EP-4736841-A1 - A MUCOADHESIVE LAYER FOR BUCCAL ADMINISTRATION OF AN ACTIVE PHARMACEUTICAL INGREDIENT

EP4736841A1EP 4736841 A1EP4736841 A1EP 4736841A1EP-4736841-A1

Abstract

Inventors

CAVELIUS, Christian
HORSTKOTTE, ELKE
JOCHEM, Aljosha-Rakim
MÜHLHÖLZL-ODÖRFER, Kathrin Ines

Assignees

IQ medical GmbH

Dates

Publication Date: 20260506
Application Date: 20241031

Claims (20)

A mucoadhesive layer for buccal administration of an active pharmaceutical ingredient (API), said layer comprising: - non-crosslinked linear polyacrylic acid; - an active pharmaceutical ingredient (API), - optionally, one or several pharmaceutically acceptable excipient(s).
The mucoadhesive layer for buccal administration according to claim 1, wherein said active pharmaceutical ingredient is selected from immunosuppressants, antifungal agents, neurotransmitters, antiasthmatic agents, anti-obesity drugs, nutraceuticals, elastase inhibitors, analgesics, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antiemetics, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoreceptor blocking agents, cardiovascular agents, cardiac inotropic agents, contrast agents, corticosteroids, cough suppressants, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, lipid regulating agents, muscle relaxants, parasympathomimetics, bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, therapeutic peptides, anti-allergic agents, stimulants, anorectics, sympathomimetics, vasodilatators, antirheumatic agents, antipsychotic agents, and anticonvulsive agents;
The mucoadhesive layer according to any of claims 1 - 2, wherein the immunosuppressant is selected from macrolides, corticosteroids, anti-metabolites, non-macrolide calcineurin inhibitors, and other immunosuppressant drugs, wherein, preferably, - said macrolides are selected from tacrolimus, sirolimus, everolimus and pimecrolimus; - said corticosteroids are selected from cortisone, prednisone, hydrocortisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, beclomethasone, alclometasone, flumetasone, fluticasone, mometasone, budesonide, ciclesonide, and desonide; - said antimetabolites are selected from methotrexate, azathioprine, mercaptopurine, and fluorouracil; - said non-macrolide calcineurin inhibitors are selected from ciclosporin and voclosporin; and - said other immunosuppressant drugs are selected from fingolimod, TNF-α-binding proteins, such as infliximab, etanercept and adalimumab; mycophenolic acid and its prodrugs, such as mycophenolate mofetil and mycophenolate sodium; and fingolimod.
The mucoadhesive layer according to any of the foregoing claims, wherein - said antifungal agents are selected from itraconazole, ketoconazole, fluconazole, clotrimazole, miconazole, econazole, tioconazole, posaconazole and voriconazole; - said neurotransmitters are selected from dopamine, levodopa, carbidopa, adrenaline (ephinephrin), noradrenalin (norepinephrin), acetylcholine, serotonine, glutamate, glycine, gamma-aminobutyric acid (GABA), oxytocin, endorphins, enkephalins, and histamines; - said antiasthmatic agents are selected from beta-2-agonists, corticosteroids, leukotriene modifiers, mast cell stabilisers, methylxanthines, anticholinergics. biologic agents, and combinations for inhalation...; - said anti-obesity drugs are selected from appetite suppressants. Lipase inhibitors, GLP-1 receptor agonists, serotonin 2C agonists, and sympathomimetic amines; - said nutraceuticals are selected from vitamins, minerals, omega-3 fatty acids, omega-6 fatty acids, herbal supplements, probiotics, prebiotics, amino acid supplements, protein supplements, antioxidants, fibre supplements, botanical extracts, and specialty nutrients; - said elastase inhibitors are selected from alpha-1 antitrypsin (AAT), sivelestat, elafin, AZD9668, ONO-5046, serpina1, peptide-based elastase inhibitors, small molecule elastase inhibitors, epigallocatechin gallate (EGCG), and diosmin; - said analgesics are selected from non-opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, adjuvant analgesics, topical analgesics, and combination analgesics; - said anthelmintics are selected from benzimidazoles, avermectins, pyrantel pamoate, praziquantel, diethyl carbamazine, niclosamide, levamisole, piperazine, oxamniquine, and bithionol; - said anti-arrhythmic agents are selected from sodium channel blockers, beta blockers, potassium channel blockers, calcium channel blockers, and other anti-arrhythmic agents not falling under any of the aforementioned blockers and being selected from adenosine, digoxine, and magnesium sulfate; - said antibiotics are selected from beta-lactams, macrolides, quinolones, fluoroquinolones, aminoglycosides, tetracyclines, sulfonamides, glycopeptides, oxazolidinones, lincosamides, nitroimidazoles, polypeptide antibiotics, rifamycins, and other antibiotics not falling under any of the aforementioned antibiotic classes and being selected from chloramphenicol, daptomycin, fosfomycin, and nitrofurantoin; - said anticoagulants are selected from vitamin K antagonists, direct oral anticoagulants, heparins, synthetic pentasaccharides, parenteral direct thrombin inhibitors, coumarins, and other anticoagulants not falling under any of the aforementioned anticoagulant classes and being selected from danaparoid and desirudin; - said antidepressants are selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, atypical antidepressants, serotonin modulators, noradrenergic and specific serotonergic antidepressants (NaSSAs), and serotonin antagonist and reuptake inhibitors; - said antidiabetics are selected from insulins, biguanides, sulfonylureasmeglitinides, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, alpha-glucosidase inhibitors, amylin analogues, bile acid sequestrants, and dopamine agonists; - said antihistamines are selected from Diphenhydramine, Chlorpheniramine (Chlor-Trimeton), Brompheniramine, Clemastine, Hydroxyzine, Promethazine, Doxylamine, Meclizine, Dimenhydrinate, Loratadine, Cetirizine, Fexofenadine, Desloratadine, Levocetirizine, Bilastine, Rupatadine, Olopatadine, Azelastine, and Ketotifen; - said antihypertensive agents are selected from diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium chzannel blockers (CCBs), alpha blockers, centrally acting antihypertensive agents, direct vasodilators, and renin inhibitors; - said antimuscarinic agents are selected from Oxybutynin, Tolterodine, Solifenacin, Darifenacin, Trospium, Fesoterodine, Ipratropium, Tiotropium, Aclidinium, Umeclidinium, Hyoscyamine, Dicyclomine, Glycopyrrolate, Scopolamine, Benztropine, Trihexyphenidyl, Atropine, Tropicamide, Cyclopentolate; - said antimycobacterial agents are selected from Isoniazid, Rifampin, Ethambutol, Pyrazinamide, Rifabutin, Rifapentine, Streptomycin, Amikacin, Kanamycin, Capreomycin, Ethionamide, Prothionamide, Cycloserine, Para-aminosalicylic acid (PAS), Levofloxacin, Moxifloxacin, Ciprofloxacin, Bedaquiline, Delamanid, Linezolid, Dapsone, Rifampin, Clofazimine, Clarithromycin, Azithromycin, Amikacin, Ethambutol, Rifabutin, Rifampin, Ciprofloxacin, Levofloxacin, Moxifloxacin, Linezolid - said antineoplastic agents are selected from alkylating agents, antimetabolites, natural product antineoplastic agents, antitumor antibiotics, hormonal antineoplastic agents, monoclonal antibodies, tyrosine kinase inhibitors, checkpoint inhibitors, platinum compounds, proteasome inhibitors, and immunomodulatory agents; - said antiemetics are selected from serotonin (5-HT3) receptor antagonists, dopamine antagonists, NK1 receptor antagonists, antihistamines, anticholinergics, benzodiazepines, cannabinoids, and steroids; - said antithyroid agents are selected from thionamides, iodine solution, and radioactive iodine; - said antiviral agents are selected from nucleoside and nucleotide analogues, protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, fusion inhibitors, neuraminidase inhibitors, polymerase inhibitors, entry inhibitors, small molecule antiviral agents not falling under any of the aforementioned antiviral agent classes; - said anxiolytic sedatives are selected from benzodiazepines, non-benzodiazepine anxiolytics, barbiturates, antihistamines, beta blockers, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants; - said astringents are selected from astringent aluminium compounds, witch hazel extract, tannins, calamine, astringent zinc compounds, astringent silver compounds, astringent alcohols, astringent acids, and astringent herbal agents; - said beta-adrenoreceptor blocking agents are selected from non-selective beta-blockers, selective beta-blockers, beta-blockers with intrinsic sympathomimetic activity (ISA), and beta-blockers with alpha-blocking activity; - said cardiovascular agents are selected from antihypertensive agents, antiarrhythmic agents, anticoagulants, antiplatelet agents, lipid-lowering agents, vasodilators, cardiac glycosides, inotropes, angiotensin receptor-neprilysin inhibitors (ARNIs), and aldosterone antagonists; - said cardiac inotropic agents are selected from cardiac glycosides, sympathomimetic amines, phosphodiesterase inhibitors, calcium sensitizers, and beta-adrenergic agonists; - said contrast agents are selected from iodinated contrast agents, gadolinium-based contrast agents, barium sulfate, microbubble contrast agents, and iron oxide nanoparticles; - said corticosteroids are selected from glucocorticoids and mineralocorticoids; - said cough suppressants are selected from opioid derivatives, non-opioid cough suppressants, and peripheral acting antitussive agents; - said diagnostic imaging agents are selected from iodinated contrast media, gadolinium-based contrast agents, barium sulfate, microbubble contrast agents, radiopharmaceuticals, and fluorescent dyes; - said diuretics are selected from thiazide diuretics, loop diuretics, potassium-sparing diuretics, carbonic anhydrase inhibitors, and osmotic diuretics; - said dopaminergics are selected from dopamine precursors, dopamine agonists, monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, and dopamine releasing agents; - said hemostatics are selected from systemic hemostatics selected from antifibrinolytics, tranexamic acid, aminocaproic acid, vitamin K, phytonadione, desmopressin; topical hemostatics selected from gelatin sponges, oxidized cellulose, microfibrillar collagen, thrombin, fibrin, chitosan; and hemostatic dressing and agents selected from kaolin and zeolite; - said lipid regulating agents are selected from statins, fibrates, bile acid sequestrants, niacin, cholesterol absorption inhibitors, omega-3 fatty acid ethyl esters, PCSK9 inhibitors and ATP citrate lyase (ACL) inhibitors; - said muscle relaxants are selected from baclofen, cyclobenzaprine, methocarbamol, tizanidine, diazepam, carisoprodol, metaxalone, orphenadrine, and chlorzoxazone; - said parasympathomimetics are selected from bethanechol, pilocarpine, carbachol, methacholine, cevimeline, neostigmine, pyridostigmine, physostigmine, edrophonium and rivastigmine; - said bisphosphonates are selected from alendronate, risedronate, ibandronate, soledronate, etidronate and pamidronate; - said prostaglandins are selected from prostaglandin E1 (PGE1, alprostadil), prostaglandin E2 (PGE2, dinoprostone), prostaglandin F2α (PGF2α, dinoprost), carboprost, misoprostol, latanoprost, travoprost, bimatoprost, and iloprost; - said radiopharmaceuticals are selected from diagnostic and therapeutic radiopharmaceuticals, wherein said diagnostic radiopharmaceuticals are selected from Technetium-99m-based, Fluorine-18-based, Iodine-123-based, Gallium-67-based and Indium-111-based radiopharmaceuticals; and wherein said therapeutic radiopharmaceuticals are selected from Iodine-131-based, Yttrium -go-based, Samarium-153-based, Lutetium-177-based, and Radium-223-based radiopharmaceuticals; - said hormones are selected from non-steroid hormones and steroid hormones; wherein said non-steroid hormones are selected from insulin, glucagon, thyroxine (T4), triiodothyronine (T3), parathyroid hormone (PTH), calcitonin, growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH) and luteinizing hormone; and wherein said steroid hormones are selected from cortisol, aldosterone, testosterone, estradiol, progesterone, dehydroepiandrosterone (DHEA), estrone, and estriol; - said anti-allergic agents are selected from antihistamines, mast cell stabilizers, corticosteroids, leukotriene receptor antagonists, immunomodulators, and degongestants; - said stimulants are selected from amphetamines, methylphenidates, xanthines, norepinephrine uptake inhibitors, modafinil-compounds, cocaine, ephedrine, and pseudoephedrine; - said anorectics are selected from sympathomimetic anorectic compounds, serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin receptor agonists, GLP-1 receptor agonists, combination medications of stimulants and anticonvulsants or of antidepressants and opioid antagonists, and orlistat, wherein said combination medications are selected from the combinations phentermine/topiramate and bupropion/nalltroxone; - said sympathomimetics are selected from direct-acting sympathomimetics, indirect-acting sympathomimetics, mixed-acting sympathomimetics, beta-agonists, and alpha-agonists, wherein said direct-acting sympathomimetics are selected from epinephrine, norepinephrine, dopamine, phenylephrine, dobutamine, and isoproterenol; said indirect-acting sympathomimetics are selected from amphetamine, methamphetamine, ephedrine and pseudoephedrine; saidf mixed-acting sympathomimetics are selected from ephedrine and metaraminol; said beta-agonists are selected from albuterol, salmeterol, formoterol and terbutaline; and said alpha-agonists are selected from clonidine, methyldopa and oxymetazoline; - said vasodilatators are selected from nitrate compounds, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), direct vasodilators, phosphodiesterase inhibitors, potassium channel openers, endothelin receptor antagonists, and prostacyclin analogues; wherein said nitrate compounds are selected from nitroglycerin, isosorbide mononitrate, and isosorbide dinitrate; said calcium channel blockers are selected from amlodipine, nifedipine, verapamil, diltiazem; said angiotensin-converting enzyme (ACE) inhibitors are selected from enalapril, lisinopril, and ramipril; said angiotensin II receptor blockers (ARBs) are selected from losartan, valsartan, and candesartan; said direct vasodilators are selected from hydralazine and minoxidil; said phosphodiesterase inhibitors are selected from sildenafil, tadalafil, and milrinone; said potassium channel openers are selected from nicorandil and diazoxide; said endothelin receptor antagonists are selected from bosentan, and ambrisentan; and said prostacyclin-analogues are selected from epoprostenol, iloprost and treprostinil; - said antirheumatic agents are selected from small molecule disease-modifying antirheumatic drugs (DMARDs), biologic disease-modifying antirheumatic drugs (DMARDs), and targeted synthetic disease-modifying antirheumatic drugs (DMARDs); wherein said small molecule disease-modifying antirheumatic drugs (DMARDs) are selected from methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, azathioprine, cyclosporine, and cyclophosphamide; said biologic disease-modifying antirheumatic drugs (DMARDs) are selected from TNF-a inhibitors, B-cell inhibitors, T-cell co-stimulation modulators and interleukin inhibitors; and wherein said targeted synthetic disease-modifying antirheumatic drugs (DMARDs) are selected from janus kinase inhibitors; - said antipsychotic agents are selected from haloperidol, fluphenazine, trifluoperazine, perphenazine, loxapine, chlorpromazine, thioridazine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, brexipiprazole, clozapine, lurasidone, ascenapine, and cariprazine; and - said anticonvulsive agents are selected from sodium channel blockers, calcium channel blockers, gamma-amino butyric acid (GABA) enhancers, glutamate inhibitors, and mixed/multiple mechanism anticonvulsive agents; wherein said sodium channel blockers are selected from phenytoin, carbamazeoine, lamotrigine, and oxcarbazepine; said calcium channel blockers are selected from ethosuximide, gabapentin, and pregabalin; said gamma-amino butyric acid (GABA) enhancers are selected from phenobarbital, clonazepam, diazepam and vigabatrin; said glutamate inhibitors are selected from topiramate and felbamate; and said mixed/multiple mechanism anticonvulsive agents are selected from valproate, levetiracetam, zonisamide, rufinamide, lacosamiode, perampanel, and brivaracetam.
The mucoadhesive layer according to any of the foregoing claims, wherein the mucoadhesive layer does not comprise any of the following: crosslinked polyacrylic acid, copolymers of methyl vinyl ether and maleic anhydride, poly(methacrylates), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, and polyoxyl castor oils.
The mucoadhesive layer according to any of the foregoing claims, wherein said one or several pharmaceutically acceptable excipient(s) is(are) selected from plasticizers, pH-adjusting agents, chelating agents, viscosity modifiers, film-forming agents, solubilizers, taste-masking agents, API-stabilizing agents, release-modifying agents and colorants.
The mucoadhesive layer according to any of the foregoing claims, comprising the following wt.% proportions: - 30 - 97 wt.% of said non-crosslinked linear polyacrylic acid; - 3 - 40 wt.% of said active pharmaceutical ingredient (API); and - optionally, 0.01 - 60 wt.% of said one or several pharmaceutically acceptable excipient(s); wherein wt.% is with reference to the total dry weight of said mucoadhesive layer; with the proviso that the wt.% proportions of said non-crosslinked linear polyacrylic acid, said active pharmaceutical ingredient (API) and said one or several pharmaceutically acceptable excipient(s) in said mucoadhesive layer add up to 100 wt.%.
The mucoadhesive layer according to claim 7, comprising the following wt.% proportions: a) 64 - 97 wt.% of said non-crosslinked linear polyacrylic acid; - 3 - 36 wt.% of said active pharmaceutical ingredient (API); optionally, 0.01 - 10 wt.% of said one or several pharmaceutically acceptable excipient(s); or b) 30 - 60 wt.% of said non-crosslinked linear polyacrylic acid; 3 - 35 wt.% of said active pharmaceutical ingredient (API); and 30 - 60 wt.% of said one or several pharmaceutically acceptable excipient(s); wherein, in both a) and b), wt.% is with reference to the total dry weight of said mucoadhesive layer; with the proviso that the wt.% proportions of said non-crosslinked linear polyacrylic acid, said active pharmaceutical ingredient (API) and said one or several pharmaceutically acceptable excipient(s) in said mucoadhesive layer add up to 100 wt.%.
The mucoadhesive layer according to claim 7 or 8, comprising the following wt.% proportions: a) 65 - 91 wt.%, preferably 68 - 85 wt.%, of said non-crosslinked linear polyacrylic acid; 9 - 35 wt.% , preferably 15 - 32 wt.%, of said active pharmaceutical ingredient (API); optionally, 0.01 - 10 wt.% of said one or several pharmaceutically acceptable excipient(s); or b) 32 - 55 wt.% of said non-cross-linked linear polyacrylic acid; 5 - 25 wt.% of said active pharmaceutical ingredient (API); and 32 - 55 wt.% of said one or several pharmaceutically acceptable excipient(s); wherein, in both a) and b), wt.% is with reference to the total dry weight of said mucoadhesive layer; with the proviso that the wt.% proportions of said non-crosslinked linear polyacrylic acid, said active pharmaceutical ingredient (API) and said one or several pharmaceutically acceptable excipient(s) in said mucoadhesive layer add up to 100 wt.%.
The mucoadhesive layer according to any of claims 7 - 9, comprising the following wt.% proportions: a) 94 - 97 wt.%, 92 - 93 wt.%, 89 - 91 wt.%, 87 - 88 wt.%, 84 - 86 wt.%, 82 - 83 wt.%, 79 - 81 wt.%, 77 - 78 wt.%, 74 - 76 wt.%, 72 - 73 wt.%, 69 - 71 wt.%, 67 - 68 wt.%, or 64 - 66 wt.% of said non-crosslinked linear polyacrylic acid; 3 - 6 wt.%, 7 - 8 wt.%, 9 - 11 wt.%, 12 - 13 wt.%, 14 - 16 wt.%, 17 - 18 wt.%, 19 - 21 wt.%, 22 - 23 wt.%, 24 - 26 wt.%, 27 - 28 wt.%, 29 - 31 wt.%, 32 - 33 wt.%, or 34 - 36 wt.% of said active pharmaceutical ingredient (API); optionally, 0.01 - 10 wt.% of said one or several pharmaceutically acceptable excipient(s); or b) 33 - 54 wt.% of said non-cross-linked linear polyacrylic acid; 10 - 20 wt.% of said active pharmaceutical ingredient (API); 33 - 54 wt.% of said one or several pharmaceutically acceptable excipient(s); wherein, in both a) and b), wt.% is with reference to the total dry weight of said mucoadhesive layer; with the proviso that the wt.% proportions of said non-crosslinked linear polyacrylic acid, said active pharmaceutical ingredient (API) and said one or several pharmaceutically acceptable excipient(s) in said mucoadhesive layer add up to 100 wt.%.
The mucoadhesive layer according to any of the foregoing claims, comprising the following weight proportions: a) 82 - 84 wt.% of said non-cross-linked linear polyacrylic acid; 15 - 18 wt.% of said active pharmaceutical ingredient (API); optionally, 0.01 - 3 wt.% of said one or several pharmaceutically acceptable excipient(s); or b) 67 - 69 wt.% of said non-cross-linked linear polyacrylic acid; 30 - 33 wt.% of said active pharmaceutical ingredient (API); optionally, 0.01 - 3 wt.% of said one or several pharmaceutically acceptable excipient(s); or c) 52 - 54 wt.% of said non-cross-linked linear polyacrylic acid; 11 - 12 wt.% of said active pharmaceutical ingredient (API); 33 - 36 wt.% of said one or several pharmaceutically acceptable excipient(s); or d) 33 - 36 wt.% of said non-cross-linked linear polyacrylic acid; 11 - 13 wt.% of said active pharmaceutical ingredient (API); 52 - 55 wt.% of said one or several pharmaceutically acceptable excipient(s); wherein, in a), b), c) and d), wt.% is with reference to the total dry weight of said mucoadhesive layer; with the proviso that the wt.% proportions of said non-crosslinked linear polyacrylic acid, said active pharmaceutical ingredient (API) and said one or several pharmaceutically acceptable excipient(s) in said mucoadhesive layer add up to 100 wt.%.
The mucoadhesive layer according to any of the foregoing claims, wherein said one or several pharmaceutically acceptable excipient(s) is(are) selected from a combination of: a) hydroxpropyl cellulose (HPC), polyvinylpyrrolidone (PVP), a plasticizer, such as glycerol, a colorant, and, optionally, a taste-masking or sweetening agent; and b) vinylpyrrolidone-vinylacetate-copolymer (e.g. Kollidon ® ), a plasticizer, such as glycerol, a colorant, and, optionally, a taste-masking or sweetening agent.
The mucoadhesive layer according to any of claims 11c) and 12a), wherein said one or several pharmaceutically acceptable excipient(s) is(are) a combination of hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), a plasticizer, such as glycerol, a colorant, and, optionally, a taste-masking or sweetening agent; wherein said mucoadhesive layer comprises 12 - 13 wt.% hydroxypropyl cellulose (HPC), 11 - 13 wt.% polyvinylpyrrolidone, 4 -5 wt.% plasticizer, 5 - 6 wt.% colorant and, optionally, 0.01 - 0.2 wt.% of a taste-masking or sweetening agent; wherein wt.% is with reference to the total dry weight of said mucoadhesive layer; with the proviso that the wt.% proportions of said non-crosslinked linear polyacrylic acid, said active pharmaceutical ingredient (API) and said one or several pharmaceutically acceptable excipient(s) in said mucoadhesive layer add up to 100 wt.%.
The mucoadhesive layer according to any of claims 11d) and 12b), wherein said one or several pharmaceutically acceptable excipient(s) is(are) a combination of vinylpyrrolidone-vinylacetate-copolymer (e.g. Kollidon ® ), a plasticizer, such as glycerol, a colorant, and, optionally, a taste-masking or sweetening agent; wherein said mucoadhesive layer comprises 42 - 45 wt.% vinylpyrrolidone-vinylacetate-copolymer (e.g. Kollidon ® ), 4 - 5 wt.% plasticizer, 5 - 6 wt.% colorant and, optionally, 0.01 - 0.2 wt.% of a taste-masking or sweetening agent; wherein wt.% is with reference to the total dry weight of said mucoadhesive layer; with the proviso that the wt.% proportions of said non-crosslinked linear polyacrylic acid, said active pharmaceutical ingredient (API) and said one or several pharmaceutically acceptable excipient(s) in said mucoadhesive layer add up to 100 wt.%.
The mucoadhesive layer according to any of the foregoing claims, wherein said non-crosslinked linear polyacrylic acid has a molecular weight in the range of from 6kDa to 700 kDa, preferably from 100 kDa to 700 kDa, more preferably from 300 kDa to 700 kDa, even more preferably from 400 to 700 kDa, even more preferably from 500 to 700 kDa, even more preferably in the range of from 500 to 600 kDa.
The mucoadhesive layer according to any of the foregoing claims, having a thickness in the range of from 20 µm to 1500 µm, preferably 20 µm to 1000 µm, more preferably 20 µm to 800 µm, more preferably 30 µm to 600 µm, even more preferably 40 µm to 400 µm, yet even more preferably 50 µm to 200 µm. and most preferably 60 µm to 150 µm; wherein said thickness refers to a thickness of said mucoadhesive layer in a dry state; alternatively said mucoadhesive layer having a thickness in the range of from 20 µm to 1500 µm, preferably 20 µm to 1000 µm, more preferably 20 µm to 800 µm, more preferably 30 µm to 600 µm, even more preferably 40 µm to 500 µm yet even more preferably 90 µm to 450 µm, yet even more preferably 90 µm to 420 µm; wherein said thickness refers to a thickness of said mucoadhesive layer in a dry state.
The mucoadhesive layer according to any of the foregoing claims, said mucoadhesive layer comprising said active pharmaceutical ingredient (API) in an amount in the range of from 0.01 mg to 10 mg per cm 2 of mucoadhesive layer, or in an amount of 0.05 - 200 mg per g of mucoadhesive layer.
The mucoadhesive layer according to any of the foregoing claims, wherein said active pharmaceutical ingredient (API) is an immunosuppressant, wherein, preferably, said immunosuppressant is selected from tacrolimus, sirolimus, mycophenolic acid and its prodrugs.
A mucoadhesive film, preferably a mucoadhesive buccal film, comprising a mucoadhesive layer according to any of claims 1 - 18, and further comprising a backing layer attached to said mucoadhesive layer, wherein said backing layer, preferably, is permeable for water.
The mucoadhesive film according to claim 19, wherein said backing layer comprises a polymer selected from cellulose, cellulose derivatives, including hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropylmethyl cellulose (HPMC), ethyl cellulose (EC), propyl cellulose (PC), and alginates, and wherein furthermore, said backing layer optionally comprises a plasticizer.

Description

The present invention relates to a mucoadhesive layer for buccal administration of an active pharmaceutical ingredient (API), and to a method of preparing such mucoadhesive layer. Moreover, the present invention also relates to a mucoadhesive film comprising a mucoadhesive layer for buccal administration of an active pharmaceutical ingredient, and to a method of preparing such mucoadhesive film. BACKGROUND OF THE INVENTION The administration of active pharmaceutical ingredients (APIs) is a critical aspect of modern medicine, ensuring that patients receive the correct dosage of medication in an effective manner. Standard administration forms include tablets, capsules, injections and topical creams, each designed to deliver the API efficiently to the target area in the body. Tablets and capsules are widely used for their convenience and ease of use, while injections are often employed for faster delivery of the medication into the blood stream. Topical creams are used for localized treatment, providing direct application to the affected area. Another form of administration that has recently received attention are buccal films which are placed against the inner cheek, allowing the API to be absorbed directly into the blood stream through the mucous membranes. Despite the advancements in these various administration forms, there remain significant challenges to be addressed in ensuring efficient and effective delivery of APIs. One major challenge is the variability in patient response due to difference in metabolism, age, weight and other factors. Additionally, ensuring the stability and bioavailability of APIs in different forms can be complex, requiring sophisticated formulation techniques. There are also issues related to patient compliance, particularly with forms that require precise timing or specific conditions for administration, or with APIs that are hardly soluble or insoluble in water. Accordingly, it was an object of the present invention to provide for an improved mucoadhesive layer for buccal administration of an active pharmaceutical ingredient. More specifically, it was an object to provide for a mucoadhesive layer for buccal administration, that allows the incorporation of sufficient amounts of active pharmaceutical ingredient (API), whilst, also, ensuring a subsequent efficient release of such API, when the respective mucoadhesive layer has been placed at the intended site of administration, for example in the buccal cavity. Even more specifically, it was an object of the present invention to provide for a mucoadhesive layer allowing for a quantitative release of active pharmaceutical ingredient, preferably of at least 20 wt.% of the total API that had previously been incorporated into the film. SUMMARY OF THE INVENTION All these objects are solved by the present invention, as defined herein in various aspects and embodiments. In a first aspect, the present invention relates to a mucoadhesive layer for buccal administration of an active pharmaceutical ingredient (API), said layer comprising: non-crosslinked linear polyacrylic acid;an active pharmaceutical ingredient (API),optionally, one or several pharmaceutically acceptable excipient(s). In one embodiment, said active pharmaceutical ingredient (API) is selected from immunosuppressants, antifungal agents, neurotransmitters, antiasthmatic agents, anti-obesity drugs, nutraceuticals, elastase inhibitors, analgesics, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antiemetics, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoreceptor blocking agents, cardiovascular agents, cardiac inotropic agents, contrast agents, corticosteroids, cough suppressants, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, lipid regulating agents, muscle relaxants, parasympathomimetics, , bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, therapeutic peptides, anti-allergic agents, stimulants, anorectics, sympathomimetics, vasodilatators, antirheumatic agents, antipsychotic agents, and anticonvulsive agents; In one embodiment, the immunosuppressant is selected from macrolides, corticosteroids, anti-metabolites, non-macrolide calcineurin inhibitors, and other immunosuppressant drugs, In a preferred embodiment, said macrolides are selected from tacrolimus, sirolimus, everolimus and pimecrolimus;said corticosteroids are selected from cortisone, prednisone, hydrocortisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, beclomethasone, alclometasone, flumetasone, fluticasone, mometasone, budesonide, ciclesonide, and desonide;said antimetabolites are selected from methotrexate, azathioprine, mercaptopurine, and fluorouracil;said non-macrolide calcineurin inhibitors are selected from ciclosporin and voclosporin; andsaid other immuno