Compositions for sustained release of poorly soluble active ingredients
AssigneeProlevi Bio AB
InventorsSahil Gupta, Daniel Bar-Shalom
Life of this patent
Estimating the term…
Abstract
The present disclosure relates to the field of sustained release compositions of active ingredients able to enhance the dissolution rate of active ingredients with poor aqueous solubility.
Claims92
A composition comprising:
- i. hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) and/or hydroxypropyl methyl cellulose in a total amount of 0.1% to 20% by weight, and
- ii. polyethylene oxide (PEO) in an amount from 80 to 99.9% by weight, and
- iii. an active ingredient or a pharmaceutically acceptable salt thereof;
- wherein said active ingredient is a class II or class IV substance in the Biopharmaceutics Classification System (BCS), and wherein at least a portion of said active ingredient or pharmaceutically acceptable salt thereof is in an amorphous form.
The composition according to any one of the preceding claims, wherein the HPMC-AS is present in an amount of about 1% to 20%, such as about 2% to 20%, such as about 5% to 15%, such as about 6% to 14%, such as about 7% to 13%, such as about 8% to 12%, such as about 9% to 11%, for example about 10%.
The composition according to any one of the preceding claims, wherein the hydroxypropyl methyl cellulose is present in an amount of about 1% to 20%, such as about 2% to 20%, such as about 5% to 15%, such as about 6% to 14%, such as about 7% to 13%, such as about 8% to 12%, such as about 9% to 11%, for example about 10%.
The composition according to any one of the preceding claims, wherein the HPMC-AS and/or hydroxypropyl methyl cellulose is present in a total amount of about 1% to 20%, such as about 2% to 20%, such as about 5% to 15%, such as about 6% to 14%, such as about 7% to 13%, such as about 8% to 12%, such as about 9% to 11%, for example about 10%.
The composition according to any one of the preceding claims, wherein the PEO has an average molecular weight between 10 kDa to 2000 kDa, such as 50 kDa to 1000 kDa, such as 100 kDa to 500 kDa, such as 150 kDa to 300 kDa.
The composition according to any one of the preceding claims, wherein PEO is present in an amount of about 80 to 99%, such as about 85% to 95%, such as about 88% to 92%, such as about 90%.
The composition according to any one of the preceding claims, wherein the PEO is present in an amount of about 85 to 95%, such as 85% to 86%, such as 86% to 87%, such as 87% to 88%, such as 88% to 89%, such as 89% to 90%, such as 90% to 91%, such as 91% to 92%, such as 92% to 93%, such as 93% to 94%, such as 94% to 95%.
The composition according to any one of the preceding claims, wherein the components a), b) and c) are in a single matrix.
The composition according to any one of the preceding claims, wherein the weight ratio between PEO and the total amount of HPMC and/or HPMC-AS is between about 8:2 and about 9:0.1.
The composition according to any one of the preceding claims, wherein the composition comprises a uniform dispersion of the active ingredient with the HPMC and/or HPMC-AS;
- or with the PEO.
The composition according to any one of the preceding claims, wherein at least a portion of the active ingredient is in an amorphous solid dispersion.
The composition according to any one of the preceding claims, wherein the composition does not comprise HPMC or wherein the composition does not comprise HPMC-AS.
The composition according to any one of the preceding claims, wherein the composition is a solid dosage form.
The composition according to any one of the preceding claims, wherein the composition is compressed into a tablet.
The composition according to any of the preceding claims, further comprising one or more further polymers each independently selected from the group consisting of ionic, non-ionic, water-insoluble polymers, and water-soluble polymers.
The composition according to any one of the preceding claims, wherein the one or more further polymers are each independently selected from the group consisting of polysaccharides, polyacrylates and polysiloxanes and derivatives thereof.
The composition according to any one of the preceding claims, wherein the one or more further polymers are each independently selected from the group consisting of polyethylene oxide glucomannan, galactan, glucan, polygalacturonic acid, polyhydroxyalkanoates, polyxylane, polygalactomannans, rhanogalacturonan, polyxyloglycan, arabinogalactan, starch, alginates, xhanthan gum, carrageenan, agar, dextran, pectins, cellulose, polyvinyl alcohol, polyvinyl butyral, polyvinyl pyrrolidone, methylcellulose, ehtylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose stearate, carboxymethyl cellulose, carbomers, polyacrylic acid, poly(methylacrylic) acid, poly(methylmethacrylate), polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxyphenylvalerate, polylactic acid, polyglycolic acid, a polyacrylic amide, and derivatives or copolymers thereof.
The composition according to any one of the preceding claims, wherein the composition does not comprise a lubricant.
The composition according to any one of the preceding claims, wherein the active ingredient has low water solubility.
The composition according to any one of the preceding claims, wherein the active ingredient is a class II substance in the Biopharmaceutics Classification System (BCS).
The composition according to any one of the preceding claims, wherein the active ingredient is a class IV substance in the Biopharmaceutics Classification System (BCS).
The composition according to any one of the preceding claims, wherein the active ingredient's highest dose is not soluble in 250 mL of water over the pH range of 1.0-7.5 at 37° C.
The composition according to any one of the preceding claims, wherein the active ingredient has a solubility in aqueous media, such as water or buffered saline below 0.1 g/L, such as below 0.05 g/L.
The composition according to any one of the preceding claims, wherein the active is an active ingredient having poor solubility according to the Biopharmaceutical classification systems (BCS) selected from any one of the group consisting of:
- afabicin, afabicin desphosphono, cobicistat, pralsetinib, piroxicam, tamoxifen glyburide, etodolac, tinidazole, bezafibrate, efavirenz, nevirapine, ergometrine, orismilast, nalmefene, asalhydromorphone, firategrast, lamotrigine, silibinin, hydrochlorothiazide, felodipine, posaconzaole, terbinafine, olorifim, cariprazine, tibolone, sertindole, daclatasvir, risperidone, pitavastatin, lovastatin, estradiol, raloxifene, mercaptopurine, atuliflapon, guanfacine, espirolactone, enzalutamide, firibastat, abrocitinib, glimpiride, ketoconazole, 1-methylnicotinamide, ibrutinib, rivaroxaban, safinamide, budesonide, ralinepag, valsartan, rimegepant, magnesium hydroxide, bicalutamide, vericiciguat, buphenine, bromocriptine, daridorexant, dipraglurant, dexlansoprazole, esomeprazole, sotagliflozin, duloxetine, belzutifan, sibutramine, loperamide, asciminib, basimglurant, deucravacitinib, fenofibrate, omeprazole, buprenorphine, rolapitant, lysine, finerenone, telmisartan, ansornitinib, mirtazapine, methimazole, temazepam, tadalafil, vardenafil, streptokinase, clopidogrel, nolatrexed, olanzapine, vilaprisan, cefuroxime, vapreotide, amprenavir, mefenamic acid, chlorzoxazone, drotaverine, butylscopolamine, danuglipron, palbociclib Isethionat, gepotidacin fostemsavir, calcium carbonate, pelubiprofen, zuclopentixol, zileuton, oxaprozin methylphenidate, phenazopyridine, flavoxate, methoxsalen, naproxen, lamotrigine, clenbuterol, hydroxyzine, loracarbef, ezogabine, phenytoin, racecadotril, crizotinib, griseofulvin, terbinafine, leniolisib, paliperidone, pemafibrate, nicardipine, amiodarone, carvedilol, methenamine, dicloxacillin, ketoconazole, tianeptine, onapristone, nitrofurantoin, loxapine, diacerein, bosentan, carbamazepine, omecamtiv mecarbil, oxacarbazepine, panobinostat, CE 224535 (CAS 724424-43-5), diclofenac, naltrexone, nicergoline, methocarbamol, metaxalone, chlorzoxazone, tizanidine, prednisolone, dipyridamole, mycophenolic acid, mycophenolate, felbamate, diosamin, sucralfate, gemfibrozil, carisoprodol, aplindore, cyclosporine, clonazepam, orlistat, sildenafil, lesinurad, cetylpyridinium, benzodiazepine, trimebutine, testosterone, betamethasone, gabapentin enacarbil, gabapentin, latanoprost, prochlorperazine, celecoxib, aceclofenac, nitazoxanide, dolutegravir, sulpiride, venetoclax, quinapril, cinacalcet, abiraterone, allopurinol, rifampicin, etravirine, acetazolamide, pyrantel, aripiprazole, sulfamethoxazole, venetoclax, ranolazine, folic acid, furosemide, azathioprine, chlorthalidone, adrulipase alfa, mifepristone, camlipixant, cethromycin, eritromycin, mesalazine, ritonavir, cisapride, apremilast, tannic acid, tolvaptan, canagliflozin, digoxin, cisplatin, ticagrelor, rifaximin, aprazolam, ketamine, albendazole, axitinib, metformin, chloropyramine, cinnarizine, clarithromycin, danazol, dextromethorphan, dimeticone, dronabinol, tramadol, dyclonine, aluminiumhydroxide, indomethacin, ketoprofen, ketorolac, letermovir, lornoxicam, maribavir, mebendazole, nicerogline, oxaprozin, oxcarbazepine, pancreatin, pemigatinib, pinaverium, pioglitazone, scopolamine, and selexipag, or a pharmaceutically acceptable salt thereof.
The composition according to any one of the preceding claims, wherein the active ingredient is present in an amount lower equal or lower than 10% by weight, such as lower than 9%, 8%, 7%, 6% or 5% by weight.
The composition according to any one of the preceding claims, wherein the active ingredient is present in an amount between 0.001 mg and 200 mg.
The composition according to any one of the preceding claims, wherein the active ingredient that regulates cardiac events or cardiovascular events.
The composition according to any one of the preceding claims, wherein the the active ingredient is an active ingredient that regulates cardiac events or cardiovascular events, that benefits from chronotherapy.
The composition according to any one of the preceding claims, wherein the active ingredient is selected form the group consisting of:
- felodipine, nicardipine, valsartan, telmisartan, chlorathalidone, digoxin, and temazepam, or a pharmaceutically acceptable salt thereof.
The composition according to any one of the preceding claims, wherein the active ingredient is selected from the group consisting of:
- felodipine, itraconazole and naproxen.
The composition according to any one of the preceding claims, wherein the active ingredient is felodipine or a pharmaceutically acceptable salt thereof.
The composition according to any one of the preceding claims, wherein the composition is able to increase the dissolution rate of the active ingredient.
The composition according to any one of the preceding claims, wherein the composition is able to increase the dissolution rate of the active ingredient compared to a composition comprising a crystalline form of the active ingredient.
The composition according to any one of the preceding claims, wherein the composition is able to increase the absorption rate of the active ingredient in the gut.
The composition according to any one of the preceding claims, wherein the composition is able to increase the oral bioavailability of the active ingredient compared to a composition comprising a crystalline form of the active ingredient.
The composition according to any one of the preceding claims, wherein the composition is able to increase tmax of the active ingredient, as compared to an equivalent amount of the active ingredient administered as an immediate release formulation.
The composition according to any one of the preceding claims, wherein tmax of the active ingredient is increased by at least about 1 hour, such as at least about 2 hours, for example at least about 3 hours, such as at least about 4 hours as compared to an equivalent amount of the active ingredient administered as an immediate release formulation.
The composition according to any one of the preceding claims, wherein the composition provides tmax of the active ingredient of 3 hours to 6 hours upon oral administration, such as tmax of 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0 hours.
The composition according to any one of the preceding claims, wherein the composition provides tmax of the active ingredient of from 3.0 to 4.0 hours, or of from 4.0 to 5.0 hours, or of from 5.0 to 6.0 hours.
The composition according to any one of the preceding claims, wherein the composition is to be administered between 18 h and 00 h, such as between 20 h and 00 h, for example at 20 h, 21 h, 22 h, 23 h or 00 h.
The composition according to any one of the preceding claims, wherein the composition is to be administered during dinner or after dinner, such as within 3 hours after dinner, such as within 2 hours after dinner, such as within 1 hour after dinner, such as within 30 minutes after dinner.
The composition according to any one of the preceding claims, wherein the composition is to be administered prior to a major sleep episode, such as within 3 hours before a major sleep episode, such as within 2 hours before a major sleep episode, for example within 1 hour before a major sleep episode, such as within 30 minutes before a major sleep episode.
The composition according to any one of the preceding claims, wherein the composition is for oral administration.
The composition according to any one of the preceding claims, wherein the composition is a single-unit oral dosage form, such as a pill, a tablet, a thermoformed unit or a capsule.
The composition according to any one of the preceding claims, wherein the composition is to be administered on an empty stomach.
The composition according to any one of the preceding claims, wherein the composition is to be administered once daily.
A composition comprising a matrix comprising:
- i. an active ingredient or a pharmaceutically acceptable salt thereof as described herein,
- ii. HPMC and/or HPMC-AS;
- and
- iii. polyethylene oxide (PEO),
- wherein the weight ratio of PEO (component iii.) to HPMC and/or HPMC-AS (component ii.) is between 8:2 and 9:0.1, and
- wherein at least a portion of the active ingredient or pharmaceutically acceptable salt thereof is in an amorphous form.
A method of manufacturing a composition comprising the steps of:
- a. preparing a melt uniform dispersion comprising an active ingredient or a pharmaceutically acceptable salt thereof together with HPMC or HPMC-AS, and
- b. cooling the melt to obtain a solid composition, wherein at least a portion of the active ingredient is in amorphous form
- c. combining the composition in b. with PEO;
- wherein the final weight ratio between PEO and the HPMC and/or HPMC-AS in the composition is between 8:2 and 9:0.1.
Dependencies are inferred from the claim text.