Patent Application
20230227600
The present invention relates to polyphosphazenes, polyurethanes based on these polyphosphazenes, methods for their manufacture and hydrogels based on the polyurethanes. The invention further relates to the use of the hydrogels in medical, veterinary and agricultural applications.
Poly(organo)phosphazenes are a family of inorganic molecular hybrid polymers with very diverse properties. The article “Preparation of polyphosphazenes: a tutorial review” by S. Rothemund and I. Teasdale, Chem. Soc. Rev., 2016, 45, 5200 gives an overview over the field.
WO 2013/190260 A2 discloses substituted poly(phosphazene) compounds comprising a combination of units having one or more of the structures (i) to (iii)
wherein: the combination comprises R1 and R2; each R1, is independently an optionally substituted alkyl- or alkyl ether-based side chain containing an isocyanate-reactive moiety, an epoxide- reactive moiety, an amine-reactive moiety, a supramolecular noncovalent bonding moiety, or combinations thereof; and each R2 is independently an optionally substituted alkyl- or alkyl ether- based side chain containing nitro, nitramine, nitrate ester, azide, an ammonium compound moiety with energetic counter-ion, or combinations thereof. Methods of making the compounds are also described.
WO 2015/192158 A1 relates to a polymer for tissue engineering from biodegradable polyphosphazenes, having photopolymerizable side groups, wherein the side groups of the polyphosphazenes are formed exclusively from amino acids and/or amino acid derivatives, which are bonded to the backbone of the polyphosphazene via the amino group of the amino acid and to a spacer attached to the acid group with a carbon chain of length m, which has a vinyl group at the free end, wherein m=0 to m=10.
Hydrogels are crosslinked 3-D polymeric networks with high water and biological liquids uptake capacity. They can structurally resemble soft tissue or a cell of the body and hydrogels have a wide application area such as drug delivery systems, tissue engineering, and wound dressings. Among these biomedical applications, polyurethane-based hydrogels have been widely used in drug release applications owing to their good mechanical strength and easy applicability to drugs and they are suitable for drug encapsulation, transportation and release.
Despite their formal similarity to peptide bonds, the urethane groups in polyurethanes have been found challenging to biologically degrade. A polyurethane hydrogel with increased susceptibility to hydrolysis would therefore be desirable.
Accordingly, a polyphosphazene as described in claim 1 is provided. This polyphosphazene bears NCO-reactive hydrogen atoms and can be cross-linked with polyisocyanates; this is the subject of claim 8 and method claim 9. The method according to claim 7 concerns the synthesis of polyphosphazenes with NCO-reactive hydrogen atoms. Hydrogels obtained from such polyurethanes are the subject of claim 12. Their uses are covered in claims 14 and 15. Advantageous embodiments are the subject of the dependent claims. They may be combined freely unless the context clearly indicates otherwise.
A polyphosphazene according to the invention has the general formula (I):
Where each radical ZH is, independent of other radicals ZH, a group comprising an NCO-reactive hydrogen atom; each radical X is, independent of other radicals X, an organic rest;
each radical R1 is, independent of other radicals R1, hydrogen or an organic radical; each radical R is, independent of other radicals R, halogen, an organic radical or the radical group NR1—X—ZH and n is a positive integer.
The at least one radical X comprises one of the following groups: —B—CH2—CH2—, —Si—CH2—CH2— or —S—CH2—CH2—, wherein the —CH2—CH2— groups are located between the B, Si or S atoms and an N atom to which radicals R1 are bond. This structural feature can be created by addition of a molecule with a B—H, Si—H or S—H bond to a C═C double bond. In the case of an S—H bond this may be designated as a thiol-ene addition. The N atom to which radicals R1 are bond connects to a P atom of the polyphosphazene chain. Ultimately, the C═C double bond precursor group may be bond to the polyphosphazene chain before addition of the B/Si/S—H group containing compound.
Without wishing to be bound by theory it is believed that the polyphosphazenes according to the invention advantageously combines the reactivity with NCO groups to form polyurethanes and the possibility of hydrolytic cleavage to give a degradable or even bio-degradable polymer. Furthermore, such polyphosphazenes and polyurethanes may be useful in the formation of hydrogels. The hydrogels themselves may also be degradable by hydrolysis. The degradation may be such that after placing the hydrogel in a mechanical shaker and immersed in phosphate buffer (pH 7.4) at 37° C. for five weeks the weight of the hydrogel is ≥65% to ≤75% of the original weight.
The degree of polymerization may be such that the number n in formula (I) is ≥3 to ≤1000 and preferably ≥10 to ≤100.
As used herein, the term “NCO-reactive hydrogen atom” denotes a hydrogen atom in the molecule which is able to react with an isocyanate functional group. The most common NCO-reactive hydrogen atoms are those bond to nitrogen, oxygen or sulfur atoms.
In the individual radicals ZH the placeholder “Z” is meant to denote a heteroatom such as nitrogen, oxygen or sulfur to which the NCO-reactive hydrogen atom is bonded. “Z” is not meant to comprise further atoms which are part of the connection to the NR1 radical. These atoms would be grouped into “X”.
The individual radicals R1, in the event that they are an organic radical, may be branched or unbranched and may comprise substituted or unsubstituted alkylene groups and/or substituted or unsubstituted arylene groups. It is preferred that R1 is hydrogen. The introduction of the NR1 moiety may be achieved by synthetic pathways where an amide nucleophile substitutes a leaving group such as a chloride anion previously bond to the phosphorus atom.
The individual radicals R, in the event that they are an organic radical, may be branched or unbranched and may comprise substituted or unsubstituted alkylene groups and/or substituted or unsubstituted arylene groups. It is preferred that the individual radicals R are the radical group NR1—X—ZH.
The individual radicals R and R1 may comprise hydrophilic moieties such as polyether groups or ionically charged groups.
In one embodiment at least one radical ZH is a hydroxyl group, a primary amino group or a secondary amino group. Preferred are the cases where all radicals ZH are hydroxyl groups or all radicals ZH are aliphatic primary or secondary amino groups.
In another embodiment at least one radical X comprises one of the following groups: —(CH2)m, —B—, —(CH2)m, —Si—or —(CH2)m—S— with m being an integer from Ito 16, wherein the —(CH2)m, — groups are located between the B, Si or S atoms and a radical ZH. This structural feature can be created starting from a compound with a HZ—(CH2)m—B/Si/S—H moiety which is then added to the polyphosphazene chain bearing a C═C double bond. Preferred values for m are ≥2 to ≤10. Particularly preferred are groups derived from mercaptoalkanols with 2, 3, 4, 5 or 6 carbon atoms or groups derived from mercaptoalkaneamines with 2, 3, 4, 5 or 6 carbon atoms.
In another embodiment at least one radical X—ZH comprises the group —(CH2)m—C(═O)—O—(CH2)o—S—(CH2)p—OH or —(CH2)m—C(=O)—O—(CH2)m—S—(CH2)p—NH2 with m, o and p independently being an integer from 1 to 16. This structural feature in the general formula (I) may be created by the reaction of a mercaptoalkanol or mercaptoalkaneamine with an amino acid ester where the alcohol portion of the ester furthermore has a C═C double bond. Preferred values for m, o and p are, independent of each other, ≥2 to ≤10. Particularly preferred are groups derived from mercaptoalkanols or mercaptoalkaneamines with 2, 3, 4, 5 or 6 carbon atoms.
In another embodiment the radical group NR1—X comprises an ester of an α-amino acid as a structural unit. Preferred are glycine esters, alanine esters, valine esters, isoleucine esters, leucine esters, methionine esters and phenylalanine esters. A preferred alcohol moiety is the C3 moiety derived from allyl alcohol.
The present invention also concerns a method of manufacturing a polyphosphazene comprising the structural unit according to general formula (II), the method comprising reacting a C═C double bond-carrying compound comprising the structural unit of general formula (III) with an element-hydrogen bond-carrying compound according to general formula H—E—L—ZH:
where: each radical E is, independent of other radicals E, B, Si or S; each radical L is, independent of other radicals L, an organic radical; each radical ZH is, independent of other radicals ZH, a group comprising an NCO-reactive hydrogen atom; each radical R1 is, independent of other radicals R1, hydrogen or an organic radical; each radical R2 is, independent of other radicals R2, halogen, an organic radical or the radical group NR1—Y—; each radical Y is, independent of other radicals Y, an organic rest and n is a positive integer.
The target molecule (II) may be seen as a case of a polyphosphazene of formula (I) where the radical X is the group Y—CH2—CH2—E—L. The reaction of H—E—L—ZH with (III) may be described, depending on the nature of E, a hydroboration, hydrosilylation or thiol-ene addition.
Particularly preferred are mercaptoalkanols or mercaptoalkaneamines with 2, 3, 4, 5 or 6 carbon atoms as H—E—L—ZH.
The degree of polymerization may be such that the number n in formulae (II) and (III) is ≥3 to ≤1000 and preferably ≥10 to ≤100. The definitions and preferred embodiments for R correspond to those outlined in conjunction with formula (I) above and shall not be repeated in the interest of brevity. Likewise, the definitions of R2 are preferably the same as for R in conjunction with formula (I) above.
The radical Y is preferably comprises an ester group with the carbonyl C atom in α-position to the N atom bearing R1.
The reaction from (II) to (III) may take place under irradiation with UV light and/or in the presence of radical starters or catalysts if desired.
A polyurethane polymer can be obtained by reacting a polyphosphazene (I) according to the invention with a polyisocyanate. Preferably the polyphosphazene is of the structure (II). Examples for suitable polyisocyanates include methylene diphenyl diisocyanate (MDI), methylene dicyclohexyl diisocyanate (H12-MDI), polymeric MDI, toluylene diisocyanate (TDI), xylylene diisocyanate (XDI), pentamethylene diisocyanate (PDI), hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI) and a mixture comprising at least two of the aforementioned polyisocyanates. Further suitable polyisocyanates include the prepolymers, isocyanurates, iminooxadiazinediones, allophanates, biurets and uretdiones of the afore-mentioned polyisocyanates. The polyurethane polymer may include polyol-derived building blocks different from polyphosphazenes (I) such as polyether polyol or polyester polyol building blocks, if desired. The polymer may be unfoamed or foamed material.
A method of manufacturing a polyurethane polymer comprises reacting a polyphosphazene (I) according to the invention with a polyisocyanate. Preferably the polyphosphazene is of the structure (II). Reference is made to the polyisocyanates mentioned above. The reaction mixture comprising the polyphosphazene (I) and the polyisocyanate may furthermore include polyester polyols and/or polyether polyols. With respect to catalysts, tin-free catalysts are preferred, especially if the polyurethane is to be used in medical applications. The NCO index (molar ratio of NCO groups to NCO-reactive H-atoms) in the reaction mixture may, for example, be in a range of 90 to 110. If desired, chemical and/or physical blowing agents may be added to the reaction mixture. Mechanical frothing of the reaction mixture is also possible.
In the event that the polyphosphazene comprises hydrophilic moieties, an aqueous preparation of the polyphosphazene may be reacted with the polyisocyanate. This allows for the in situ formation of a hydrogel. Alternatively or additionally, an aqueous preparation of the polyisocyanate may be used. However, careful reaction timing would then be required owing to the reactivity of polyisocyanates with water.
In an embodiment of the polyurethane polymer or the method of its manufacture the polyisocyanate is an NCO-terminated prepolymer obtained by the reaction of a monomeric polyisocyanate and a polyether polyol. Polyether polyols are advantageous as their hydrophilicity facilitates the formation of hydrogels. Preferred are poly(oxyethylene) and poly(oxyethylene-co-propylene) polyols such as those obtained via double metal cyanide (DMC) catalysis. Particularly preferred are polyether polyols with ≥60 weight-% or ≥70 weight-% of ethylene oxide units, based on the total weight of the polyether polyol. Hydroxyl numbers (DIN 53240) of the polyol may be in the range of ≥20 mg KOH/g to ≤250 mg KOH/g, preferably ≥25 mg KOH/g to ≤50 mg KOH/g.
The polyol is preferably started on a short-chained polyalkylene oxide, for example on a glycerine-started poly(oxypropylene)triol with a hydroxyl number of ≥250 mg KOH/g to ≤400 mg KOH/g or a propylene glycol-started poly(oxypropylene)diol with a hydroxyl number of ≥200 mg KOH/g to ≤300 mg KOH/g.
With respect to the monomeric polyisocyanate, aliphatic diisocyanates such as pentamethylene diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, methylene dicyclohexyl diisocyanate and their isocyanurates, iminooxadiazinediones, allophanates, biurets and uretdiones are preferred. The NCO content of the prepolymer (DIN EN ISO 11909) may be in a range of ≥2% to ≤5%.
In another embodiment of the polyurethane polymer or the method of its manufacture the polyether polyol is a random copolymer of an alkylene oxide and a comonomer selected from: lactides, glycolides, cyclical dicarboxylic acid anhydrides and mixtures of at least two of the aforementioned compounds. These polyols have been found to be biodegradable owing to the incorporation of the comonomers. Details, including their synthesis, can be found in the published patent application WO 2013/092504 A1. It is preferred that the alkylene oxide is ethylene oxide and/or a mixture of ethylene oxide and propylene oxide. Hydroxyl numbers (DIN 53240) of the polyol may be in the range of ≥20 mg KOH/g to ≤250 mg KOH/g, preferably ≥25 mg KOH/g to ≤50 mg KOH/g.
The polyol is preferably started on a short-chained polyalkylene oxide, for example on a glycerine-started poly(oxypropylene)triol with a hydroxyl number of ≥250 mg KOH/g to ≤400 mg KOH/g or a propylene glycol-started poly(oxypropylene)diol with a hydroxyl number of ≥200 mg KOH/g to ≤300 mg KOH/g. The number average molecular weight of the polyol, as determined by gel permeation chromatography (THF as eluent, polystyrene standards), may be ≥200 g/mol to ≤10000 g/mol and preferably ≥1000 g/mol to ≤8000 g/mol.
The comonomer content may be ≥5 weight-% to ≤40 weight %, preferably ≥10 weight-% to ≤30 weight %, based on the total weight of the polyether polyol. The comonomers may be used in their monomeric, dimeric, trimeric or polymeric forms, for example as dilactide in the case of lactides.
A hydrogel can be obtained by contacting a polyphosphazene (I) according to the invention and/or a polyurethane according to the invention with water. This is easily achievable by immersing the polyphosphazene or polyurethane in water. The water may be buffered, for example to a pH of 7.4.
In an embodiment the hydrogel further comprises, distributed within the hydrogel, a pharmaceutical compound, a pesticide, a herbicide, a pheromone or a combination of at least two of the aforementioned compounds.
Suitable pharmaceutical compounds include:
1. Anti-infectives, such as antibiotics, including penicillin, tetracycline, chlortetracycline bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin; sulfonamides, including sulfacetamide, sulfamethazine, sulfadiazine, sulfamerazine, sulfamethizole and sulfisoxazole; antivirals, including idoxuridine; and other anti-infectives including nitrofurazone and sodium propionate.
2. Anti-allergenics such as antazoline, methapyrilene, chlorpheniramine, pyrilamine and prophenpyridamine.
3. Anti-inflammatories such as hydrocortisone, cortisone, dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 21-phosphate, and prednisolone acetate.
4. Decongestants such as phenylephrine, naphazoline, and tetrahydrazoline.
5. Miotics and antichlolinesterases such as pilocarpine, eserine salicylate, carbachol, di-isopropyl fluorophosphate, phospholine iodide, demecarium bromide, physostigmin and neostigmin.
6. Mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine.
7. Sympathomimetics such as epinephrine.
8. Neuroleptics such as reserpine and chlorpromazine.
9. Estrogens such as estrone, 17β-estradiol, ethinyl estradiol, and diethyl stilbesterol.
10. Progestational agents such as progesterone, 19-norprogesterone, norethindrone, megestrol, melengestrol, chlormadinone, ethisterone, medroxyprogesterone, norethynodrel and 17α-hydroxy-progesterone.
11. Humoral agents such as the prostaglandins, for example, PGE1, PGE2, and PGF2.
12. Antipyretics such as ibuprofen, acetylsalicylic acid, sodium salicylate, and salicylamide.
13. Antispasmodics such as atropine, methantheline, papaverine, and methscopolamine bromide.
14. Cardioactive agents such as benzydroflumethiazide, flumethiazide, chlorothiazide, and aminotrate.
One type of preferred pharmaceutical compounds is a progestogen or a drug having a progestogenic activity. In particular the compound may be selected from the group of progesterone and its derivatives, cyproterone acetate, desogestrel, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone acetate, norethisterone, norethisterone acetate, norgestimate, drospirenone, gestodene, 19-nor-17-hydroxy progesterone esters, 17α-ethinyltestosterone and derivatives thereof, 17α-ethinyl-19-nor-testosterone and derivatives thereof, ethynodiol diacetate, dydrogesterone, norethynodrel, allylestrenol, medrogestone, norgestrienone, ethisterone, dl-norgestrel or a mixture of at least two of the aforementioned compounds.
Another type of preferred pharmaceutical compound is a drug capable of preventing or suppressing endometrial bleeding. In particular the compound may be selected from the group of prostaglandin synthesis inhibitors, NSAIDs, inhibitors of leukotriene, oxytocin antagonists, pancreatic trypsin inhibitors, COX-inhibitors, antifibrinolytic drugs, estrogens, antiestrogens, aromatase inhibitors, cytokine inhibitors, glucocorticoids, progestogens with pronounced glucocorticoid acticity, danazol, gestrinone, angiogenesis inhibitors or a mixture of at least two of the aforementioned compounds.
It is possible to combine the progestogen or a drug having a progestogenic activity with the drug capable of preventing or suppressing endometrial bleeding. Particularly preferred is the combination of levonorgestrel with tranexamic acid, mefenamic acid, danazol or an angiogenesis inhibitor. This is useful in an intrauterine device.
Another type of preferred pharmaceutical compound is a calcium channel blocker, in particular nimodipine or nifedipine.
Another type of preferred pharmaceutical compound is a cytostatic agent such as cisplatin, rituximab, bevacizumab, trastuzumab, imatinib, lenalidomide, pemetrexed, bortezomib, cetuximab, leuprolein or abiraterone.
Lastly, opioid analgetics and non-opioid analgetics are also a type of preferred pharmaceutical compound.
The pharmaceutical compounds (drugs) can be in different forms, such as uncharged molecules, components of molecular complexes, or non-irritating, pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, etc. For acidic drugs, salts of metals, amines, or organic cations (e.g., quaternary ammonium) can be employed. Furthermore, simple derivatives of the drugs (such as ethers, esters, amides, etc.) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, etc., can be employed.
Also contemplated are a hydrogel according to the invention for use as a post-operative separator between internal organs of a human or an animal and a hydrogel according to the invention for use as a delayed-release formulation for the pharmaceutical compound, pesticide, herbicide, pheromone or combination of at least two of the aforementioned compounds distributed within the hydrogel.
Post-operative separators (adhesion barriers) can be used to reduce or prevent unwanted tissue adhesions in a patient after surgery by separating the internal tissues and organs while they heal. The prevention of intraabdominal adhesions is expressly contemplated.
In its use as a delayed release formulation the hydrogel can be viewed as a drug delivery device or system. Drug delivery systems of the invention can take a wide variety of shapes and forms for administering the drugs at controlled rates to different areas of the body. Thus, the invention includes external and internal drug-delivery systems such as skin patches, sublingual or buccal tablets, peroral dosage forms, implantates for releasing a drug in the tissues of a living organism, pessaries, prosthesis, artificial glands, vaginal or rectal suppositories, cervical rings, troches, drug-dispensing intrauterine devices and ocular inserts.
The present invention will be further described with reference to the following figures and examples without wishing to be bound by them.
Desmodur LP DSB 3227 (“DSB 3227”) designates a trifunctional NCO-terminated prepolymer with an NCO content of 2.6% (DIN EN ISO 11909) obtained from hexamethylene diisocyanate and a trifunctional poly(oxyethylene) polyol having an ethylene oxide content of 70 to 75 weight % and a number-average molecular weight of 4500 g/mol.
1 g allylglycine polyphosphazene (prepared according to WO 2015/192158) was weighed into a UV-transparent vessel and dissolved in 10 mL MeOH. Then, 0.51 mL (7.28 mmol) mercaptoethanol was added to the solution. As photoinitiator, 0.01 g (0.04 mmol) 2,2-dimethoxy-2-phenylacetophenone (DMPA) was added and the solution purged with N2 for 30 minutes. The solution was then irradiated for 3 hrs at 5° C. in a UV-reactor (254 nm). The volatiles were removed under vacuum at 40° C. and 337 mbar, followed by further drying under vacuum. 1H-NMR DMSO-d6: 1.83 (s 2H) 2.5 (s 4H) 3.52 (m 2H) 3.63 (m 2H) 4.09 (s 1H) 4.78 (s 1H) 7.63 (m 0.3H) ppm. 31P-NMR: 0.89 and 10.71 and 13C-NMR: 28.20; 28.83; 34.23; 42.95; 61.27; 63.50; 129-133; 172.76 ppm.
A 10% w/w solution of the polyphosphazene polyol of example 1 in DMSO was prepared. 0.57 mL of the solution was added to 0.5 g Desmodur LP DSB 3227 and stirred vigorously. Subsequently, the mixture was poured into a glass form with a thickness of 1 mm and dimensions of 10*10 cm. After evacuation of air, the reaction was allowed to proceed for 72 h at room temperature for gelation to occur. The reaction was quenched upon the addition of 5 mL MeOH. FTIR: 1667 C═O; 2269 N═C═O; 2865 C—H; 3505 N—H. Solid state 31P-NMR: 0.51 ppm. Soaking in 37° C. phosphate buffer (pH=7.4) produced a hydrogel.
For degradation studies, samples of hydrogels obtained according to example 2 were placed in a mechanical shaker in phosphate buffer pH 7.4 at 37° C. and dried and weighed at regular time intervals. The results are depicted in
Cytotoxicity studies of the following selection of materials were carried out. “Ppz-OH” designates the polyphosphazene polyol of example 1.
The hydrogels were tested against three cell lines: human embryonic kidney (HEK), normal dermal fibroblasts and normal vascular fibroblasts and were shown to have excellent biocompatibility. The results are depicted in
In this series of experiments three exemplary active pharmaceutical ingredients (APIs) having the international nonproprietary names (INNs) of ibuprofen, nimodipine and nifedipine were incorporated into hydrogels and their release was monitored.
Drug loading was conducted by in-situ gelation. To the gelation mixture of DSB 3227 (1.2877 g) and a solution of the polyphosphazene polyol of example 1 (0.185 g in 3.1 mL DMSO), API (ca. 200 mg) was added before mixing. After pouring the mixture in a culture dish, the gel was cured under vacuum for 48 h. The gels were then soaked in DMSO:H2O mixture (10 mL, 1:1 ratio). At certain time intervals samples (1 mL) were taken from the stirred solution and new buffer was added. These samples were measured by UV-Vis spectroscopy with the concentration of APIs released measured from calibrations curves for the free compounds. Where necessary, the samples were further diluted to achieve a value below 1 for this calculation.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20182537.9 | Jun 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/066802 | 6/21/2021 | WO |
