CN104984343A - PH-independent controlled-release medicinal composition with non-opioid medicines and alcohol-influence tolerance - Google Patents

PH-independent controlled-release medicinal composition with non-opioid medicines and alcohol-influence tolerance Download PDF

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Publication number
CN104984343A
CN104984343A CN201510407830.0A CN201510407830A CN104984343A CN 104984343 A CN104984343 A CN 104984343A CN 201510407830 A CN201510407830 A CN 201510407830A CN 104984343 A CN104984343 A CN 104984343A
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China
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weight
pharmaceutical composition
controlled release
release
copolymer
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CN201510407830.0A
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CN104984343B (en
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H·巴尔
T·福尔斯特
G·雷恩纳
M·古特斯查克
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Roma Chemical Co ltd
Evonik Operations GmbH
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Evonik Roehm GmbH
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Abstract

The invention relates to a pH-independent controlled-release medicinal composition. The pH-independent controlled-release medicinal composition comprises at least one active component of non-opioid medicines, wherein a core is coated by at least one coating layer for controlling release of the medicinal composition; the coating layer comprises the following polymeric mixtures according to the dry weight of the polymeric mixtures: (i) 40 percent to 95 percent of at least one water-insoluble and actually-neutral vinyl polymer or copolymer, and (ii) 5 percent to 60 percent of at least one anionic polymer or copolymer which is insoluble in a buffering medium with the pH value being lower 4.0 and is at least soluble in the range from pH 7.0 to pH 8.0. The coating layer is characterized by additionally containing the following polymeric mixtures according to the dry weight of the polymeric mixtures: 110 percent to 250 percent of non-porous inert lubricant, 1 percent to 35 percent of at least one neutral cellulose compound and 1 percent to 25 percent of at least one emulsifying agent.

Description

The pharmaceutical composition of the dependent controlled release of pH of the non-opium medicine of ethanol tolerant impact
Technical field
The present invention relates to the pharmaceutical composition of the dependent controlled release of pH of non-opium medicine, described medicine has for the sensitivity of ethanol on the reduction of the impact of release active compound.
Background technology
US 2003/0118641 A1 describes the process of the abuse potential of the oral pharmaceutical form reduced containing extractible opioid drug.In this process, especially provide the reactive compound that antagonism causes by the domestic solvent commonly used such as isopropyl alcohol, Little water., Chinese liquor vinegar, hot water or peroxide, 0.01HCl in rare alcohol to extract.Suggestion uses and forms the polymer of substrate and the reactive compound of ion exchange material such as styrene-divinylbenzene polymer formulation Micronised form.Ion exchange material is conclusive for increasing the effect resisting reactive compound extraction.The polymer forming substrate obviously serves as the texturizing agent of drug core.Specifically illustrate the long list of the possible material of the polymer for the formation of substrate, in this list, especially comprise polymethacrylates.Preferred matrix formers is C 1-C 6-hydroxyalkyl-cellulose.
US 2004/0052731 A1 describes the medicament forms being particularly suitable for opioid activity compound, and it reduces contributing to the abuse potential brought by improper administration.Lipophilic active chemical variants and water insoluble additive such as such as fatty acid or crosslinked water soluble polysaccharide combine by suggestion.
US 2005/0163856 A1 describes the therapeutic process of the medicament forms treatment pain patients used containing oxycodone, and described medicament forms has the abuse potential reducing and brought by stripping and improper administration subsequently in a solvent.For this purpose, reactive compound should use the polymer of the formation substrate being selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose or hydroxyethyl-cellulose to prepare.
WO 2006/002884 A1 describes the oral delivery form guarding against abuse, and it contains the polymer that resistance to fracture is at least 500N, particularly polyoxygenated alkene.
WO 2006/094083 A1 describes the medicament forms with controlled venlafaxine release characteristic.In order to reduce the abuse potential brought owing to adding ethanol, reactive compound is attached in the substrate of gelling cross linked polymer such as xanthan gum.Other hydrophobic polymer can be added, especially polymethacrylates, as additive.
WO 2006/125483 describes polymeric blends for the preparation of having the application of the pharmaceutical preparation of coating and having the pharmaceutical preparation of mixed polymeric coating.This polymeric blends is intended to the release mode providing change, is exclusively used in the particular treatment requirement of different pharmaceutical composition, and these require not by using standard polymers to be achieved.Not about the instruction of ethanol tolerance medicament forms.In an embodiment, use is described nE with fS is with 5 to 50 % by weight the mixture of the ratio of FS carries out the medicament forms of coating.But do not use in an embodiment or there is no recommendation a large amount of Talcum as used in the present invention in the description.The suitable thickness of coating is the 2-20 % by weight of core core weight, more much lower than coating thickness of the presently claimed invention.
WO 1994/0022431 A1 describes containing the oral drug preparation for the morphine of the treatment effective dose of administration.It contains the individual particle that at least 50 granular sizes are 0.7 to 1.4 millimeters.Each granule has the core core containing morphine salt with barrier layer coating.Barrier layer contains at least one and is selected from ethyl cellulose, by acrylate or the copolymer of methacrylic acid Lipase absobed and the water-msoluble ingredients of native paraffin and plasticizer, for providing the drug release by coating barrier layer, it does not rely in fact the pH that scope is 1.0 to 7.0.The serum-concentration of the morphine that at least 12 hours periods after giving preparation described in single dose obtain is at least 50% of maximum serum-concentration.
US 2007/053698 discloses the method for the sustained release administration of opiates (including but not limited to hydromorphone and oxycodone), the method with the common picked-up of moisture alcohol in show the character of improvement.
Definition
The pharmaceutical composition of the dependent controlled release of pH
The pharmaceutical composition of the dependent controlled release of pH refers to the pharmaceutical composition comprising ingredient, the acceptable film forming polymer of described ingredient pharmacy and the optional acceptable excipient of other pharmacy are prepared, and wherein pharmaceutical composition shows the dependent controlled release of pH of ingredient.
Active constituents of medicine except opioid drug
The pharmaceutical composition of the dependent controlled release of pH comprises core core, comprises at least one active constituents of medicine except opioid drug.The pharmaceutical composition comprising one or more opioid drugs (opiates agonist) is excluded clearly outside the present invention.
Preferably be usually formulated as the active constituents of medicine of Co ntrolled release dosage form or sustained release forms.
The active constituents of medicine be applicable to is such as metoprolol.
The pharmaceutical substance used can find in reference book, such as such as, and the Rote Liste or the Merck Index.
For the active component of the object of the invention or pharmaceutical substance be in order to following object for human body or animal body:
1. cure, relax, prevent or diagnose medical conditions, the patient's condition, somatic damage or pathological state;
2. disclose the situation of health, state or function, or the mental status;
3. substitute the active substance or body fluid that are produced by human body or animal body;
4. avoid or eliminate pathogen, parasite or allogenic material, or make it harmless; Or
5. affect the situation of health, state or function, or the mental status.
These pharmaceutically active substances can belong to one or more active component classification, such as ACE inhibitor, adrenergic, Adrenocorticosteroids, acne therapeutic agent, aldose reductase inhibitor, aldosterone antagonist, Alpha-glucosidase inhibitor, α 1 antagonist, alcohol abuse medicine, aminoacid, amoebacide, anabolic hormones medicine, analeptic, anesthesia additive, anesthetics (non-imbedibility), anesthetics (locally), analgesic (except opioid drug), androgen, angor therapeutic agent, antagonist, antiallergic agent, antiallergic agent is PDE inhibitor such as, for the antiallergic agent for the treatment of asthma, other antiallergic agent (such as leukotriene antagonist, anti-anemic drug, antiandrogen, antianxiety drugs, anti-arthritic, anti-arrhythmic, antiatherosclerotic, antibiotics, anticholinergic, anticonvulsant, antidepressants, antidiabetic drug, diarrhea, antidiuretic, antidote, Bendectin, antuepileptic, antifibrinolytics, antuepileptic, anthelmintic (antihelmintics), antihistaminic, antihypotensive, antihypertensive, antihypertensive, antihypotensive, anticoagulation, antifungal agent, antiestrogen, antiestrogen (on-steroidal), anti-Parkinson's drug, anti-inflammatory agents, antiproliferative activity composition, Anti-protozoal activity composition, antirheumatic, antischistosomal drug, spasmolytic, antithrombotic, antitussive, appetite suppressant, atherosclerosis drug, bacteriostatic, beta blocker, receptor blocking agent, bronchodilator, carbonic anhydrase inhibitors, chemotherapeutic agents, choleretic, cholinergic drug, cholinergic agonist, cholinesterase inhibitor, the medicament for the treatment of ulcerative colitis, cox-2 inhibitors diuretic, ectoparasiticide, emetic, enzyme, enzyme inhibitor, enzyme inhibitor, to the active component of resisting emesis, cellosolve, fungistatic, gout medicine, therapeutic agent for glaucoma, glucocorticoids, glucocorticoid class, hemorrhage, cardiac glycoside, histamine H 2 antagonist, hormones and inhibitor thereof, immunization therapy medicine, cardiac tonic, anticoccidiosis medicine, laxative, lipid lowerers, gastro-intestinal therapeutic agent, malaria treatment agent, migraine remedy, microbicide, Crohn disease, cancer transfer inhibitor, migraine remedy, mineral preparations, increase the active component of mobility, muscle relaxant, neuroleptic drug, for the active component of estrin treatment, osteoporosis, Debrox, anti-Parkinson's drug, plant amedica, proton pump inhibitor, prostaglandin, be used for the treatment of the active component of benign prostatic hyperplasia, be used for the treatment of the active component of pruritus, psoriasis active component, psychoactive drug, free radical scavenger, Renin antagonists, thyroid therapeutic agent, be used for the treatment of seborrheal active component, resist seasick active component, spasmolytic, α-and β-sympathomimetic, anticoagulant, tranquilizer, therapeutic agent for ulcer, other therapeutic agent for ulcer, be used for the treatment of the medicament of urolithiasis, anti-viral medicine, vitamins, cytokine, the active component of therapeutic alliance is used from cytostatic agent one.
The example of the active component except opioid drug be applicable to is such as acarbose, aspirin, Abacavir, aceclofenac, aclarubicin, acyclovir, D actinomycin D, adalimumab, adefovirdipivoxil, adefovir dipivoxil, S-adenosylmethionine, epinephrine and epinephrine derivant, alpha-galactosidase, β-A Jiaxi enzyme, A Lun pearl monoclonal antibody, Almogran, alphacept, allopurinol, Almogran, alosetron, Alprostadil, amantadine, ambroxol, amisulpride, amlodipine, amoxicillin, 5 aminosalicylic acid, amitriptyline, amlodipine, amoxicillin, APV, Antril (Synergen), Anastrozole, androgen and androgen derivant, apomorphine, Aripiprazole, arsenic trioxide, Artemether, atenolol, atorvastatin, atosiban, azathioprine, Azelaic Acid, barbituric acid derivatives, balsalazide, basiliximab, beclapermin, beclometasone, bemiparin, Benzodiazepines, betahistine, bexarotene (bexaroten), bezafibrate, bicalutamide, bimatoprost, bosentan, botulinus toxim, brimonidine, brinzolamide, budesonide, budipine, bufexamac, bumetanide, amfebutamone, butizine, calcitonin, calcium antagonist, calcium salt class, Candesartan, capecitabine, captopril, carbamazepine, carifenacin, carvedilol, Caspofungin, cefaclor, cefadroxil, cefalexin cefalosporins, cefditoren, cefprozil, celecoxib, cepecitabine, cerivastatim, cetirizine, cetrorelix, Cetuximab, chenodeoxycholic acid, chorionic gonadotrophin, ciclosporin, cidofovir, cimetidine, ciprofloxacin, cisplatin, cladribine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, clopidogrel, caffeine, colestyramine, cromoglicic acid, bactrim, coumarin and coumarin derivative, darbepoetin, cysteamine, cysteine, cytosine arabinoside, cyclophosphamide, cyproterone, cytosine arabinoside, daclizumab, dalfopristin, danaparoid, dapiprazole, darbepoetin, defepripone, desipramine, desirudin, desloaratadine, Desmopressin, desogestrel, desonide, dexibuprofen, dexketoprofen, disoproxil, diazepam and diazepam derivant, dihydralazine, diltiazem, dimenhydrinate, dimethyl sulfoxine, dimeticon, pivaloyloxymethyl, dipyridarnoi, dolasetron, domperidone and domperidone (domperidane) derivant, donepzil, dopamine, doxazosin, doxorubizin, doxylamine, diclofenac, divalproex, dronabinol, drospirenone, flexing gram solidifying α, dutasteride, ebastine, econazole, efavirenz, eletripan, emidastine, emtricitabine, enalapril, encepur, entacapone, enfurvirtide, ephedrine, epinephrine, eplerenone, Epoetin and Epoetin derivant, according to general Losartan, eptifibatide, ertapenem, esomeprazole, estrogen and oestrogen derivatives, Embrel, ethenzamide, ethinestradiol, etofenamate, etofibrate, etofylline, etonogestrel, etoposide, exemestane, exetimib, famciclovir, famotidine, faropenan daloxate, felodipine, fenofibrate, fenticonazole, fexofenadine, finasteride, fluconazol, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, Flupirtine, flutamide, fluvastatin, follitropin, Fomivirsen, fondaparinux, formoterol, fosfomicin, Frova, furosemide, fusidic acid, gadobenate, galantamine, gallopamil, ganciclovir, ganirelix, Gatifloxacin, gefitinib, gemfibrozil, gentamycin, gepirone, progestogen and progestin derivative, Semen Ginkgo, glatiramer, glibenclamide, glipizide, glucagon, Sorbitol and sorbitol derivatives, glucosamine and aminoglucose sugar derivatives, glucosides antibiotics, glutathion, glycerol and glycerol derivatives, hypothalamic hormone class, goserelin, grepafloxacin, gyrase inhibitor, guanethidine, gyrase inhibitor, protohemin, halofantrine, haloperidol, as the urea derivative of oral antidiabetic, heparin and heparin derivatives, cardiac glycoside, hyaluronic acid, hydralazine, hydrochlorothiazide and hydrochlorothiazide derivant, hydroxyomeprazole, hydroxyzine, ibritumomab, ibuprofen, idarubicin, ifliximab, ifosfamide, iloprost, imatinib, imidapril, Imiglucerase, imipramine, imiquimod, imidapril, indomethacin, indoramine, infliximab, insulin, insulin Glargine preparation, interferons, irbesartan, irinotecan, isoconazole, isoproterenol, itraconazole, Ivabradine, iodine and iodine derivant, St.-John's-wort, potassium salt class, ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole, La Luoni enzyme, latanoprost, leflunomide, lepirudin, lercanidipine, leteprinim, letrozole, levacetylmethadol, levetiracetam, levocetirizine, levodopa, Li Kaofeilong, Linezolid, lipinavir, thioctic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramine, lodoxamide, lomefloxacin, lomustine, loperamide, Lopinavir, loratadine, lornoxicam, losartan, benflumetol, lutropin, magnesium salts, macrolides antibiotics, mangafodipir, maprotiline, mebendazole, mebeverine, meclizine, mefenamic acid, mefloquine, meloxicam, memantine, mepindolol, meprobamate, meropenem, mesalazine, mesuximide, dipyrone, metformin, methotrexate, 5-amino-4-oxopentanoie acid methyl ester, methylnaloxone, methylnaloxone, methyl naltrexone, methylphenidate, methylprednisolone, methixene (metixen), metoclopramide, metoprolol, metronidazole, mianserin, mibefradil, miconazole, mifepristone, miglitol, miglustad, minocycline, minoxidil, misoprostol, mitomycin, mizolastine, modafinil, moexipril, montelukast, moroctocog, Moxifloxacin, ergot alkaloids, naloxone, naproxen, naratriptan, narcotine, natamycin, Nateglinide, nebivolol, nefazodone, viracept see nelfinaivr, neostigmine, neramexan, nevirapine, nicergoline, nikethamide, nifedipine, niflumic acid, nimodipine, nimorazole, nimustine, Nesiritide, nisoldipine, norfloxacin, novamine sulphone, narcotine, nystatin, ofloxacin, oktotride, olanzapine, Olmesartan, olsalazine, oseltamivir, omeprazole, omoconazole, ondansetron, orlistat, oseltamivir, oxaceprol, oxazacillin, oxaliplatin, oxaprozin, oxcarbacepin, oxiconazole, oxymetazoline, palivizumab, palanosetron, pantoprazole, acetaminophen, parecoxib, paroxetine, pegaspargase, glycol interferon, pegfilgrastrim, penciclovir, oral penicillin class, pentifylline, pentoxifylline, peptide antibiotics, perindopril, perphenazine, Pethidine, plant extract, phenazone, pheniramine, phenylbutyric acid, phenytoin, phenothiazine, fragrant cycolin, Phenylbutazone, phenytoin, pimecrolimus, pimozide, pindolol, pioglitazone, piperazine, piracetam, pirenzepine, piribedil, pirlindole (pirlindol), piroxicam, pramipexole (pramipexol), Pramlintide, pravastatin, prazosin, procaine, promazine, propiverine, Propranolol, propanoic derivatives, isopropylantipyrine, prostaglandin, prothionamide, proxyphylline, Quetiapine, quinapril, quinaprilat, quinupristin (quinupristine), ramipril, ranitidine, rabeprazole, raloxifene (raloxifen), ranolazine, rasburicase, reboxetine (reboxetin), repaclinides, reproterol, reserpine, revofloxacin, ribavirin, rifampicin, riluzole, rimexolone, Risedronate, risperidone, ritonavir, Rituximab, rivastimen, risatriptan, rofecoxib, ropinirole (ropinirol), ropivacaine, rosiglitazone, roxatidine, Roxithromycin, ruscogenine (ruscogenin), rosuvastatin, rutin and rutin derivatives, cevadilla, albuterol, salicylic acid salt, salmaterol, Saperconazole, thyroid hormones, scopolamine, selegiline, Sertaconazole, Sertindole, Sertraline, sevelamer, sibutramine, sildenafil, silicates, simvastatin, sirolimus, sitosterol, sotalol, spaglumic Acid, sparfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralfate, sulbactam, sulfonamide, sulfasalazine, sulpiride, sultamicillin, sultiame (sultiam), sumatriptan, succinylcholine chloride, tacrine, tacrolimus, tadanafil, taliolol, Talsaclidine, tamoxifen, tasonermin, tazarotene, ftorafur, tegaserod, Ketek, telmisartan, temoporfin, temozolomide, tenatoprazole, tenecteplase, teniposide, tenofovir, tenoxicam, teriparatide, terazosin, terbinafine, terbutaline, terfenadine, teriparatide, terlipressin, tertatolol, testosterone and testosterone derivative, Tetracyclines, tetrahydrozoline (tetryzoline), tezosentan, theobromine, theophylline, theophylline derivant, thiamazole, phosphinothioylidynetrisaziridine, thr. somatomedin class, tiagabine, tiapride, tibolone, ticlopidine, timolol, tinidazole, tioconazole, thioguanine, tiotropium, tioxolone, tirazetam, tiropramide, tirofiban, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone, tolterodine, topiramate, hycamtin, torasemide, trandolapril, tranylcypromine, trapidil, Herceptin, travoprost, trazodone, trepostinil, triamcinolone and triamcinolone derivant, triamterene, trifluperidol, trifluridine, trimetazidine, trimethoprim, trimeprimine, tripelennamine, triprolidine, trifosfamide, tromantadine, trometamol, tropalpine, trovafloxacin, troxerutin, tulobuterol, Trypsin, tyramine, Tyrothricin, urapidil, ursodesoxycholic acid, theophylline ursodesoxycholic acid, valaciclovir, valdecoxib, valganciclovir, valproic acid, valsartan, vancomycin, Vardenafil, dimension storehouse oronain, venlafaxine, verapamil, Verteporfin, vidarabine, vigabatrin, viloxazine, vinblastine, vincamine, vincristine, vindesine, vinorelbine, vinpocetine, viquidil, vitamin D and vitamin D-derivatives, voriconazole, warfarin, Buddhist nun's gram Landrina, ximelagatran, xipamide, zafirlukast, zalcitabine, Zaleplon, zanamivir, zidovudine, Ziprasidone, zoledronic acid, assistant rice-koji, zolpidem, zoplicone, zotepine.
If needed, active component also can use with the form of the acceptable salt of their pharmacy or derivant, and when chiral acti ve composition, likely uses racemate or the mixture of optical isomer and diastereomer.If needed, compositions of the present invention can also comprise two or more active pharmaceutical ingredients.
The dependent controlled release of pH
The dependent controlled release of pH of ingredient refer to when be exposed in pharmaceutical composition in vitro dissolution test have different pH value in the USP medium of buffering time, described pH value is positioned at the scope of about pH 1 to about pH 7 and changes with about 1 pH interval, and ingredient discharges or the amount of stripping remarkable difference in the medium with different pH value in media as well in certain time interval.
The USP medium through buffering with different pH value is well known by persons skilled in the art.The USP medium with different pH value can have the pH value of such as pH 1.2, pH 2.0, pH 5.8, pH 6.8 and pH 7.4.In Vitro Dissolution test can in USP dissolving device such as II device (paddle method), 37 DEG C, carry out under stripping stir speed (S.S.) 100rpm, certain time interval can be such as 1,2,3,4,5,6,7,8,9 or 10 hour or even longer hourage.
When testing in the medium with different pH value pH 1.2,2.0,4.5,6.8 and 7.4, the rate of dissolution in the medium with different pH value is significantly different.
Such as, compare with the behavior of the dependent controlled release of pH of the present invention, the behavior of typical pH dependent/non-dependent controlled release such as described in WO1994/022431A1 (especially see the 13rd page, table 5).
Especially, the pH release behavior of pharmaceutical composition of the present invention is because of its stomach juice-resistant but pH is dependent, this refers in the USP medium of pH 1.2, in 2 hours, only have the ingredient of 10% to be released, and in the USP medium of higher ph, such as in the USP medium of pH 7.4, the ingredient significantly beyond 10% in 2 hours is released.By contrast, the form of the pH dependent/non-dependent controlled release of WO1994/022431A1 (see, the 13rd page, table 5) shows the rate of release of identical 15% after 2 hours in the buffer medium of pH 1.2 or pH 7.4.
Polymeric blends
Term polymer mixture refers to the mixture of following composition in the sense of the present invention:
I) with the dry weight basis of polymeric blends, be vinyl polymer or the copolymer of the water-insoluble basic neutrality of at least one of 40 – 95 % by weight, and
Ii) with the dry weight basis of polymeric blends, be at least one anionic polymer or the copolymer of 5 – 60 % by weight, it is insoluble in the buffer medium of pH lower than 4.0, and at least solvable in the scope of pH7.0 to pH8.0.
Also be the part that the cellulosic cpd of the neutrality be present in coatings is not calculated as this polymeric blends, but relative to the dry weight calculating separately of this polymeric blends.The emulsifying agent be present in coatings be also based on not containing neutral cellulosic polymers at interior compound i) and and ii) the dry weight of polymeric blends calculate.
The non-porous lubricant of inertia
With the dry weight basis of polymeric blends, coatings can contain the non-porous inert lubricant of 110-250 % by weight, preferably 140-220 % by weight in addition.
Lubricant (being sometimes also referred to as fluidizer) helps prevent polymer that the acceptable material of coalescent pharmacy occurs during coating process.
Porous lubricant such as SiO 2 powder is unsuitable for object of the present invention.Loose structure may cause capillary effect, and this effect promotes medium (medium particularly containing the aquiferous ethanol) enhancing to the infiltration of coating containing aqueous alcohol (ethanol).
Inertia refers to lubricant usually insoluble not with other material generation chemical reaction and in water and/or ethanol or only slightly soluble.
Insoluble or only slightly soluble refer to that the solute of every 1 weight portion requires the solvent more than 10 weight portions.In addition, the non-porous lubricant of inertia does not affect in fact the glass transition temperature of the polymeric blends of coating.
Lubricant such as glyceryl monostearate (GMS) (it can not be applied to coatings to give the toleration to the aqueous medium containing ethanol with enough amounts) itself is unaccommodated in the sense of the present invention.Therefore, glyceryl monostearate (GMS) is not inertia in the sense of the present invention.
Non-porous inert lubricant can be the silica component of stratiform (layered), pigment or stearate compound.
Inert lubricant can be calcium stearate or magnesium stearate.Inert lubricant can be TiO 2.
The non-porous lubricant of inertia is most preferably Talcum.
Ethanol tolerance pharmaceutical preparation
Ethanol tolerance pharmaceutical preparation has under ethanol exists not by the preparation of the release dynamics of appreciable impact.Alcohol resistance may be important registration requirement in the near future.Coating on conventional drug coating, particularly piller, does not have enough alcohol tolerations.Surprisingly, found insoluble film former and the combined coating of solubility film former to provide larger alcohol toleration.
The release in vitro data that ethanol tolerance (or being sometimes referred to as stable) preparation derives from following test by contrast define, and described test carries out (details is see adnexa) and if if not keeping release profiles difference to be released between 20% to 80% lower than described in 15% and accumulated dose containing the release in the medium of alcohol lower than 20% of accumulated dose, keep release profiles difference lower than 30% in not containing the medium of alcohol and in containing the respective media of 40% ethanol under 6.8pH.
Object and achievement
Starting point of the present invention is the controlled release drug form for oral administration.Such medicament forms be intended to usually during by intestinal for more or more longer release of active compounds.Its blood level concentrations this blood level after initial rising attempting to realize by means of the appropriate formulation of medicament forms reactive compound will remain in treatment optimum range as far as possible for a long time.Should avoid too high reactive compound blood level concentrations especially, it may have toxic effect.
When the delayed release preparation of oral pharmaceutical form, the impact of the impact of gastric juice and intestinal juice, particularly ionic strength and environment pH, is considered in fact in the mode that this area itself is known.Problem is that the ideal ratio for release active compound supposed due to the general life style of patient, carelessness or can be changed to use ethanol or containing the addicted behavior of the beverage of ethanol herein.In these cases, being in fact designed to is under the medicament forms of water-bearing media is exposed to the medium of the ethanol containing greater or lesser intensity extraly completely.
Because the stripping of oral delayed release medicament forms in alcohol beverages or oral delayed release medicament forms are with while alcohol beverages or overlappingly to absorb, can occur undesirable or or even serious release active compound acceleration or slow down.In most cases, the existence of ethanol causes the release of described composition accelerated.This acceleration is subject matter, and it is not too crucial to slow down usually.Must consider, relative to the release % under the condition that there is not 40% ethanol, the release of active constituents of medicine is accelerated or the absolute value of increase is serious more than 30%.
Because and the patient of not all knows the risk of absorbing controlled release drug form and the beverage containing ethanol or does not observe and maybe can not observe suitable warning, prompting or suggestion simultaneously, therefore object is the oral delayed release medicament forms of design, makes their model of action be subject to the impact of ethanol existence as few as possible.
Of the present invention be not stimulate, promote or make the beverage that likely absorbs together with the medicament forms of delayed release containing ethanol motivatedly, but reduce or avoid the possible fatal consequence brought by intentional or unintentional misuse or abuse.
Object of the present invention
Because the unpredictability of vivo effect, so the present invention is based on as can by the conditions in vitro of the Fundamentals of Measurement of objective understanding.As the test condition of harshness, can select according to USP method 1 (basket method), 100rpm, at pH 6.8 through buffering (European Pharmacopoeia (EP)), is adding and is not adding under the conditions in vitro in the medium of 40% (v/v) ethanol.
Be achieved when one object of the present invention is under the pharmaceutical composition of controlled release meets the following conditions:
According to USP method 1 (basket method), 100rpm, pH1.2 is buffered in, under all the other times are buffered in the condition of pH 6.8 (European Pharmacopoeia (EP)) at first 2 hours, when active constituents of medicine is not when adding under 40% (v/v) ethanol condition the degree that release reaches lower than 20%, the difference adding the rate of release under 40% (v/v) ethanol condition should not be greater than do not add the corresponding release value under 40% (v/v) ethanol condition ± 15%.Such as, active constituents of medicine not to add under 40% (v/v) ethanol condition under release reaches the condition of the degree of 18% wherein, the difference adding the rate of release under 40% (v/v) ethanol condition should not be greater than do not add the release value under 40% (v/v) ethanol condition ± 15%, this means add the releasing degree under 40% (v/v) ethanol condition can in the scope of 3 to 33%.
According to USP method 1 (basket method), 100rpm, pH1.2, all the other times are buffered under the condition of pH 6.8 (European Pharmacopoeia (EP)) at first 2 hours, when active constituents of medicine is not when to add under 40% (v/v) ethanol condition release and reach the degree of 20-80%, the difference adding the rate of release under 40% (v/v) ethanol condition should not be greater than do not add the corresponding release value under 40% (v/v) ethanol condition ± 30%.Such as, active constituents of medicine not to add under 40% (v/v) ethanol condition under release reaches the condition of the degree of 50% wherein, the difference adding the rate of release under 40% (v/v) ethanol condition should not be greater than do not add the release value under 40% (v/v) ethanol condition ± 30%, this means add the releasing degree under 40% (v/v) ethanol condition can in the scope of 20 to 80%.
The pharmaceutical composition meeting the controlled release of this condition is considered to tolerate due to patient and ethanol or the serious accelerated release in vitro of reactive compound that contains the relevant carelessness of the use of beverage of ethanol or addicted behavior and bring.
This situation relates in fact together with the picked-up of controlled release form absorbs alcoholic beverage simultaneously or subsequently, thus make described medicament forms be exposed to stomach or enteral containing under the strong medium of ethanol.
An object of the present invention is to provide the pharmaceutical composition for non-opium medicine of the impact of ethanol tolerant.
Another object of the present invention is to provide ethanol tolerant and also tolerates impact that gastric uses, without the need to adding special enteric coating as with having the enteric film forming polymer of a large amount of anion radicals such as s or l or the pharmaceutical composition of the controlled release of L100-55 coating.
This is realized by the pharmaceutical composition of controlled release of the present invention, to it is characterized in that when having or do not have interpolation 40% ethanol (v/v) releasing degree of active component is 10% or lower in simulated gastric fluid pH1.2 in 2 hours.
Another object is the bin stability of pharmaceutical composition, it should be improved to further with f 2in the scope of 60 – 100 that-value represents (bin stability=good).
Measuring method
The measurement of the percentage of reactive compound can be undertaken by the online ultraviolet spectroscopy such as under the wavelength being suitable for corresponding reactive compound.HPLC is also likely adopted to measure.Described methodology is well known to those skilled in the art.
The release of reactive compound can measure according to USP, particularly USP 28-NF23, general rules <711>, stripping, device 2 (paddle method), mode <724> " delayed release (enteric coating) goods-general drug release standard ", needs correctly to quote! Method B (100rpm, 37 DEG C), I type basket, there is following change: by medicament forms first 2 hours with 0.1N HCl be buffered in pH1.2, all the other times are buffered in pH 6.8 (European Pharmacopoeia (EP), it is equivalent to artificial intestinal medium) with phosphate buffer and test.The ethanol of 30% of appropriate amount in media as well or preferably 40% (v/v) is used to carry out the measurement of the aqueous medium containing ethanol.
Bin stability
Usually, drug substance (should allow suitable tolerance) and evaluate under condition of storage, inspection heat stability and, if be suitable for, to the sensitivity (ICH Guideline Q1A (R2), 6February 2003) of dampness.
The acceleration environment of drug substance: 40 DEG C ± 2 DEG C, 75%RH (relative humidity) ± 5%RH, hermetic container, lasts 6 months.Bin stability can pass through so-called similarity coefficient f 2or f 2-value represents.Similarity coefficient f 2and squared-distance average between two release characteristics before and after storing is inversely proportional to.In the past 10 years, f 2calculate the recommend method become in several FDA manual industry.Computational methods are well known by persons skilled in the art.F 2value is 100 mean that between two release characteristics before storage, average squared-distance does not have deviation.
The deviation of the release characteristic is before storage with f 2when but value is expressed as more than 50 is less than the similarity of 60, think that bin stability is acceptable.The deviation of the release characteristic is before storage with f 2when value is expressed as 60 to 100, think that bin stability is good.Storage stability test is well known to those skilled in the art.
The present invention describes in detail
The present invention relates to:
The pharmaceutical composition of the dependent controlled release of pH, comprises:
Core core, it comprises the active constituents of medicine of at least one non-opium medicine, and wherein this core core is controlled the coatings coating of pharmaceutical composition release by least one,
Wherein coatings comprises the polymeric blends of following material:
I) with the dry weight basis of polymeric blends, 40-95 % by weight, preferably 60-95 % by weight, the most preferably at least one of 70-90 % by weight vinyl polymer that is water-insoluble, neutrality in fact or copolymer, and
Ii) with the dry weight basis of polymeric blends, 5-60 % by weight, preferably 5-40 % by weight, the most preferably at least one anionic polymer of 10-30 % by weight or copolymer, it is insoluble and at least solvable in the scope of pH 7.0 to pH 8.0 in lower than the buffer medium of pH4.0
Be characterised in that,
This coatings comprises in addition, contain in fact or contain the non-porous inert lubricant of 110-250 % by weight, preferably 140-220 % by weight, the cellulosic cpd of 1-35 % by weight, preferably at least one neutrality of 2 – 30 % by weight, most preferably 5 – 25 % by weight, with at least one emulsifying agent of 1-25 % by weight, preferably 5-20 % by weight, most preferably 5-15 % by weight, it is all the dry weight basis with polymeric blends.
Core core
In the mode that this area itself is known, the core core containing active component or piller core core constitute the basis of the coating of alkene class (being total to) polymer.Granulation not containing the ball (celphere) of active component or not carrying out containing on the piller of core core, can prepare piller core core.First, preparation has or does not have the circular base containing active component of core core.By means of fluidized bed process, by liquid application on placebo piller or other suitable carrier material, solvent or suspending agent can be evaporated.According to preparation method, can additional drying step.Spraying process and drying subsequently can repeat several times, until application of the active constituents of medicine of scheduled volume completely.
By convention, active component to be joined in organic solvent or water and to mix.In order to ensure the gratifying sprayability of mixture, be usually necessary that preparation has relatively low viscous mixture.Concentration is adding of the cleaning agent such as Tween of 0.1 to 20 % by weight, preferably 0.5 to 10 % by weight, is conducive to reducing surface tension.
Except active component, they can contain other drug excipient: binding agent, such as cellulose and its derivates, polyvinylpyrrolidone (PVP), wetting agent, disintegrate auxiliary agent, disintegrating agent, (methyl) acrylate, starch and derivant, sugared solubilizing agent or other material.
Suitable application process is known, such as, see Bauer, Lehmann, Osterwald, Rothgang " arzneiformen " [Coated Pharmaceutical Forms] Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, the 7th chapter, 165-196 page.
Details can be learnt from textbook further by those skilled in the art.Such as, see:
-Voigt,R.(1984):Lehrbuch der pharmazeutischen Technologie[Textbook of Pharmaceutical Technology]；Verlag Chemie Weinheim-Beerfield Beach/Florida-Basle。
-Sucker, H., Fuchs, P., Speiser, P.:Pharmazeutische Technologie [Pharmaceutical Technology], George Thieme Verlag Stuttgart (1991), particularly the 15th and 16 chapters, 626-642 page.
-Gennaro, A., R. (Editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pennsylvania (1985), the 88th chapter, the 1567-1573.
-List,P.H.(1982):Arzneiformenlehre[Pharmaceutical Form Theory],Wissenschaftliche Verlagsgesellschaft mbH,Stuttgart。
Piller core core can pass through such as rotor coalescent (rotor agglomeration), precipitation or spraying process full circle, special in ultrasonic eddy current spraying process, obtain having to sizing such as 50 to 2500 microns, be still core core without coating or piller core core.This advantage had is that whole core core volume can be used for active component load.Thus active component load is increased again relative to the embodiment with inert core.
Direct compacting (direct compaction) method can be used to prepare the core core of micro tablet.
Except active constituents of medicine, core core can comprise other drug excipient: binding agent, such as cellulose and its derivates, polyvinylpyrrolidone (PVP), wetting agent, disintegrate auxiliary agent, disintegrating agent, starch and derivant thereof, sugared solubilizing agent or other material.
Control the coatings of pharmaceutical composition release
Core core at least by one, preferably by one or more, preferably only by a coatings institute coating, control the release of pharmaceutical composition.Coatings gives release mode to the tolerance effects of the aqueous medium containing ethanol.The coatings controlling pharmaceutical composition release also can be referred to as exterior coating, because this coatings surrounds core core.
(outward) coatings controls the release of pharmaceutical composition.Coatings gives release mode to the tolerance effects of the aqueous medium containing ethanol.
Under core core composition and the inconsistent situation of coating constituents, isolation end coating can be used between core core and (outward) coatings.
Control pharmaceutical composition release coatings can in addition by non-functional, preferred water miscible table coating cover, this table coating does not affect in fact release characteristic.
After the core core prepared containing active component or piller core core, they are fed in the spraying process of coatings, thus obtain coating core core or coated pellets respectively.Coating is by means of by organic solution or preferably by aqueous dispersion spray and prepare.In order to implement object, it is important for obtaining coating that is uniform, atresia at this.By convention, after spraying process and before conditioning process starts by coated pellets in addition sequentially dry a few minutes.By convention, polymer coating contains the usual excipient of pharmacy, such as, such as, and releasing agent or plasticizer.
With core core weighing scale, the coatings that control pharmaceutical composition discharges exists with the amount of at least 10 % by weight.With core core weighing scale, coating preferably exists with the amount of 20-200 % by weight, preferably 30-100 % by weight, more preferably 40-80 % by weight.
The amount of coating can be equivalent to the average thickness of coatings in about 20-200 micron, preferably 50-150 micrometer range.
Coated pellets
The pharmaceutical composition of controlled release can preferably with have 100 to 5000 microns, preferably 100 to 2000 microns, most preferably the form of the coated pellets of the grand mean diameter of 300-1000 micron, micro tablet or tablet exist.
The pharmaceutical composition of controlled release of the present invention can grand mean diameter be 100 to 700 microns, preferably greater than 200 microns more than 500 microns or the form of the coated pellets of 250-400 micron exist.
The pharmaceutical composition of controlled release of the present invention can grand mean diameter be 1400 to 5000 microns, the form of the coated pellets of preferably 1500 to 4000 microns, most preferably 1800 to 3500 microns, micro tablet or tablet exists.
The grand mean diameter of coated pellets be 100 to 700 microns, preferably greater than 200 microns more than 500 microns or be 250 to 400 microns time, the amount that coatings should count at least 100 % by weight with core core weight exists.
The grand mean diameter of coated pellets be 1400 to 5000 microns, preferably greater than 2000 microns more than 2500 microns or be 2500 to 3500 microns time, the amount that coatings should count at least 30 % by weight with core core weight exists.
Micro tablet
The pharmaceutical composition of controlled release can preferably exist with the form of the micro tablet of coating, and wherein micro tablet has the average diameter of 1 to 5 millimeters.
Tablet
Complete by of the present invention, the tablet of the coating with stomach acidity toleration and alcohol resistance is likely provided, such as, from 1mm to the size of maximum 50mm.This is favourable for being harmful to gastric mucosa of providing with tablet form or active component unstable in gastric juice.
Water-insoluble, neutral in fact vinyl polymer or copolymer
Water-insoluble, neutral in fact vinyl polymer or copolymer are understood and refer to water insoluble within the scope of the pH of whole 1 to 14 and those polymer that an are swellable in water or copolymer.
Vinyl polymer derives from the polymerization of monomer such as (methyl) acrylic monomer with alkene class group.
" neutral in fact " refers to polymer in a sense if any also only containing a small amount of ionic group.Even if there is a small amount of ionic group, but the physical-chemical property of this base polymer is almost identical with the physical-chemical property not containing the polymer of any ionic group." in fact neutral " refer in particular in a sense polymer contain lower than 5, lower than 4, lower than 3, lower than 2 or lower than 1 % by weight the monomer residue with anion or cation side base.Preferably, water-insoluble neutral vinyl polymer or copolymer be not containing any cation group.Most preferably, therefore water-insoluble, neutral in fact vinyl polymer or copolymer not containing any ionic group, and are neutral water-insoluble vinyl polymers (100% is neutral).
Especially, water-insoluble (methyl) acrylic polymer of the monomer residue of the cation quaternary ammonium group containing 5 or 10 % by weight, such as type rS or rL, is not suitable for object of the present invention, because the pharmaceutical composition obtained is not enough to the impact of tolerance 40% ethanol.
Usually, a kind of water-insoluble, neutral in fact vinyl polymer of an or type or copolymer is only had to be present in pharmaceutical composition.But, if properly, these polymer of two or more water-insoluble polymer or copolymer or two or more type or copolymer also may be had to exist each other simultaneously or are present in mixture.
The insoluble polymer of polyvinyl acetate type
The copolymer that suitable insoluble polymer has the polymer of polyvinyl acetate type or derived by it.
The polymer of water-insoluble polyvinyl acetate type or the example of copolymer are polyvinyl acetate (PVAc, Kollicoat), vinyl base pyrrolidinone-co thing ( vA64).
Water-insoluble (methyl) acrylic acid series copolymer
In water-insoluble (methyl) acrylic acid series copolymer, neutral or methacrylate copolymer neutral is in fact applicable to object of the present invention.
Neutral (methyl) acrylate copolymer ( nE type)
Neutral or neutral in fact methacrylate copolymer contain degree at least more than 95 % by weight, particularly at least 98 % by weight degree, preferably at least 99 % by weight degree, particularly at least 99 % by weight degree, more preferably 100 % by weight degree there is neutral group particularly C 1-C 4(methyl) acrylate monomer of-alkyl group.
Suitable (methyl) acrylate monomer with neutral group is such as methyl methacrylate, ethyl methacrylate, butyl methacrylate, acrylic acid methyl ester., ethyl acrylate, butyl acrylate.Preferable methyl acrylic acid methyl ester., ethyl acrylate and acrylic acid methyl ester..
The methacrylate monomer with anionic group such as acrylic acid and/or methacrylic acid can amount lower than 5 % by weight, preferably more than 2 % by weight, more preferably no more than 1 % by weight or 0.05 to 1 % by weight and existing on a small quantity.
(methyl) acrylate copolymer that is that suitable example is made up of to the acrylic or methacrylic acid lower than 5 % by weight, preferably 0 to 2 % by weight or 0.05 to 1 % by weight ethyl acrylate of 20 to 40 % by weight, the methyl methacrylate of 60 to 80 % by weight and 0, neutral or neutrality in fact ( nE).
nE and the copolymer that NM is made up of the radical polymerization unit of the ethyl acrylate of 30 % by weight and the methyl methacrylate of 70 % by weight.
Suitable insoluble polymer be by more than 95 to up to 100 % by weight the C of acrylic or methacrylic acid 1-C 4-Arrcostab and the copolymer formed lower than the radical polymerization unit of the acrylic or methacrylic acid of 5 % by weight.
Water-soluble anionic polymer
Water-soluble anionic polymer in the sense of the present invention refers to such polymer, this polymer is at suitable buffer medium, preferably according in the buffer medium of American Pharmacopeia or European Pharmacopoeia standard, insoluble lower than pH 5.0 times, and at pH 7.0 to pH 8.0, preferably at pH 6.0 to 8.0, most preferably solvable in the scope of pH 5.5 to 8.0.In the suitable aqueous medium through cushioning, the major part of polymer solvable in the scope of pH 7.0 to pH 8.0 is insoluble in pure water or demineralised water.
Water-soluble anionic cellulose derivative
Anionic cellulose derivative is based on native cellulose chain and carry out chemical modification with anionic compound.Polymer can be passed through and partly and fully neutralizes, and preferably uses basic ion to carry out.The example of anionic cellulose derivative is CAP (CAP), hydroxypropylmethyl cellulose phthalate (HPMCP), carboxymethyl cellulose (CMC), HPMC-AS (HPMCAS) or cellulose acetate succinate (CAS).
Water-soluble anionic (methyl) acrylate copolymer
Suitable water soluble anion (methyl) acrylate copolymer by 25 to 95 % by weight, preferably 40 to 95 % by weight, particularly 60 to 40 % by weight the C of the acrylic or methacrylic acid through radical polymerization 1-C 4-Arrcostab and 75 to 5 % by weight, preferably 60 to 5 % by weight, particularly 40 to 60 % by weight have (methyl) acrylate monomer of anionic group radical polymerization unit composition.
Described ratio generally adds up to 100 % by weight.But, also may exist in addition and a small amount of mostly be 10 % by weight or be 0 to 10 % by weight most, the other monomer that can carry out the copolyreaction of alkene class of such as 1 to 5 % by weight, such as, such as hydroxyethyl methylacrylate or 2-(Acryloyloxy)ethanol, and do not damage or change fundamental character of the present invention.But, preferably there is not the other monomer that can carry out the copolyreaction of alkene class.Generally preferably, except those monomers be specifically recited, in water-soluble anionic (methyl) acrylate copolymer, there is not other monomer.
The C of acrylic or methacrylic acid 1-C 4-Arrcostab is methyl methacrylate particularly, ethyl methacrylate, butyl methacrylate, acrylic acid methyl ester., ethyl acrylate and butyl acrylate.
(methyl) acrylate monomer with anionic group is such as acrylic acid, preferable methyl acrylic acid.
Suitable anion (methyl) acrylate copolymer by the methacrylic acid of 40 to 60 % by weight and the methyl methacrylate of 60 to 40 % by weight or 60 to 40 % by weight ethyl acrylate form those.( l type or l 100-55 type).
l is the copolymer of the methyl methacrylate of 50 % by weight and the methacrylic acid of 50 % by weight.The pH that concrete active component starts to discharge described in intestinal juice or simulated intestinal fluid can be pH 6.0.
l 100-55 is the copolymer of the ethyl acrylate of 50 % by weight and the methacrylic acid of 50 % by weight. l 30D-55 is containing 30 % by weight the dispersion of L 100-55.The pH that concrete active component starts to discharge described in intestinal juice or simulated intestinal fluid can be pH 5.5.
Similarly, anion (methyl) acrylate copolymer be made up of the methacrylic acid of 20 to 40 % by weight and the methyl methacrylate of 80 to 60 % by weight be also suitable ( s type).The pH that concrete active component starts to discharge described in intestinal juice or simulated intestinal fluid can be pH 7.0.
Suitable (methyl) acrylate copolymer by the methyl methacrylate of 10 to 30 % by weight, the acrylic acid methyl ester. of 50 to 70 % by weight and 5 to 15 % by weight methacrylic acid form those ( fS type).Described in intestinal juice or simulated intestinal fluid, the pH of the concrete initial release of active component can be pH 7.0.
fS is by the copolymer of the methyl methacrylate of 25 % by weight, the acrylic acid methyl ester. of 65 % by weight and the methacrylic polymeric of 10 % by weight. fS30D is containing 30 % by weight the dispersion of FS.
The copolymer with following composition is also suitable:
The methacrylic acid of 20 to 34 % by weight and/or acrylic acid,
The acrylic acid methyl ester. of 20 to 69 % by weight, and
The ethyl acrylate of 0 to 40 % by weight, and/or, if appropriate,
The other monomer that can carry out the copolyreaction of alkene class of 0 to 10 % by weight,
Condition is that this copolymer is no more than 60 DEG C according to the glass transition temperature of ISO 11357-2,3.3.3 trifle.Be somebody's turn to do (methyl) acrylate copolymer suitable especially, because become for tablet for compacting piller, it has good elongation at break properties.
The copolymer with following composition is also suitable:
The methacrylic acid of 20 to 33 % by weight and/or acrylic acid,
The acrylic acid methyl ester. of 5 to 30 % by weight, and
The ethyl acrylate of 20 to 40 % by weight, and
Higher than the butyl methacrylate of 10 to 30 % by weight, with if appropriate,
The other monomer that can carry out the copolyreaction of alkene class of 0 to 10 % by weight,
Wherein the ratio of monomer adds up to 100 % by weight,
Condition is according to ISO 11357-2,3.3.3 trifle (neutral temperature T mg) glass transition temperature of this copolymer is 55-70 DEG C.Such copolymer is suitable especially, because become for tablet for compacting piller, it has good engineering properties.
Above-mentioned copolymer is made up of following radical polymerization unit especially:
The methacrylic acid of 20 to 33 % by weight, preferably 25 to 32 % by weight, particularly preferably 28 to 31 % by weight or acrylic acid, preferable methyl acrylic acid,
The acrylic acid methyl ester. of 5 to 30 % by weight, preferably 10 to 28 % by weight, particularly preferably 15 to 25 % by weight,
The ethyl acrylate of 20 to 40 % by weight, preferably 25 to 35 % by weight, particularly preferably 18 to 22 % by weight, and
Higher than the butyl methacrylate of 10 to 30 % by weight, preferably 15 to 25 % by weight, particularly preferably 18 to 22 % by weight,
Wherein this monomer composition is through selecting, thus makes the glass transition temperature of this copolymer be 55-70 DEG C, preferably 59-66 DEG C, particularly preferably 60-65 DEG C.
About this point, glass transition temperature refers to the neutral temperature T according to ISO 11357-2, trifle 3.3.3 mg.Do not adding under plasticizer condition, residual monomer content (REMO) is lower than 100ppm, and the rate of heat addition is 10 DEG C/min and in a nitrogen atmosphere, measures.
Copolymer preferably arrive in fact fully comprise 90,95 or 99 to 100 % by weight, methacrylic acid, acrylic acid methyl ester., ethyl acrylate and butylmethacrylate monomer in the scope that is in above-mentioned amount.
But, likely exist in addition a small amount of scope 0 to 10 % by weight, such as 1 to 5 % by weight the other monomer that can carry out the copolyreaction of alkene class, such as, such as, methyl methacrylate, butyl acrylate, hydroxyethyl methylacrylate, vinyl pyrrolidone, vinyl malonic acid, styrene, vinyl alcohol, vinyl acetate and/or its derivant, and must not damage fundamental character.
The preparation of anion (methyl) acrylate copolymer
Anion (methyl) acrylate copolymer can the known mode in this area itself be produced (such as, see EP 0 704 207 A2 and EP 0 704 208 A2) by the radical polymerization of monomer.Copolymer of the present invention can the known mode in this area itself be produced by the free-radical emulsion polymerization reaction in aqueous phase preferably under the existence of anion emulsifier, such as, is undertaken by method described in DE-C 2 135 073.
If can by forming initiator at free radical and suitably also having for regulating the conventional method of the radical polymerization of the continous way under the condition of the regulator of the molecular weight of not diluted or discontinuous (batch process) with solution polymerization process, by pearl polymerisation method or prepare copolymer with emulsion polymerization.Average molecular weight Mw (weight average is such as determined by measuring solution viscosity) can in the scope of such as 80 000 to 1 000 000 (g/mol).The emulsion polymerisation preferably carried out in aqueous phase, under the existence of water soluble starter and (preferred anionic) emulsifying agent.
When polymerisation in bulk, can by rolling, extruding, pelletize or thermal cutting obtain the polymer of solid form.
(methyl) acrylate copolymer is obtained by the polymerisation in bulk of free radical, polymerisation in solution, pearl polymerisation or emulsion polymerisation according to the known mode in this area itself.They must reach particle size range of the present invention by suitable grinding, drying or spray process are processed.This is by simply rolling the piller that is extruded and cools or carrying out thermal cutting to carry out.
Use powder can be favourable, particularly about with the mixture of other powder or liquid in.Suitable device for the manufacture of powder is well known to those skilled in the art, such as air jet mill, and peg type disc grinder (pinned disc mills), multicell grind.If properly, also suitable sifting step may be comprised.Suitable mill for industrial mass is such as with the subtend jet mill of the gauge pressure work of about 6 bar (opposed jet mill) (Multi No.4200).
Part neutralization
Anionic polymer available bases partially or even wholly neutralizes.Suitable alkali be in EP 0 088 951 A2 or WO 2004/096185 clear mention those, or by its derivative those.Specifically: sodium hydroxide solution, potassium hydroxide solution (KOH), ammonium hydroxide, or organic base is such as triethanolamine such as, sodium carbonate, potassium carbonate, sodium bicarbonate, tertiary sodium phosphate, trisodium citrate or ammonia, or the amine such as triethanolamine or three (methylol) aminomethane of physiology's tolerance.Suitable cation organic base is in addition basic amino acid histidine, arginine and/or lysine.
Many granule medicaments form
The pharmaceutical composition of controlled release of the present invention can have pellet form, and it is comprised in the form of many granule medicaments form such as compressed tablets, capsule, pouch, effervescent tablet or reconstitutable powder.
Table coating and end coating
The pharmaceutical composition of controlled release of the present invention can carry out coating with end coating and/or table coating further.
End coating can be positioned between core core and the coatings (key-course) controlling pharmaceutically active substance release.End coating can have the effect making the inconsistent material of core core of possibility and the separating substances of key-course each other.End coating does not affect in fact release characteristic.End coating is in fact preferably water solublity, and such as, its material that can comprise such as hydroxypropyl emthylcellulose (HPMC) is as film former.The average thickness of end coating is very thin, such as, is no more than 15 microns, preferably more than 10 microns.
Table coating is also preferably water miscible in fact.Table coating can have to be made medicament forms band color or protects medicament forms from the effect of environmental effect such as protection against the tide between the storage life.Table coating can comprise binding agent, and such as water-soluble polymer is if polysaccharide or HPMC or sugar compounds are as sucrose.Table coating can contain a small amount of drug excipient in addition as pigment or lubricant.Table coating does not affect in fact release characteristic.
Expression base coating and table coating well known to a person skilled in the art.
Prepare the method for medicament forms of the present invention
The pharmaceutical composition of controlled release of the present invention can the known mode in this area itself be produced by such as following pharmacy conventional process: direct pressing; the compacting of dry, wet or agglomerated grain and full circle subsequently, wet granulation or non-slurry pelletizing or directly pill or by powder-stuck (powder stratification) to not containing the globule of active component or neutral core core (blank core core) or containing on the granule of active component and by spraying process or by fluidized bed prilling applying polymer coating.
Excipient/usual additive
Core core also contains excipient or usual additive respectively in addition in the manner known to persons skilled in the art except active constituents of medicine.Other excipient is not crucial for the present invention.
Coatings is except polymeric blends, non-porous inert lubricant, neutral cellulosic cpd and emulsifying agent are as distinguishing except basis in the manner known to persons skilled in the art in addition containing excipient or usual additive.If but excipient is comprised in coatings, they are always different from necessary composition, and necessary composition is polymeric blends, non-porous inert lubricant, neutral cellulosic cpd and emulsifying agent.As compared to the composition (namely polymeric blends, non-porous inert lubricant, neutral cellulosic cpd and emulsifying agent) of necessity, other excipient is not crucial for the present invention.Other excipient is not contributed favourable invention effect.Preferably, with the dry weight basis of total coatings, the amount of excipient other in coatings lower than 5 % by weight, more preferably less than 2 % by weight.Most preferably there is no other excipient in coatings.
The excipient that pharmacy is usual, is also referred to as usual additive occasionally, is added in preparation of the present invention, is preferably added at the production period of granule or powder.Certainly necessarily toxicology is acceptable and can be used for medicine to the calm strategical vantage point of patient especially all the time for all excipient used or usual additive.
The usual excipient of pharmacy is used for the use amount of drug coating or coating and application is well known to those skilled in the art.Usual excipient possible in pharmacy or the example of additive are releasing agent, pigment, stabilizing agent, antioxidant, pore former, penetrant, polishing material, aromatic substance and flavoring agent.They are used as processing aid and are intended to guarantee reliable and reproducible production process and good long-term storing stability, or they realize other favourable character in medicament forms.They to be added into before processing in polymer formulations and can to affect the permeability of coating, likely utilize this point as other controling parameters when in place.
pigment:
As previously mentioned, pigment can be used in coatings, play the effect of non-porous inert lubricant, to promote the impact of ethanol tolerant.If add pigment in addition not have contributive excipient as to the present invention, they can be joined table coating above coatings to provide certain color.Play in coatings non-porous inert lubricant effect or as the present invention not had to the pigment of contributive excipient yes usually nontoxic and being suitable for pharmacy object.About this point, also refer to, such as: Deutsche Forschungsgemeinschaft, Farbstoffe f ü r Lebensmittel, Harald, Boldt Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau the 74, No.4,156th page (1978); Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980.
The example of pigment is orange, carmine lake, based on the colored pigment of aluminium oxide or azo dye, sulfonic acid dye, orange S (E110, C.I.15985, FD & C Yellow 6), indigo carmine (E132, C.I.73015, FD & C Blue 2), tartrazines (E 102, C.I.19140, FD & C Yellow 5), ponceau 4R (E 125, C.I.16255, FD & C Cochineal Red A), D C Yellow No. 10 (E 104, C.I.47005, FD & C Yellow 10), erythrosine (E127, C.I.45430, FD & C Red 3), azorubine (E 122, C.I.14720, FD & C Carmoisine), amaranth (E 123, C.I.16185, FD & C Red 2), acid viride nitens (E 142, C.I.44090, FD & C Green S).
E numeral and EU number relevant pigment.About this point, also refer to: " Deutsche Forschungsgemeinschaft, Farbstoffe f ü r Lebensmittel, Harald Boldt Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau the 74, No.4,156th page (1978); Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980.Described by FD & C numeral relates in the following, food is used for by FDA (FDA) approval, approval number in medicine and cosmetics: U.S.Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors:Code of Federal Regulations-Title 21 Color Additive Regulations Part 82, Listing of Certified Provisionally Listed Colors and Specifications (CFR 21Part 82).
plasticizer
Other additive also plasticizer.Plasticizer can advantageously be added in coatings.Usual amounts based on such as coatings (methyl) acrylate copolymer weight 0 to 50 % by weight, preferably 5 to 20 % by weight.Preferably do not add plasticizer to coatings.
Plasticizer can affect the function of polymeric layer, different from the difference of type (lipotropy or hydrophilic) and addition.Plasticizer reduces glass transition temperature and promote film forming by carrying out Physical interaction with polymer, different according to the difference of addition.Suitable material usually has the molecular weight between 100 to 20 000 and contain one or more hydrophilic radical such as hydroxyl, ester group or amino in molecule.
The example of suitable plasticizer is citric acid alkyl esters, glyceride, alkyl phthalates, sebacic acid alkyl esters, sucrose ester, Isosorbide Dinitrate, ethyl sebacate, and dibutyl sebacate and Macrogol 200 are to 12 000.Preferred plasticizer is triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS).The esters of normally liquid will be should be mentioned that at room temperature in addition, such as citrate, phthalic acid ester, sebacate or Oleum Ricini.The ester of preferred use citric acid and decanedioic acid.
In preparation, add plasticizer can carry out in known manner, namely directly join in aqueous solution or after the Grape berry of mixture and add.Also may use the mixture of plasticizer.
neutral cellulosic cpd is added in coating
Dry weight basis with polymeric blends (compound i) and ii)), coatings comprises the cellulosic cpd of at least one neutrality of 1 to 35 % by weight, preferably 2 – 30 % by weight, most preferably 5 – 25 % by weight in addition.Neutral cellulosic cpd is a kind of cellulose derivative of neutrality and can be preferably cellulosic ethylether or methyl ether.Most preferably, neutral cellulosic cpd is hydroxyethyl-cellulose or hydroxypropyl emthylcellulose (HPMC).
emulsifying agent is added in coating
The present inventor finds, adds the toleration that one or more emulsifying agents seem indirectly to improve pharmaceutical composition in coating.Infer that the existence of detergent in sprayed suspension facilitates film forming procedure and become more complete.Film is seemingly than the impact of the film do not formed containing a certain amount of emulsifying agent in coating more ethanol tolerant more completely.The film do not formed containing a certain amount of emulsifying agent in coating is considered to than the film formed under the existence of emulsifying agent a little more porous.Therefore, the effect of emulsifying agent in film forming procedure, although not yet really understand, may be similar to the effect being different from and coated pellets being cured to process.More surprisingly, whether comprise ethanol in medium and all seemingly passive impact or change be there is no on release characteristic itself.
Therefore, dry weight basis with polymeric blends (compound i) and ii)), the pharmaceutical composition of controlled release of the present invention can comprise at least one emulsifying agent of 2 to 20 % by weight, preferably 5 – 15 % by weight, preferred nonionic emulsifier in addition.
Preferred emulsifier is the polyoxyethylene deriv of Isosorbide Dinitrate.
Most preferably, detergent be polyoxy-ethylene sorbitan monoleate (Polyethylene Glycol Arlacel-80, CAS registration number 9005-65-6, such as 80).
The bin stability improved
Surprisingly, when cellulosic cpd or emulsifying agent are used in pharmaceutical composition separately, bin stability is not affected.In this case, bin stability is still acceptable, this means still to leave some room for improvement.But when being used together with emulsifying agent by cellulosic cpd, bin stability becomes much better, and can be referred to as excellence.
Application
The pharmaceutical composition of the dependent controlled release of pH of the present invention can be used for being reduced in oral after the risk that discharges of the enhancing of the active constituents of medicine comprised that brings due to the simultaneously or subsequently beverage (misuse) of picked-up containing ethanol.
Embodiment
Method
Model drug
Metoprolol is used to study as model drug.
Stripping is studied
According to USP 28-NF23, general rules <711>, stripping, tests, first 2 hours simulated gastric fluid at pH 1.2, then in the buffer medium of pH 6.8.
Stripping parameter:
Device: USP I type (basket method)
RPM：100/min
Temperature: 37.5 ± 0.5 DEG C
Stripping volume: 500ml.
Take out volume: use pipet manually to take out 5ml, do not supplement medium
Detection mode: HPLC
Dissolution medium 1:
Simulated gastric fluid pH 1.2 (European Pharmacopoeia=EP)
Dissolution medium 2:
Simulated gastric fluid pH 1.2 (European Pharmacopoeia=EP), containing 40% (v/v) ethanol
Dissolution medium 3:
Phosphate buffered saline (PBS) pH 6.8 (European Pharmacopoeia=EP)
Dissolution medium 4:
The KH of the phosphate buffered saline (PBS) pH 6.8, EP-0.9g of the alcohol containing 40%v/v 2pO 4, the K of 1.8g 2hPO 4, the NaCl of 7.65g, uses the alcohol of 540ml demineralised water and 360ml.
Copolymer
nEethyl acrylate by 30 % by weight and 70 % by weight the copolymer that forms of the radical polymerization unit of methyl methacrylate.
fSthe copolymer that the radical polymerization unit of the methyl methacrylate by 25 % by weight, the acrylic acid methyl ester. of 65 % by weight and the methacrylic acid of 10 % by weight forms.
Formulation details
In the fluid bed processing unit (plant) using bottom spray, the core core (sugared ball, celphere) of 1700-2000 micron is loaded metoprolol.Polyvinylpyrrolidone ( k25) as binding agent.By the core core of 900g celphere be bonded in 80g binding agent ( k25) the 270g metoprolol coating in.
prepared by film coating suspension:
Will dispersion mixes in the suitable container applying gentle agitation.Applying high shear force is by lubricant and different dissolution of polymer or be dispersed in water.
Lubricant-suspension is poured into and applies gentle agitation in dispersion.Stir in whole coating process and continue to carry out.
coating process:
In fluid unit, under suitable conditions, namely under the bed temperature of the about 10-20g film coating suspension/spray rate of minute/kilogram of core core and about 25-28 DEG C, the piller with medicine layer is carried out coating with different film coating suspension.After coating, by piller in fluid bed processing unit (plant) 50 DEG C of fluidisations 1 hour.Micronized Talcum is used as excipient.Coated pellets has the average diameter of about 3000 microns.
storage stability
The deviation of the release characteristic is before storage with f 2when but value is expressed as more than 50 is less than the similarity of 60, think that bin stability is acceptable.The deviation of the release characteristic is before storage with f 2when value is expressed as 60 to 100, think that bin stability is good.

Claims (23)

  1. The pharmaceutical composition of the dependent controlled release of 1.pH, comprises:
    Core core, it comprises the active constituents of medicine of at least one non-opium medicine, and its center core is controlled the coatings coating of pharmaceutical composition release by least one,
    Wherein coatings comprises the polymeric blends of following material:
    I) with the dry weight basis of polymeric blends, the vinyl polymer that at least one of 40-95 % by weight is water-insoluble, neutral in fact or copolymer, described water-insoluble, neutral in fact vinyl polymer or copolymer are polymer or its derivative copolymer or (methyl) acrylic acid series copolymer of polyvinyl acetate type, and
    Ii) with the dry weight basis of polymeric blends, the at least one anionic polymer of 5-60 % by weight or copolymer, it is insoluble and at least solvable in the scope of pH7.0 to pH 8.0 in the buffer medium lower than pH 4.0, described anionic polymer or copolymer are water-soluble anionic cellulose derivative or water-soluble anionic (methyl) acrylate copolymer
    Be characterised in that,
    The cellulosic cpd of this coatings in addition containing the non-porous inert lubricant of 110-250 % by weight, at least one neutrality of 1-35 % by weight, with at least one emulsifying agent of 1-25 % by weight, it is all the dry weight basis with polymeric blends, the cellulosic cpd of wherein said neutrality is cellulosic ethylether or methyl ether, described non-porous inert lubricant is the silica component of stratiform, pigment or stearate compound, and described emulsifying agent is nonionic emulsifier.
  2. 2. the pharmaceutical composition of the controlled release of claim 1, is characterised in that, inert lubricant is Talcum.
  3. 3. the pharmaceutical composition of the controlled release of claim 1, is characterised in that, inert lubricant is calcium stearate or magnesium stearate.
  4. 4. the pharmaceutical composition of the controlled release of claim 1, is characterised in that, water-insoluble, neutral in fact vinyl polymer or copolymer be by more than 95 to up to 100 % by weight the C of acrylic or methacrylic acid 1-C 4-Arrcostab and the copolymer formed lower than the radical polymerization unit of the acrylic or methacrylic acid of 5 % by weight.
  5. 5. the pharmaceutical composition of the controlled release of one of claim 1-4, is characterised in that, water-insoluble, neutral in fact polymer is polymer or the copolymer of polyvinyl acetate type.
  6. 6. the pharmaceutical composition of the controlled release of one of claim 1-4, is characterised in that, water-soluble anionic polymer is by the C of the acrylic or methacrylic acid of 25 to 95 % by weight 1-C 4-Arrcostab and 5 to 75 % by weight have (methyl) acrylate monomer of anionic group radical polymerization unit composition (methyl) acrylate copolymer.
  7. 7. the pharmaceutical composition of the controlled release of claim 6, be characterised in that, water-soluble anionic polymer is made up of the radical polymerization unit of the methyl methacrylate of 10 to 30 % by weight, the acrylic acid methyl ester. of 50 to 70 % by weight and 5 to 15 % by weight methacrylic acids.
  8. 8. the pharmaceutical composition of the controlled release of one of claim 1-4, is characterised in that, neutral cellulosic cpd is hydroxypropyl emthylcellulose.
  9. 9. the pharmaceutical composition of the controlled release of claim 1-4, is characterised in that, emulsifying agent is the polyoxyethylene deriv of Isosorbide Dinitrate.
  10. 10. the pharmaceutical composition of the controlled release of claim 9, is characterised in that, emulsifying agent is polyethoxylated sorbitan alcohol monoleate.
  11. The pharmaceutical composition of the controlled release of one of 11. claim 1-4, is characterised in that, according to USP paddle method, and 100rpm, at pH 6.8 under the conditions in vitro of buffering, adding and do not adding in the medium of 40% (v/v) ethanol, it has following character:
    When active constituents of medicine is not when adding under 40% (v/v) ethanol condition the degree that release reaches lower than 20%, the difference adding the rate of release under 40% (v/v) ethanol condition be no more than do not add the corresponding release value under 40% (v/v) ethanol condition ± 15%
    When active constituents of medicine is not when to add under 40% (v/v) ethanol condition release and reach the degree of 20-80%, the difference adding the rate of release under 40% (v/v) ethanol condition be no more than do not add the corresponding release value under 40% (v/v) ethanol condition ± 30%.
  12. The pharmaceutical composition of the controlled release of one of 12. claim 1-4, is characterised in that, active constituents of medicine is the acceptable salt of pharmacy of metoprolol or metoprolol.
  13. The pharmaceutical composition of the controlled release of one of 13. claim 1-4, is characterised in that, it is the form of the piller be comprised in many granule medicaments form.
  14. The pharmaceutical composition of the controlled release of 14. claim 13, is characterized in that, described many granule medicaments form is compressed tablets, capsule, pouch or reconstitutable powder form.
  15. The pharmaceutical composition of the controlled release of 15. claim 13, is characterized in that, described many granule medicaments form is effervescent tablet.
  16. The pharmaceutical composition of the controlled release of one of 16. claim 1-4, is characterised in that, it has end coating and/or table coating.
  17. The pharmaceutical composition of the controlled release of one of 17. claim 1-4, is characterised in that, it take grand mean diameter as the form existence of the coated pellets of 100 to 5000 microns.
  18. The pharmaceutical composition of the controlled release of 18. claim 17, is characterised in that, the grand mean diameter of coated pellets is 100 to 700 microns.
  19. The pharmaceutical composition of the controlled release of 19. claim 17, is characterised in that, the grand mean diameter of coated pellets is 1400 to 5000 microns.
  20. The pharmaceutical composition of the controlled release of 20. claim 19, is characterised in that, with the weighing scale of core core, coatings exists with the amount of at least 30 % by weight.
  21. 21. the pharmaceutical composition of the controlled release of one of claim 1 to 4, is characterised in that, when having or do not have interpolation 40% ethanol (v/v), in 2 hours, in simulated gastric fluid pH 1.2, the releasing degree of active component is 10% or lower.
  22. The pharmaceutical composition of the controlled release of one of 22. claim 1-21, is characterized in that, the enhancing of the active constituents of medicine comprised brought due to the simultaneously or subsequently beverage of picked-up containing ethanol after being reduced in orally ingestible or reduce the risk of release.
  23. The method of the pharmaceutical composition of the controlled release of one of 23. preparation claim 1-12; described method is in known manner by direct pressing; the compacting of dry, wet or agglomerated grain and full circle subsequently, wet granulation or non-slurry pelletizing or directly pill or by making powder stratification be attached to not containing the globule of active component or neutral core core or containing on the granule of active component and by spraying process or by fluidized bed prilling applying polymer coating.
CN201510407830.0A 2008-09-24 2008-09-24 The pharmaceutical composition of the dependent controlled release of pH for the non-opium drug that ethanol tolerant influences Expired - Fee Related CN104984343B (en)

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US20030077297A1 (en) * 1999-02-26 2003-04-24 Feng-Jing Chen Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US20050163856A1 (en) * 1999-07-29 2005-07-28 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
WO2006125483A1 (en) * 2005-05-25 2006-11-30 Evonik Röhm Gmbh Use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating
WO2008049657A2 (en) * 2006-10-26 2008-05-02 Evonik Röhm Gmbh Use of (meth)acrylate copolymers in slow-release pharmaceutical forms for reducing the influence of ethanol on active ingredient release

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030077297A1 (en) * 1999-02-26 2003-04-24 Feng-Jing Chen Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US20050163856A1 (en) * 1999-07-29 2005-07-28 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
CN1382051A (en) * 1999-08-27 2002-11-27 南方研究所 Injectable bupernorphine microparticle compositions and their use
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WO2008049657A2 (en) * 2006-10-26 2008-05-02 Evonik Röhm Gmbh Use of (meth)acrylate copolymers in slow-release pharmaceutical forms for reducing the influence of ethanol on active ingredient release

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