pulmonary inflammation such as pneumonia, acute respiratory distress syndrome (ARDS), vascular damage, carotid plaque and varicosities.

All variants, embodiments and examples of the third main aspect can be combined With the first and second main aspects unless expressly stated otherwise.

DosagesIt Will be appreciated that appropriate doses and dosages of the active compounds, andcompositions comprising the active compounds, can vary from patient to patient. All dosages disclosed here below are applicable to all aspects disclosed herein.1 Determining the optimal dosage Will generally involve the balancing of the level oftherapeutic benefit against any risk or deleterious side effects of the treatments describedherein. The selected dosage level Will depend on a variety of factors including, but notlimited to, the activity of the particular compound, the route of administration, the time ofadministration, the rate of excretion of the compound, the duration of the treatment, otherdrugs, compounds, and/or materials used in combination, and the age, sex, Weight,condition, general health, and prior medical history of the patient. The amount ofcompound and route of administration Will ultimately be at the discretion of thephysician, although generally the dosage Will be to achieve local concentrations at the siteof action Which achieve the desired effect Without causing substantial harrnful or deleterious side-effects.

Administration in vivo can be affected in one dose, continuously or interrnittently (e. g. individed doses at appropriate intervals) throughout the course of treatment. Methods ofdeterrnining the most effective means and dosage of administration are well known tothose of skill in the art and will vary with the forrnulation used for therapy, the purpose ofthe therapy, the target cell being treated, and the subject being treated. Single or multipleadministrations can be carried out with the dose level and pattem being selected by the treating physician.

A suitable dose or dosage of the substance is in the range of about 0.005-15mg/kg weightof the subject, preferably 0.05 to 5mg/kg weight of the subject, more preferably 0.5 to 3mg/kg weight of the subject. During a course of a week or seven days an amount of 50-140mg may be administered to the subject. Preferably the dosing or administration shouldbe done 2-3 times/7days, preferably 1-2 times/7 days in order to avoid accumulation of the substance in the subject.

When forrnulating the pharrnaceutical compositions described herein, the clinician mayutilize preferred dosages as warranted by the condition of the subject being treated. Forexample, in one embodiment, the substance according to the invention may beadministered at a dosing schedule described herein, e.g., once every one, two, three, four, five, six or seven days.

Also, in general, the substance according to the invention and an optional additionalchemotherapeutic agent(s) or other agents do not have to be administered in the samepharrnaceutical composition, and may, because of different physical and chemicalcharacteristics, have to be administered by different routes. The deterrnination of themode of administration and the advisability of administration, where possible, in the samepharrnaceutical composition, is well within the knowledge of the skilled clinician. Theinitial administration can be made according to established protocols known in the art,and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

The actual dosages of the compounds employed may be varied depending upon the requirements of the subject and the severity of the condition being treated. Deterrnination of the proper dosage for a particular situation is Within the skill of the art. Generally,treatment is initiated With smaller dosages Which are less than the optimum dose of thecompound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached.

Diabetes related complicationsThe substance and the composition according to the present invention may be used to prevent or treat complications caused by or related to diabetes.

Insulin tend to increase the expression of SSAO Which is believed to be one of thereasons for some of the complications seen in diabetes patients. Without being bound bytheory the substance according to the present invention is believed to bind to and therebyblock or inhibit SSAO Which then preVents, limits or treats the complication relating tothe expression of SSAO.

A non-limiting list of diabetes related complications that can be preVented or treated are Vascular damage, neuropathy, nephropathy and retinopathy.

EXPERIMENTAL PART EXAMPLE 1 - SYNTHESIS OF CARBAZATE-FUNCTIONALIZED POLYVINYL ALCOHOL(PVAC) Polyvinyl alcohol (5 g, 13-23 kDa) Was dissolved in dimethyl sulfoxide (100 mL) Whilestirring for 1 hour at 80°C under argon gas. Carbonyl diimidazole (10 g) Was added andstirring continued at room temperature oVemight. Hydrazine hydrate (10 mL) Was thenadded, the reaction stirred ovemight, and the product collected and purified by repeatedprecipitation in ethanol. The degree of substitution Was deterrninedspectrophotometrically by performing a trinitrobenzene sulfonic acid assay describedelseWhere (Stephen L. Snyder and Philip Z. Sobocinski; Analytical Biochemistry 64, 284-288, 1975).

EXAMPLE 2 - INHIBITION oF SSAOA study performed by the use of Fluoro:SSAO kit (Cell Technology Inc.USA) Was conducted according to instructions. Two different doses of PVAC Were applied; 20 ug/ml and 80 ug/ml. The inhibitory effect, as assessed by the measurement of hydrogenperoxide-conjugated chromophore, was dose dependent showing an approximately 80 %reduction of enzyme activity with 20 ug/ml and 90 % reduction with 80 ug/mL PVAC.Thus, the PVAC effect was highly efficient and doses below 20 ug/ml serum arepredicted to be suitable in an in Vivo situation (corresponding to a dose of 60 mg in adult p ati ent) .

EXAMPLE 3 - TREATMENT OF RETINOPATHYA single subcutaneous PVAC injection of 2 mg PVAC resulted in improved clear eyeVision in human subject with body weight 80 kg. The effect was apparent after a few days and lasted for l-2 weeks.

Claims (1)

CLAIMS A Substance comprising a carrier exhibiting at least one scavenger structure, said scavenger structure comprising a nucleophilic centre complying With the forrnulaX1(-R° °-)(-R”)mHn (forrnula I) Wherein a) X1 is a single-bonded heteroatom selected amongst N, O and S and exhibits a freeelectron pair, b) m is 0 or 1 and n is 1 or 2 With the sum ofm plus n being 2 for X1 = N and 1 forX1 = S and O, c) -R° ”- is a bivalent organic group providing attachment to the carrier Via one of itsfree Valences and direct attachment to the heteroatom X1 at the other one of its freeValences, and d) R°- is a monovalent organic group directly attached to the heteroatom X1 Via itsfree Valence; for use as a medicament for blocking or inhibiting semicarbazide sensitive amine oxidase (SSAO), preferably blocking or inhibiting SSAO expressed and produced by vascular smooth muscle cells and/or endothelial cells and/or soluble SSAO. The substance according to claim 1 Wherein the medicament is for blocking or inhibiting SSAO for preVenting or treating diabetes related complications. The substance according to claim 1 or 2 Wherein that the nucleophilic center is or ispart of a group selected amongsta) amino groups, preferably primary or secondary amino groups,b) hydrazide groups, a semicarbazide group, a carbazate group, a thiosemicarbazidegroup, a thiocarbazate group,c) aminooxy groups, and d) thiol groups. The substance according to any of the preceding claims, Wherein that the carrier is a Water-soluble polymer, preferably polyVinyl alcohol. The Substance according to claim any of the preceding claims, Wherein that thesubstance is carbazate-functionalized polyVinyl alcohol or semicarbazide functionalized polyVinyl alcohol. The substance according to any one of claims 1 to 5 Wherein the carrier is a polymerand Wherein the number of scavengers per monomeric unit of the carrier is 15-5 0%, preferably 20-40%. The substance according to any one of claims 1 to 5 Wherein the carrier is a polymerhaving a molecular Weight of 2.000 dalton or higher, preferably 10.000 dalton orhigher, more preferably 10.000 to 30.000 dalton. The substance according to claim 2 Wherein the diabetes related complication is selected from neuropathy, nephropathy and retinopathy. The substance according to claim 1 Wherein the blocking or inhibition of SSAO isused for preVenting or treating congestiVe heart failure, neuropathy, nephropathy and retinopathy. The substance according to claim 1 Wherein the blocking or inhibition of SSAO isused for preventing or treating pulmonary inflammation, pulmonary severe acuterespiratory syndrome preferably as complication after Viral infection including CoVid-19 infection and/or acute respiratory distress syndrome (ARDS). The substance according to claim 1 Wherein the blocking or inhibition of SSAO is used for preventing or treating vascular damage, carotid plaque and varicosities. A pharrnaceutical composition comprising the substance defined in any of claims 1-11 and pharrnaceutically acceptable adjuvants for use as a medicament for blockingor inhibiting semicarbazide sensitive amine oxidase (SSAO), preferably blocking orinhibiting SSAO expressed and produced by smooth muscle cells and/or endothelialcells in blood vessels and/or soluble SSAO. The pharrnaceutical composition according to claim 12 Wherein the medicament for blocking or inhibiting SSAO is used for treating diabetes related complications. The composition according to claim 12 or 13 Wherein the composition is suitable forparenteral administration preferably intraVenous administration or subcutaneous administration. The composition according to claim 12 or 13 Wherein the composition is suitable for oral administration. The composition according to any one of claim 12 to 15, Wherein the concentrationof the substance is 20-500 ug/ml, preferably 30-150 ug/ml, more preferably 40-120 ug/ml. The composition according to any one of claim 12 to 15, Wherein the concentrationof the substance is 20-500 ug/mg, preferably 30-150 ug/mg, more preferably 40-120 ug/mg. The composition according to claim 13, Wherein the diabetes related complication is selected from neuropathy, nephropathy and retinopathy. The composition according to claim 12 Wherein the blocking or inhibition of SSAOis used for preVenting or treating congestiVe heart failure, neuropathy, nephropathy and retinopathy. The composition according to claim 12 Wherein the blocking or inhibition of SSAOis used for preventing or treating pulmonary inflammation, pulmonary severe acuterespiratory syndrome (SARS) as complication after Viral infection including Covid- 19 infection and/or acute respiratory distress syndrome (ARDS). A method of blocking or inhibiting SSAO preferably expressed by smooth musclecells and/or endothelial cells in blood vessels and/or soluble SSAO in a subject inneed thereof comprising administering a first dose or dosage of the substanceaccording to anyone of claims 1-9 or administering a first dose or dosage of the pharrnaceutical composition according to anyone of claims 10-17 to the subject. The method according to claim 21 Wherein the medicament for blocking or inhibiting semicarbazide sensitive amine (SSAO) is used for preventing or treating diabetesrelated complications or for preventing or treating congestive heart failure,neuropathy, nephropathy and retinopathy, Wherein the diabetes related complication is preferably selected from neuropathy, nephropathy and retinopathy. The method according to claim 21 Wherein the blocking or inhibition of SSAO isused for preventing or treating vascular damage, carotid plaque, Varicosities,neuropathy, nephropathy, retinopathy, pulmonary inflammation or pulmonary severeacute respiratory syndrome (SARS) preferably as complication after Viral infection including CoVid-19 infection and/or acute respiratory distress syndrome (ARDS). The method according to any one of claim 21 to 23, Wherein the first dose or dosageis 0.005 to 15mg/kg Weight of the subject, preferably 0.05 to 5mg/kg Weight of thesubject, more preferably 0.5 to 3 mg/kg Weight of the subject. The method according to any one of claim 21 to 24 Wherein the administration isdone by parenteral administration preferably intraVenous injection, intramuscular or subcutaneous injection. The method according to any one of claim 21 to 25 Wherein the administration is done by oral administration. The method according to any one of claim 21 to 26 Wherein the administration is done by inhalation including the use of a nebulizer. The method according to claim 27 Wherein the subject suffers from pulmonaryinflammation, pulmonary severe acute respiratory syndrome (SARS) preferably ascomplication after Viral infection including CoVid-19 infection and/or acute respiratory distress syndrome (ARDS). The method according to any one of claim 21 to 28 Wherein the first dose or dosage is administrated 1-3 times/7 days, preferably 1 times/7 days. The method according to any one of claim 21 to 28 Wherein the subject suffers from acute pulmonary inflammation and Wherein the first dose or dosage is administrated

1. -3 times/ 1 day, preferably 1 times/ 1 day during 1-7 days or preferably untilrespiratory improvement occurs, Where after administrating a first dose or dosage 1-2 times/7 days. The method according to any one of c1aims 18 to 24 Wherein the method is or is part of an immunotherapy. Use of the substance according to any one of c1aim 1 to 11 or the compositionaccording to any one of c1aim 12 to 20 as an immunomodulating agent or an immunomodulating composition.