CN104984343B - The pharmaceutical composition of the dependent controlled release of pH for the non-opium drug that ethanol tolerant influences - Google Patents

The pharmaceutical composition of the dependent controlled release of pH for the non-opium drug that ethanol tolerant influences Download PDF

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Publication number
CN104984343B
CN104984343B CN201510407830.0A CN201510407830A CN104984343B CN 104984343 B CN104984343 B CN 104984343B CN 201510407830 A CN201510407830 A CN 201510407830A CN 104984343 B CN104984343 B CN 104984343B
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weight
pharmaceutical composition
controlled release
release
dependent controlled
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CN104984343A (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 present invention relates to the pharmaceutical compositions of the dependent controlled release of pH, it includes the active pharmaceutical ingredients of at least one non-opium drug, wherein core is coated by the coatings that at least one control pharmaceutical composition discharges, wherein coatings include the polymeric blends of following substance: i) in terms of the dry weight of polymeric blends, at least one water-insoluble of 40-95 weight %, substantially neutral vinyl polymer or copolymer, and ii) in terms of the dry weight of polymeric blends, the at least one anionic polymer or copolymer of 5-60 weight %, it is insoluble in the buffer medium lower than pH 4.0 and at least solvable in the range of pH 7.0 arrives 8.0 pH, it is characterized in that, non-porous inert lubricant of the coatings in addition containing 110-250 weight %, 1-35 weight The cellulosic cpd of at least one neutrality of % and at least one emulsifier of 1-25 weight %, are all in terms of the dry weight of polymeric blends.

Description

The medicine group of the dependent controlled release of pH for the non-opium drug that ethanol tolerant influences Close object
Technical field
The present invention relates to the pharmaceutical composition of the dependent controlled release of the pH of non-opium drug, the drug, which has, to be directed to The reduced sensibility of influence of the ethyl alcohol to release active compound.
Background technique
2003/0118641 A1 of US, which is described, reduces the indiscriminate of the oral pharmaceutical form containing extractible opioid drug With the process of possibility.In this process, confrontation is especially provided by common household solvent such as isopropanol, vodka Reactive compound caused by wine, white wine vinegar, hot water or peroxide, the 0.01HCl in dilute alcohol extracts.It is recommended that use forms base The active ingredient of the polymer and ion exchange material of matter such as styrene-divinylbenzene polymer formulation Micronised form Object.Ion exchange material is conclusive for increasing the effect that confrontation reactive compound extracts.The polymer for forming matrix is aobvious So serve as the texturizing agent of drug core.The long list for being used to form the possibility substance of the polymer of matrix is specifically illustrated, It especially include polymethacrylates in the list.Preferred matrix formers are C1-C6Hydroxyalkyl-cellulose.
2004/0052731 A1 of US describes the medicament forms of particularly suitable opioid activity compound, will be helpful to Reduce the abuse potential as brought by improper administration.It is recommended that lipophilic active chemical variants and water insoluble additive are all As the water-soluble polysaccharide of such as fatty acid or crosslinking combines.
2005/0163856 A1 of US describes the treatment using the medicament forms treatment pain patients containing Oxycodone Journey, the medicament forms have reduction as dissolving out in a solvent and abuse potential brought by subsequent improper administration.Thus Purpose, reactive compound should use the formation matrix selected from hydroxypropyl cellulose, hypromellose or hydroxyethyl cellulose Polymer prepared.
2006/002884 A1 of WO describes the oral delivery form for guarding against abuse, is at least containing resistance to fracture The polymer of 500N, especially polyoxygenated alkene.
2006/094083 A1 of WO describes the medicament forms with controlled Venlafaxine release characteristic.In order to reduce Reactive compound, is integrated to the base of gelling cross-linked polymer such as xanthan gum by the abuse potential as brought by addition ethyl alcohol In matter.Other hydrophobic polymer, especially polymethacrylates can be added, as additive.
WO 2006/125483 describe polymeric blends be used to prepare coating pharmaceutical preparation application and have The pharmaceutical preparation of mixed polymeric coating.The polymeric blends are intended to provide the release mode of change, are exclusively used in different pharmaceutical The particular treatment requirement of ingredient, these requirements cannot be achieved by using standard polymers.Not about ethanol tolerance medicine The instruction of object form.In embodiment, use is describedNE withFS is with 5 to 50 weight % 'sThe medicament forms that the mixture of the ratio of FS is coated.However it is not used or is saying in embodiment A large amount of talcum as used in the present invention is not recommended to use in bright book.The suitable 2-20 weight with a thickness of core weight of coating % is measured, it is more much lower than coating thickness of the presently claimed invention.
1994/0022431 A1 of WO describes the oral drug preparation of the morphine containing the therapeutically effective amount for administration. It contains the individual particle that at least 50 granular sizes are 0.7 to 1.4 millimeters.Each particle has to be contained with what barrier layer was coated The core of morphine salt.Barrier layer contain it is at least one selected from ethyl cellulose, by acrylate or methacrylic acid Lipase absobed The water-msoluble ingredients and plasticizer of copolymer and native paraffin, for providing the drug release for passing through coating barrier layer, in fact The pH for being 1.0 to 7.0 independent of range in matter.The morphine obtained during giving at least 12 hours after preparation described in single dose Serum-concentration be at least the 50% of maximum serum-concentration.
US 2007/053698 disclose the sustained release of opiates (including but not limited to Hydromorphone and Oxycodone) to The method of medicine, this method show improved property in terms of the total intake with aqueous alcohol.
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 drug ingedient, the drug ingedient It is prepared with pharmaceutically acceptable film forming polymer and the optional pharmaceutically acceptable excipient of others, wherein pharmaceutical composition Object shows the dependent controlled release of pH of drug ingedient.
Active pharmaceutical ingredient in addition to opioid drug
The pharmaceutical composition of the dependent controlled release of pH includes core, including at least one medicine in addition to opioid drug Object active constituent.Pharmaceutical composition comprising one or more opioid drugs (opium excitomotor) clearly is excluded Except the present invention.
Preferably it is usually formulated as the active pharmaceutical ingredient of controlled release dosage form or sustained release forms.
Suitable active pharmaceutical ingredient is such as metoprolol.
The pharmaceutical substance used can be found in reference book, such as, the Rote Liste or the Merck Index。
Active component or pharmaceutical substance for the purpose of the present invention is to be used for human body or animal body for following purpose:
1. curing, mitigating, prevent or diagnosing illness, the patient's condition, somatic damage or pathological state；
2. disclosing situation, state or the function or the state of mind of body；
3. active material or body fluid that substitution is generated by human body or animal body；
4. avoiding or eliminating pathogen, helminth or allogenic material, or keep its harmless；Or
5. influencing situation, state or the function or the state of mind of body.
These pharmaceutically active substances can belong to one or more active constituent classifications, such as Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, adrenergic Drug, Adrenocorticosteroids, acne therapeutic agent, aldose reductase inhibitor, aldosterone antagonist, alpha-Glucosidase suppression Preparation, 1 antagonist of α, alcohol abuse drug, amino acid, amoebacide, anabolic hormones drug, analeptic, anesthesia addition Agent, arcotic (non-imbedibility), arcotic (part), antalgesic (in addition to opioid drug), androgen, colic pain therapeutic agent, Antagonist, antiallergic, antiallergic such as PDE inhibitor, the antiallergic for treating asthma, other antiallergic (examples Such as leukotriene antagonist, Antianemic Agents, antiandrogen, anxiolytic, anti-arthritic, antiarrhymic, anti-artery congee Sample hardens medicine, antibiotics, anticholinergic drug, anticonvulsive drug, antidepressants, antidiabetic, antidiarrheal agent, antidiuretic, solution Poison, antiemetic, antiepileptic, antifibrinolytics, antiepileptic, helminthagogue (antihelmintics), anti-group Amine medicine, antihypotensive, antihypertensive, antihypertensive, antihypotensive, anticoagulation, antifungal, antiestrogen, Antiestrogen (on-steroidal), anti-Parkinson's drug, anti-inflammatory agents, antiproliferative activity ingredient, Anti-protozoal activity ingredient, wind resistance Wet medicine, schistosomicide, antispasmodic, antithrombotic, pectoral, appetite inhibitor, atherosclerosis drug, bacteriostatic, β-resistance Disconnected agent, receptor blocking agent, bronchodilators, carbonic anhydrase inhibitor, chemotherapeutic agents, cholagogic, cholinergic drug, choline Can agonist, anticholinesterase, treat the medicament of ulcerative colitis, cox-2 inhibitors diuretics, kill it is ectoparasite Worm medicine, emetic, enzyme, enzyme inhibitor, enzyme inhibitor, the active constituent to emesis, cellosolve, fungistatic, gout drug, blueness Light eye therapeutic agent, glucocorticoids, glucocorticosteroid class, hemostat, cardiac glycoside, 2 antagonist of histamine H, steroids and its Inhibitor, immunization therapy medicine, cardiotonic drug, anticoccidiosis medicine, laxatives, lipid-lowering medicine, gastro-intestinal therapeutic agent, malaria treatment agent, migraine Drug, microbicide, Crohn disease, cancer transfer inhibitor, migraine remedy, mineral preparations, the activity for increasing motility Ingredient, muscle relaxant, neuroleptic drug, the active constituent for estrin treatment, osteoporosis, Debrox, anti-pa The gloomy medicine of gold, botanical medicine, proton pump inhibitor, prostaglandin, the active constituent for treating benign prostatic hyperplasis, for treating The active constituent of itch, psoriasis active constituent, psychoactive drug, free radical scavenger, Renin antagonists, thyroid gland treatment It is agent, small for treating seborrheal active constituent, the seasick active constituent of confrontation, antispasmodic, α-and β-sympathetic transmitter releasers, blood Plate agglutination inhibitor, sedative, therapeutic agent for ulcer, other therapeutic agent for ulcer, the medicament for treating uriasis, anti-viral medicine, Vitamins, cell factor, the active constituent for being used for together with cytostatic agent combination therapy.
The example of the suitable active component in addition to opioid drug is such as acarbose, aspirin, A Baka Wei, Aceclofenac, Aclarubicin, acyclovir, D actinomycin D, adalimumab, adefovirdipivoxil, adefovir dipivoxil, Adenosylmethionine, adrenaline and adrenaline derivative, alpha-galactosidase, β-A Jiaxi enzyme, Alemtuzumab, A Mo Qu Tan, alphacept, Allopurinol, almotriptan, Alosetron, Alprostadil, amantadine, ambroxol, Amisulpride, ammonia Flordipine, Amoxicillin, 5 aminosalicylic acids, amitriptyline, Amlodipine, Amoxicillin, amphinate, anakinra, Ah Nagqu azoles, androgen and androgen derivative, apomorphine, Aripiprazole, arsenic trioxide, Artemether, atenolol, atropic Cut down statin, Atosiban, imuran, azelaic acid, barbituric acid derivatives, Balsalazide, basiliximab, beclapermin, Beclomethasone, bemiparin, Benzodiazepines, Betahistine, bexarotene (bexaroten), Bezafibrate, Bicalutamide, Bimatoprost, Bosentan, botulinus toxim, Brimonidine, brinzolamide, budesonide, budipine, bufexamac, Bumetanide, Bupropion, butizine, calcitonin, calcium antagonist, calcium salt class, Candesartan, capecitabine, captopril, Carbamazepine, carifenacin, Carvedilol, Caspofungin, Cefaclor, cefadroxil, cefalexin Cefalosporins, Cefditoren, Cefprozil, celecoxib, cepecitabine, cerivastatim, cetirizine, It is Cetrorelix, Cetuximab, chenodeoxycholic acid, chorionic gonadotrophin, cyclosporine, cidofovir, Cimetidine, Ciprofloxacin, suitable Platinum, Cladribine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, clopidogrel, caffeine, cholestyramine Amine, Cromoglycic acid, Compound New Nomin, cumarin and coumarin derivative, darbepoetin, cysteamine, cysteine, cytarabine, Cyclophosphamide, cyproterone, cytarabine, daclizumab, Dalfopristin, danaparoid, Dapiprazole, darbepoetin, Defepripone, desipramine, Desirudin, desloaratadine, minirin, Desogestrel, desonide, right cloth Ibuprofen, Dexketoprofen, disoproxil, diazepam and diazepam derivative, Dihydralazine, your sulphur, dramamine, diformazan it is sub- Sulfone, dimeticon, pivaloyloxymethyl, dipyridarnoi, Dolasetron, domperidone and domperidone (domperidane) derivative, donepzil, dopamine, Doxazosin, doxorubizin, doxylamine, Diclofenac, The solidifying α of divalproex, Dronabinol, Drospirenone, buckling gram, dutasteride, Ebastine, econazole, efavirenz, Eletripan, emidastine, emtricitabine, enalapril, encepur, Entacapone, enfurvirtide, ephedrine, Adrenaline, eplerenone, Epoetin and Epoetin derivative, according to general Losartan, eptifibatide, ertapenem, esomeprazole, Estrogen and oestrogen derivatives, Etanercept, Ethenzamide, ethinestradiol, etofenamate, Etofibrate, second Hydroxyl theophylline, Etonogestrel, Etoposide, Exemestane, exetimib, famciclovir, famotidine, faropenan Daloxate, felodipine, fenofibrate, Fenticonazole, fexofenadine, Finasteride, Fluconazole, fludarabine, fluorine osmanthus Sharp piperazine, fluorouracil, Prozac, Flurbiprofen, Flupirtine, Flutamide, Fluvastatin, follitropic hormone, Fomivirsen, Fondaparinux, Formoterol, fosfomicin, SB 209509, frusemide, Fusidic Acid, gadobenate, galanthamine, Gallopamil, Ganciclovir, Ganirelix, gatifloxacin, Gefitinib, Gemfibrozil, gentamicin, Gepirone, progestational hormone With progestin derivative, ginkgo, glatiramer, glibenclamide, Glipizide, glucagons, D-sorbite and sorbitol derived Object, Glucosamine and aminoglucose sugar derivatives, glucosides antibiotics, glutathione, glycerol and glycerol derivatives, hypothalamus Steroids, Goserelin, Grepafloxacin, gyrase inhibitor, guanethidine, gyrase inhibitor, X-factor, halogen are general Group, haloperidol, the urea derivative as oral antidiabetic, heparin and heparin derivatives, cardiac glycoside, hyaluronic acid, Hydrolazine, Hydrochioro and Hydrochioro derivative, hydroxyomeprazole, hydroxyzine, ibritumomab, brufen, she Up to than star, ifliximab, ifosfamide, iloprost, Imatinib, Imidapril, Imiglucerase, imipramine, miaow quinoline Mo Te, Imidapril, Indomethacin, indoramin, infliximab, insulin, insulin glargine preparation, interferons, strategic point Bei Shatan, Irinotecan, Isoconazole, isoprel, Itraconazole, Ivabradine, iodine and iodine derivative, hypericum erectum category Plant, ketoconazole, Ketoprofen, Ketotifen, lacidipine, Lansoprazole, La Luoni enzyme, Latanoprost, takes fluorine rice at sylvite class It is spy, lepirudin, Lercanidipine, leteprinim, Letrozole, levacetylmethadol, Levetiracetam, levocetirizine, left-handed more Bar, Li Kaofeilong, Linezolid, lipinavir, lipoic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramine, Lodoxamide, Lomefloxacin, lomustine, Loperamide, Lopinavir, Loratadine, Lornoxicam, Losartan, lumefantrine, Luteotropin, magnesium salts, macrolides antibiotics, mangafodipir, maprotiline, mebendazol, mebeverine, Meike Lip river Piperazine, mefenamic acid, Mefloquine, Meloxicam, Memantine, mepindolol, Meprobamate, Meropenem, Mesalazine, first amber Amine, analgin, melbine, methopterin, 5- amino -4-oxopentanoic acid methyl esters, methylnaloxone, Methylnaloxone, methyl naltrexone, methylphenidate, methylprednisolone, methixene (metixen), Metoclopramide, Mei Tuoluo That, metronidazole, Mianserin, mibefradil, Miconazole, mifepristone, Miglitol, miglustad, minocycline, rice Promise ground that, Misoprostol, mitomycin, Mizolastine, modafinil, Moexipril, montelukast, moroctocog, not Xisha star, ergot alkaloids, naloxone, naproxen, naratriptan, coscopin, Natamycin, Nateglinide, Nebivolol, Nefazodone, Nai Feinawei, neostigmine, neramexan, nevirapine, Nicergoline, nikethamidum, nifedipine, Buddhist nun's fluorine Acid, Nimodipine, Nimorazole, Nimustine, Nesiritide, Nisoldipine, Norfloxacin, novamine sulphone, that can Fourth, nystatin, Ofloxacin, oktotride, Olanzapine, Olmesartan, Olsalazine, oseltamivir, Omeprazole, Austria Not health azoles, Ondansetron, orlistat, oseltamivir, Oxaceprol, oxacillin, oxaliplatin, olsapozine, Oxcarbacepin, Oxiconazole, oxymetazoline, palivizumab, palanosetron, Pantoprazole, paracetamol, Parecoxib, Paxil, Pegaspargase, glycol interferon, pegfilgrastrim, Penciclovir, oral mould Plain class, Pentifylline, pentoxifylline, peptide antibiotics, Perindopril, perphenazine, pethidine, plant extracts, peace for than Woods, pheniramine, phenylbutyric acid, phenytoinum naticum, phenthazine, Fen Sailin, phenylbutazone, phenytoinum naticum, Elidel, Pimozide, Yin It is diindyl Luo Er, Pioglitazone, piperazine, Piracetam, pirenzepine, piribedil, pirlindole (pirlindol), piroxicam, general Clarke rope (pramipexol), pramlintide, Pravastatin, prazosin, procaine, promazine, Propiverine, Propranolol, Propanoic derivatives, propyphenazone, prostaglandin, protionamide, Proxypbylline, Quetiapine, quinapril, quinoline Puli Drawing, Quinupristin (quinupristine), Ramipril, ranitidine, Rabeprazole, Raloxifene (raloxifen), thunder Promise piperazine, rasburicase, Reboxetine (reboxetin), repaclinides, Reproterol, Reserpine, revofloxacin, Ribavirin, rifampin, Riluzole, Rimexolone, Risedronate, Risperidone, Ritonavir, Rituximab, Rivastimen, risatriptan, rofecoxib, Ropinirole (ropinirol), Ropivacaine, Rosiglitazone, Luo Sha are replaced Fourth, roxithromycin, ruscogenine (ruscogenin), rosuvastatin, rutin and rutin derivatives, cevadilla, salbutamol, Salicylic acid salt, salmeterol, Saperconazole, thyroid hormones, hyoscine, selegiline, Sertaconazole, Sertindole, house Qu Lin, sevelamer, sibutramine, sildenafil, silicates, Simvastatin, sirolimus, sitosterol, Sotalol, Spaglumic Acid, Sparfloxacin, spectinomycin, spiramvcin, Spirapril, spirolactone, stavudine, streptomysin, ulcerlmin, Shu Ba Smooth, sulfonamide, salicylazosulfapyridine, Sulpiride, Sultamicillin, Sultiame (sultiam), sumatriptan, Suxamethonium Chloride, he Crin, Tadalafei, taliolol, Talsaclidine, tamoxifen, tasonermin, tazarotene, Tegafur, replaces tacrolimus Additive color sieve, Telmisartan, Temoporfin, Temozolomide, tenatoprazole, Tenecteplase, Teniposide, replaces promise good fortune at Ketek Wei, tenoxicam, Teriparatide, Terazosin, Terbinafine, Terbutaline, RMI 9918, Teriparatide, terlipressin, Tertatolol, testosterone and testosterone derivative, Tetracyclines, Tetryzoline, tezosentan, theobromine, theophylline, theophylline derivative, Methimazole, phosphinothioylidynetrisaziridine, thr. growth factor class, Tiagabine, Tiapride, Tibolone, ticlopidine, timolol, Tinidazole, Tioconazole, thioguanine, tiotropium, tioxolone, tirazetam, tiropramide, tirofiban, Tizanidine, appropriate drawing How general azoles woods, orinase, Tolcapone, Tolnaftate, Tolperisone, Tolterodine, Topiramate, Hycamtin, Torasemide, group be Benefit, parnitene, trapidil, Herceptin, travoprost, Trazodone, trepostinil, triamcinolone and song Anxi dragon derivative, dyrenium, Trifluperidol, Trifluridine, Trimetazidine, trimethoprim, trimipramine, Tripelennamine, Triprolidine, trifosfamide, tromantadine, tromethamine, tropalpine, trovafloxacin, Troxerutin, Tuo Luote Sieve, tyrasamine, tyrothricin, Urapidil, ursodesoxycholic acid, theophylline ursodesoxycholic acid, Valaciclovir, cuts down ground at Trypsin Examine former times, valganciclovir, valproic acid, Valsartan, vancomycin, Vardenafil, dimension library oronain, Venlafaxine, Verapamil, dimension For pool sweet smell, arabinosy ladenosine, sabril, Viloxazine, vincaleukoblastinum, pervone, vincristine, eldisine, vinorelbine, length Chun Xiding, viquidil, vitamin D and vitamin D derivative, warfarin, Buddhist nun gram Landrina, ximelagatran, are wished at voriconazole Pa amine, zafirlukast, zalcitabine, Zaleplon, zanamivir, Zidovudine, Ziprasidone, zoledronic acid, assistant meter Qu, azoles Pyrrole is smooth, zoplicone, Zotepine.
If desired, active component can also be used in the form of their pharmaceutically acceptable salt or derivative, and In the case where chiral acti ve ingredient, it is possible to use the racemate or mixture of optical isomer and diastereomer.If It needs, composition of the invention can also include two or more active pharmaceutical ingredients.
The dependent controlled release of pH
The dependent controlled release of the pH of drug ingedient refers to when being exposed to tool in pharmaceutical composition in vitro dissolution test When having in the USP medium through buffering of different pH value, the pH value is located in the range of about pH 1 to about pH 7 and with about 1 pH Interval changes, and the amount that drug ingedient is discharged or dissolved out in the medium in certain time interval is in the medium with different pH value It is dramatically different.
The USP medium through buffering with different pH value is known to the skilled in the art.USP with different pH value Medium 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 be molten in USP Out in device such as II device (paddle method), 37 DEG C, dissolve out stirring rate 100rpm under carry out, certain time interval can for Such as 1,2,3,4,5,6,7,8,9 or 10 hour or even longer hourage.
When being tested in the medium with different pH value pH 1.2,2.0,4.5,6.8 and 7.4, with different pH Rate of dissolution in the medium of value is dramatically different.
For example, compare with the behavior of the dependent controlled release of pH of the invention, typical pH dependent/non-dependent controlled release Behavior for example described in WO1994/022431A1 (referring particularly to page 13, table 5).
Particularly, the pH release behavior of pharmaceutical composition of the invention is because of its stomach juice-resistant but pH dependence, this Refer in the USP medium of pH 1.2 only have 10% drug ingedient to be released in 2 hours, and is situated between in the USP of higher ph In matter, such as in the USP medium of pH 7.4, the drug ingedient in 2 hours significantly beyond 10% is released.In contrast, The form (referring to page 13, table 5) of the pH dependent/non-dependent controlled release of WO1994/022431A1 is pH's 1.2 or pH 7.4 Identical 15% rate of release is shown in buffer medium after 2 hours.
Polymeric blends
Term polymeric blends refer to the mixture of following component in the sense of the present invention:
It i) is the basic neutral of at least one water-insoluble of 40-95 weight % in terms of the dry weight of polymeric blends Vinyl polymer or copolymer, and
Ii) in terms of the dry weight of polymeric blends, be 5-60 weight % at least one anionic polymer or copolymer, It is insoluble and at least solvable in the range of pH7.0 to pH8.0 in buffer medium of the pH lower than 4.0.
And the neutral cellulosic cpd being present in coatings is not calculated as this polymeric blends A part, but the dry weight relative to this polymeric blends individually calculates calculating.The emulsifier being present in coatings Be also based on without the compound i) and and ii including neutral cellulosic polymers) the dry weights of polymeric blends calculate 's.
The non-porous lubricant of inertia
In terms of the dry weight of polymeric blends, coatings can be in addition containing 110-250 weight %, preferably 140-220 weight Measure the non-porous inert lubricant of %.
Lubricant (sometimes referred to as glidant) is to aid in the medicine for preventing polymer from coalescing during coating process Learn acceptable substance.
Porous lubricant such as SiO 2 powder is unsuitable for the purpose of the present invention.Porous structure may cause capillary effect It answers, which promotes increasing of the medium (especially containing the medium of hydrous ethanol) containing aqueous alcohol (ethyl alcohol) to the infiltration of coating By force.
Inertia refers to that chemical reaction and insoluble or only in water and/or ethyl alcohol does not occur usually with other materials for lubricant Slightly soluble.
It is insoluble or only slightly soluble refers to that the solute requirement of every 1 parts by weight is more than the solvent of 10 parts by weight.In addition, inertia is non-porous Lubricant does not influence the glass transition temperature of the polymeric blends of coating substantially.
(it cannot be applied to coatings with enough amounts to assign to containing to lubricant such as glyceryl monostearate (GMS) The tolerance of the aqueous medium of ethyl alcohol) it itself is unsuitable in the sense of the present invention.Therefore, glyceryl monostearate It (GMS) is not inert in the sense of the present invention.
Non-porous inert lubricant can be silica component, pigment or the stearate chemical combination of stratiform (layered) Object.
Inert lubricant can be calcium stearate or magnesium stearate.Inert lubricant can be TiO2。
The non-porous lubricant of inertia is most preferably talcum.
Ethanol tolerance pharmaceutical preparation
Ethanol tolerance pharmaceutical preparation is the preparation with the release dynamics not significantly affected in the presence of ethyl alcohol.Ethyl alcohol Tolerance may be important registration in the near future and require.Conventional drug coating, the especially coating on piller do not have There are enough alcohol tolerances.Surprisingly it has been found that the coating that insoluble film forming agent is combined with soluble film forming agent is mentioned Bigger alcohol tolerance is supplied.
Ethanol tolerance (or sometimes referred to as stable) preparation derives from the release in vitro data of following tests by comparison It is defined, the test carries out at 6.8pH (thin in the medium of not alcohol-containing and in the respective media containing 40% ethyl alcohol Section is referring to attachment) and keep release profiles difference low if the release in the medium in not alcohol-containing is lower than the 20% of accumulated dose In 15% and keeping if the release of accumulated dose is between 20% to 80% release profiles difference lower than 30%.
Purpose and achievement
Starting point of the invention is the controlled release drug form for oral administration.Such medicament forms meaning It is intended to usually during through intestines for more or more efficient ground release of active compounds.It is attempted by means of medicament forms The blood level will as far as possible for a long time after initial increase to realize the blood level concentrations of reactive compound for appropriate formulation It is maintained in treatment optimum range.Excessively high reactive compound blood level concentrations should be especially avoided, there may be toxicity Effect.
In the case where the delayed release preparation of oral pharmaceutical form, the influence, particularly ionic strength of gastric juice and intestinal juice With the influence of environment pH, substantially considered with this field per se known manner.Problem be it is assumed herein that for living Property compound release ideal ratio can be due to the general life style of patient, carelessness or to using ethyl alcohol or containing ethyl alcohol Beverage addicted behavior and be changed.In these cases, be actually designed to be entirely water-bearing media drug shape Formula is extraly exposed under the medium of the ethyl alcohol containing greater or lesser intensity.
Due to dissolution or oral delayed release medicament forms and alcohol of the oral delayed release medicament forms in alcohol beverages While class beverage or overlapping is absorbed, and the acceleration of undesirable or even serious release active compound can occur or subtract Slowly.In most cases, the presence of ethyl alcohol causes the ingredient release accelerated.This acceleration is main problem, and is slowed down It is usually significantly less critical.It must be taken into account that relative to release % under conditions of 40% ethyl alcohol is not present, active pharmaceutical ingredient It is serious that release acceleration or increased absolute value, which are more than 30%,.
Because and not all patient both knows about while absorbing the wind of controlled release drug form and the beverage containing ethyl alcohol Danger or do not abide by or can not abide by it is appropriate warning, prompt or suggest, it is therefore intended that designing oral delayed release drug Form, so that their mode of action is influenced by existing for ethyl alcohol as few as possible.
The purpose of the present invention is not clearly stimulation, promotes or make it possible to take the photograph together with the medicament forms of sustained release Take the beverage containing ethyl alcohol, but be reduced or avoided by it is intentional or unintentional misuse or abuse and bring may it is fatal after Fruit.
The purpose of the present invention
Because of the unpredictability of vivo effect, the present invention is based on as can be by the body of the Fundamentals of Measurement of objective understanding Outer condition.As harsh test condition, can choose according to USP method 1 (basket method), 100rpm, in pH 6.8 through buffering (Europe Continent pharmacopeia (EP)), under the conditions in vitro in the medium for being added and being added without 40% (v/v) ethyl alcohol.
One object of the present invention is achieved when the pharmaceutical composition of controlled release meets under the following conditions:
According to USP method 1 (basket method), 100rpm was buffered in pH1.2 at first 2 hours, remaining time is buffered in pH Under conditions of 6.8 (European Pharmacopoeia (EP)), reach low when active pharmaceutical ingredient discharges under the conditions of being added without 40% (v/v) ethyl alcohol When 20% degree, the difference of rate of release under the conditions of 40% (v/v) ethyl alcohol is added, which should not exceed, is being added without 40% (v/v) ± 15% of the corresponding release value under the conditions of ethyl alcohol.For example, active pharmaceutical ingredient is being added without 40% (v/v) wherein Under conditions of release reaches 18% degree under the conditions of ethyl alcohol, the difference of rate of release under the conditions of 40% (v/v) ethyl alcohol is added It is different to should not exceed ± 15% of release value under the conditions of being added without 40% (v/v) ethyl alcohol, it means that 40% (v/v) is being added Releasing degree under the conditions of ethyl alcohol can be in the range of 3 to 33%.
According to USP method 1 (basket method), 100rpm was buffered in pH1.2, remaining time at first 2 hours in pH 6.8 Under conditions of (European Pharmacopoeia (EP)), reach 20- when active pharmaceutical ingredient discharges under the conditions of being added without 40% (v/v) ethyl alcohol When 80% degree, the difference of rate of release under the conditions of 40% (v/v) ethyl alcohol is added, which should not exceed, is being added without 40% (v/ V) ± 30% of the corresponding release value under the conditions of ethyl alcohol.For example, active pharmaceutical ingredient is being added without 40% (v/v) ethyl alcohol wherein Under the conditions of under conditions of release reaches 50% degree, the difference of rate of release under the conditions of 40% (v/v) ethyl alcohol is added is not It should be greater than ± 30% of release value under the conditions of being added without 40% (v/v) ethyl alcohol, it means that 40% (v/v) ethyl alcohol is being added Under the conditions of releasing degree can be in the range of 20 to 80%.
The pharmaceutical composition for meeting the controlled release of this condition is considered tolerance due to patient and ethyl alcohol or contains ethyl alcohol Beverage the serious accelerated release in vitro of bring reactive compound using relevant careless or addicted behavior.
This situation substantially relates to subsequently or simultaneously absorb alcohol beverage together with the intake of controlled release form, thus So that the medicament forms are exposed under stomach or the strong medium containing ethyl alcohol of enteral.
It is an object of the present invention to provide the pharmaceutical compositions for non-opium drug of the influence of ethanol tolerant.
It is a further object to provide ethanol tolerant and it is also resistant to the influence used in stomach, special without adding Enteric coating as with have a large amount of anion radical enteric film forming polymer such asS orL orThe pharmaceutical composition of the controlled release of L100-55 coating.
This is that the pharmaceutical composition of controlled release through the invention is realized, it is characterised in that with and without addition The releasing degree of active constituent is 10% or more in simulate the gastric juice pH1.2 in 2 hours in the case where 40% ethyl alcohol (v/v) It is low.
Another purpose is the storage stability of pharmaceutical composition, it should which it is further improved to f2What value indicated In the range of 60-100 (storage stability=good).
Measurement method
The measurement of the percentage of reactive compound can be for example, by the wavelength for being suitable for corresponding reactive compound Under online ultraviolet spectroscopy carry out.It is also possible to being measured using HPLC.The method is that those skilled in the art are known 's.
The release of reactive compound can be measured according to USP, especially USP 28-NF23, general rules<711>, dissolution, device 2 (paddle method), mode<724>" the general drug release standard of sustained release (enteric coating) product-", need correctly to quote！Method B Following change occurs for (100rpm, 37 DEG C), I type basket: by medicament forms first 2 hours with 0.1N HCl be buffered in pH1.2, its The remaining time is buffered in pH 6.8 (European Pharmacopoeia (EP) is equivalent to artificial intestines medium) with phosphate buffer and is tested.Make The measurement of the aqueous medium containing ethyl alcohol is carried out in the medium proper amount of 30% or preferably 40% (v/v) ethyl alcohol.
Storage stability
Evaluated in general, drug substance (should allow tolerance appropriate) under condition of storage, examine thermal stability and, If applicable, to the sensibility of moisture (ICH Guideline Q1A (R2), 6February 2003).
The acceleration environment of drug substance: 40 DEG C ± 2 DEG C, 75%RH (relative humidity) ± 5%RH, closed container lasts 6 Month.Storage stability can pass through so-called similarity factor f2Or f2Value indicates.Similarity factor f2With two of storage front and back Average squared-distance is inversely proportional between release characteristic.In past ten years, f2Calculating has changed into several FDA manual industries In recommended method.Calculation method is known to the skilled in the art.f2Value be 100 mean before storage after two release Putting squared-distance average between feature does not have deviation.
The deviation of release characteristic after before storage is with f2When value is expressed as 50 or more but is less than 60 similitude, it is believed that Storage stability is acceptable.The deviation of release characteristic after before storage is with f2When value is expressed as 60 to 100, it is believed that storage Stability is good.Storage stability test is well known to those skilled in the art.
The present invention is described in detail
The present invention relates to:
The pharmaceutical composition of the dependent controlled release of pH includes:
Core, it includes the active pharmaceutical ingredients of at least one non-opium drug, and wherein the core is controlled by least one The coatings coating of pharmacy compositions release,
Wherein coatings include the polymeric blends of following substance:
I) in terms of the dry weight of polymeric blends, 40-95 weight %, preferably 60-95 weight %, most preferably 70-90 weight At least one water-insoluble of %, substantially neutral vinyl polymer or copolymer are measured, and
Ii) in terms of the dry weight of polymeric blends, 5-60 weight %, preferably 5-40 weight %, most preferably 10-30 weight % At least one anionic polymer or copolymer, it is insoluble and at least in pH 7.0 in the buffer medium lower than pH4.0 It is solvable in the range of to pH 8.0,
It is characterized in that,
The coatings also comprise, substantially contain or containing the non-of 110-250 weight %, preferably 140-220 weight % Porous inert lubricant, the fiber of at least one neutrality of 1-35 weight %, preferably 2-30 weight %, most preferably 5-25 weight % At least one emulsifier of plain compound and 1-25 weight %, preferably 5-20 weight %, most preferably 5-15 weight %, be all with The dry weight meter of polymeric blends.
Core
With this field per se known manner, the core containing active constituent or piller core constitute alkenes (co) polymerization The basis of the coating of object.Granulation can carry out on the ball (blank capsule core) without active constituent or the piller without core, can To prepare piller core.Firstly, circular base containing active constituent of the preparation with and without core.By means of fluidized bed Method can evaporate solvent or suspending agent by liquid application on placebo piller or other suitable carrier materials.According to preparation Method, can be with additional drying step.Spraying process and subsequent drying may be repeated several times, predetermined until applied completely The active pharmaceutical ingredient of amount.
By convention, active constituent is added in organic solvent or water and is mixed.In order to which guarantee mixture makes us full The sprayability of meaning, it is generally necessary to prepare the mixture with opposite low viscosity.Concentration is 0.1 to 20 weight %, preferably 0.5 arrives The addition of the detergent such as Tween of 10 weight %, advantageously reduces surface tension.
In addition to active constituent, they contain other drug excipient: adhesive, such as cellulose and its derivates, Polyvinylpyrrolidone (PVP), moisturizer, disintegration auxiliary agent, disintegrating agent, (methyl) acrylate, starch and its derivative, sugar increase Solvent or other materials.
Suitably method of administration is known, for example, with reference to Bauer, Lehmann, Osterwald, Rothgang " Arzneiformen"[Coated Pharmaceutical Forms]Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, the 7th chapter, the 165-196 pages.
Details can further be learnt from textbook by those skilled in the art.For example, with reference to:
-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), especially the 15th He 16 chapters, the 626-642 pages.
-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 can coalesce (rotor agglomeration), precipitating or spraying process full circle by such as rotor, It is vortexed spraying process especially through ultrasound, obtains core with given such as 50 to 2500 microns of size, being still no coating Or piller core.This has the advantage of entire core volumes can be used for active constituent load.To which active constituent load is opposite It is increased again in the embodiment with inert core.
It can be used and be compacted (direct compaction) method directly to prepare the core of micro tablet.
Other than active pharmaceutical ingredient, core may include other drug excipient: adhesive, such as cellulose and its Derivative, polyvinylpyrrolidone (PVP), wetting agent, disintegration auxiliary agent, disintegrating agent, starch and its derivative, sugared solubilizer or its Its substance.
Control the coatings of pharmaceutical composition release
Core is only coated by a coatings at least by one, preferably by one or more, preferably, controls pharmaceutical composition The release of object.Coatings assign release mode to the tolerance effects of the aqueous medium containing ethyl alcohol.Control pharmaceutical composition release Coatings be also referred to as exterior coating because the coatings surround core.
The release of (outer) coatings control pharmaceutical composition.Coatings assign release mode to the aqueous medium containing ethyl alcohol Tolerance effects.
In the case where core ingredient is incompatible with coating constituents, isolation bottom can be applied between core and (outer) coatings Coating.
The coatings of control pharmaceutical composition release can in addition by non-functional, preferably water-soluble table coating cover, Table coating is on release characteristic essentially without influence.
After core of the preparation containing active constituent or piller core, they are supplied in the spraying process of coatings, To obtain coating core or coated pellets respectively.Coating by organic solution or preferably by aqueous dispersion spraying by means of making It is standby.In order to implement purpose, uniform, non-porous coating is obtained herein and is important.By convention, after spraying process and In addition coated pellets are sequentially dried a few minutes before starting by conditioning process.By convention, it is usual to contain pharmacy for polymer coating Excipient, such as, for example, release agent or plasticizer.
With core poidometer, the coatings for controlling pharmaceutical composition release exist with the amount of at least 10 weight %.With core Poidometer, coating preferably exist with the amount of 20-200 weight %, preferably 30-100 weight %, more preferable 40-80 weight %.
The average thickness that the amount of coating can be equivalent to coatings is in about 20-200 microns, preferably 50-150 micron range It is interior.
Coated pellets
The pharmaceutical composition of controlled release preferably with have 100 to 5000 microns, preferably 100 to 2000 microns, it is optimal Select the form presence of the coated pellets, micro tablet or tablet of 300-1000 microns of overall average diameter.
The pharmaceutical composition of controlled release of the invention can be 100 to 700 microns, preferably greater than 200 with overall average diameter Micron or more than 500 microns or the form of 250-400 micron of coated pellets presence.
The pharmaceutical composition of controlled release of the invention can be 1400 to 5000 microns with overall average diameter, preferably 1500 arrive The form presence of 4000 microns, most preferably 1800 to 3500 microns of coated pellets, micro tablet or tablet.
Coated pellets overall average diameter be 100 to 700 microns, preferably greater than 200 microns or more than 500 microns or When being 250 to 400 microns, the amount that coatings should be calculated as at least 100 weight % with core weight exists.
It is 1400 to 5000 microns, preferably greater than 2000 microns or micro- more than 2500 in the overall average diameter of coated pellets Rice or be 2500 to 3500 microns when, coatings should be calculated as with core weight at least 30 weight % amount exist.
Micro tablet
The pharmaceutical composition of controlled release exists preferably in the form of the micro tablet of coating, and wherein micro tablet has 1 to 5 millimeters of average diameter.
Tablet
By completion of the invention, it is possible to the tablet with the coating of stomach acidity tolerance and alcohol resistance is provided, Such as from 1mm to the size of maximum 50mm.This for provide in form of tablets it is harmful to gastric mucosa or in gastric juice it is unstable Active constituent for be advantageous.
Water-insoluble, substantially neutral vinyl polymer or copolymer
Water-insoluble, substantially neutral vinyl polymer or copolymer is understood the pH model referred to entire 1 to 14 Enclose interior not soluble in water and only those of swellable polymer or copolymer in water.
Vinyl polymer derives from the polymerization of monomer such as (methyl) acrylic monomer with alkenes group.
" substantially neutral " refers to that polymer if any also only contains a small amount of ionic group in a sense. Even if there are a small amount of ionic group, but the physical-chemical property of this quasi polymer polymerizeing with without any ionic group The physical-chemical property of object is almost the same." substantially neutral " refers in particular to polymer in a sense and contains lower than 5, is low The monomer residue with anion or cationic side group in 4, lower than 3, lower than 2 or lower than 1 weight %.Preferably, water is insoluble Property neutral vinyl polymer or copolymer be free of any cation group.Most preferably, water-insoluble, it is substantially neutral Vinyl polymer or copolymer be free of any ionic group at all, and be therefore neutral water-insoluble vinyl polymer (100% is neutral).
Especially, (methyl) of the water-insoluble of the monomer residue of the cation quaternary ammonium group containing 5 or 10 weight % Acrylic polymer, such as typeRS orRL is not suitable for the purpose of the present invention, because Pharmaceutical composition to obtain is not enough to be resistant to the influence of 40% ethyl alcohol.
In general, only a kind of or a type of water-insoluble, substantially neutrality vinyl polymer or copolymer are deposited It is in pharmaceutical composition.However, if applicable, it is also possible to there are two types of or more water-insoluble polymer or copolymerization These of object or two or more seed types polymer or copolymer exist simultaneously with one another or are present in mixture.
The insoluble polymer of polyvinyl acetate type
The polymer or copolymer as derived from it that suitable insoluble polymer has polyvinyl acetate type.
The polymer of water-insoluble polyvinyl acetate type or the example of copolymer be polyvinyl acetate (PVAc, Kollicoat), vinyl base pyrrolidinone-co object (VA64)。
(methyl) acrylic acid series copolymer of water-insoluble
In (methyl) acrylic acid series copolymer of water-insoluble, the methacrylate of neutral or substantial neutrality is total Polymers is suitable for the invention purpose.
Neutral (methyl) acrylate copolymer (NE type)
The methacrylate copolymer of neutral or substantial neutrality contains the degree at least over 95 weight %, special Be at least the degree of 98 weight %, the degree of the degree of preferably at least 99 weight %, particularly at least 99 weight %, more preferably 100 weight % degree have neutral group especially C1-C4(methyl) acrylate monomer of alkyl group.
Suitable (methyl) acrylate monomer with neutral group is such as methyl methacrylate, methacrylic acid Ethyl ester, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate.It is preferred that methyl methacrylate, propylene Acetoacetic ester and methyl acrylate.
Methacrylate monomers with anionic group such as acrylic acid and/or methacrylic acid can be lower than 5 weights Amount %, preferably more than 2 weight %, it is more preferably no more than the amount of the 1 weight weight of % or 0.05 to 1 % and exists on a small quantity.
Suitable example be by the ethyl acrylate of 20 to 40 weight %, the methyl methacrylate of 60 to 80 weight % and 0 is forming, neutral to the acrylic or methacrylic acid lower than 5 weight %, preferably 0 to the 2 weight weight of % or 0.05 to 1 % Or substantially neutral (methyl) acrylate copolymer (NE)。
NE andNM is the first of the ethyl acrylate and 70 weight % by 30 weight % The copolymer of the free radical polymerization unit composition of base methyl acrylate.
Suitable insoluble polymer be by more than 95 to the acrylic or methacrylic acid for being up to 100 weight % C1-C4The copolymer of Arrcostab and the free radical polymerization unit composition of the acrylic or methacrylic acid lower than 5 weight %.
Water-soluble anionic polymer
Water-soluble anionic polymer in the sense of the present invention refers to such polymer, and the polymer is suitable Buffer medium, it is insoluble in the case where being lower than pH 5.0 preferably in the buffer medium according to United States Pharmacopeia or European Pharmacopoeia standard, and It is solvable in the range of in pH 7.0 to pH 8.0, preferably in pH 6.0 to 8.0, most preferably in pH 5.5 to 8.0.Suitably passing through In the aqueous medium of buffering, the major part of soluble polymer insoluble in pure water or goes mine in the range of pH 7.0 to pH 8.0 In matter water.
Water-soluble anionic cellulose derivative
Anionic cellulose derivative is based on native cellulose chain and carries out chemical modification with anionic compound.Polymer It can be by partially and completely neutralizing, it is preferable to use basic ion carries out.The example of anionic cellulose derivative is that vinegar phthalein is fine Tie up plain (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethyl cellulose (CMC), acetate succinate hydroxyl Propyl methocel (HPMCAS) or cellulose acetate succinate (CAS).
Water-soluble anionic (methyl) acrylate copolymer
Suitable water soluble anion (methyl) acrylate copolymer is by 25 to 95 weight %, preferably 40 to 95 weights Measure the C of the acrylic or methacrylic acid through free radical polymerization of the weight of %, particularly 60 to 40 %1-C4Arrcostab and 75 to 5 (methyl) acrylate monomer with anionic group of weight %, preferably 60 to the 5 weight weight of %, particularly 40 to 60 % Free radical polymerization unit composition.
The ratio generally adds up to 100 weight %.However, it is also possible to be additionally present of a small amount of up to 10 weight %, Or be 0 to 10 weight %, such as the other monomer for being able to carry out alkenes copolyreaction of 1 to 5 weight %, such as, such as first Base hydroxy-ethyl acrylate or hydroxy-ethyl acrylate, without damaging or changing fundamental character of the invention.It is preferable, however, that there is no another The outer monomer for being able to carry out alkenes copolyreaction.It is generally preferred that other than those of being specifically recited monomer, in water Other monomer is not present in anion (methyl) acrylate copolymer of dissolubility.
The C of acrylic or methacrylic acid1-C4Arrcostab especially methyl methacrylate, ethyl methacrylate, first Base butyl acrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
(methyl) acrylate monomer with anionic group is such as acrylic acid, preferably methacrylic acid.
Suitable anion (methyl) acrylate copolymer is by the methacrylic acid and 60 to 40 of 40 to 60 weight % Those of the ethyl acrylate of the methyl methacrylate of weight % or 60 to 40 weight % composition.(L type OrL 100-55 type).
L is the copolymerization of the methyl methacrylate of 50 weight % and the methacrylic acid of 50 weight % Object.The pH that the concrete activity ingredient described in intestinal juice or simulated intestinal fluid starts release can be pH 6.0.
L 100-55 is being total to for the ethyl acrylate of 50 weight % and the methacrylic acid of 50 weight % Polymers.L 30D-55 is containing 30 weight %The dispersion of L 100-55.In intestinal juice Or the pH that concrete activity ingredient described in simulated intestinal fluid starts to discharge can be pH 5.5.
Similarly, it is made of the methyl methacrylate of the methacrylic acid of 20 to 40 weight % and 80 to 60 weight % Anion (methyl) acrylate copolymer be also it is suitable (S type).The institute in intestinal juice or simulated intestinal fluid Stating the pH that concrete activity ingredient starts to discharge can be pH 7.0.
Suitably (methyl) acrylate copolymer is methyl methacrylate, 50 to 70 weights by 10 to 30 weight % Measure % methyl acrylate and 5 to 15 weight % methacrylic acid composition those of (FS type).In intestines The pH of the starting release of concrete activity ingredient described in liquid or simulated intestinal fluid can be pH 7.0.
FS is the methyl acrylate and 10 weights of methyl methacrylate by 25 weight %, 65 weight % Measure copolymer made of the methacrylic polymeric of %.FS30D is containing 30 weight % The dispersion of FS.
Copolymer with consisting of is also suitable:
The methacrylic acid and/or acrylic acid of 20 to 34 weight %,
The methyl acrylate of 20 to 69 weight %, and
The ethyl acrylate of 0 to 40 weight %, and/or, if appropriate,
The other monomer for being able to carry out alkenes copolyreaction of 0 to 10 weight %,
Condition is the copolymer according to ISO 11357-2, and the glass transition temperature of 3.3.3 trifle is no more than 60 DEG C.It should (methyl) acrylate copolymer is especially suitable, because for compacting piller is at tablet, with good extension at break Property.
Copolymer with consisting of is also suitable:
The methacrylic acid and/or acrylic acid of 20 to 33 weight %,
The methyl acrylate of 5 to 30 weight %, and
The ethyl acrylate of 20 to 40 weight %, and
Higher than the butyl methacrylate of 10 to 30 weight %, and if appropriate,
The other monomer for being able to carry out alkenes copolyreaction of 0 to 10 weight %,
Wherein the ratio of monomer adds up to 100 weight %,
Condition is according to ISO 11357-2,3.3.3 trifle (neutral temperature Tmg) glass transition temperature of the copolymer is 55-70℃.Such copolymer is especially suitable, because for compacting piller is at tablet, with good machinery Property.
Above-mentioned copolymer is especially made of free radical polymerization unit below:
The methacrylic acid or propylene of 20 to 33 weight %, preferably 25 to 32 weight %, particularly preferred 28 to 31 weight % Acid, preferably methacrylic acid,
The methyl acrylate of 5 to 30 weight %, preferably 10 to 28 weight %, particularly preferred 15 to 25 weight %,
The ethyl acrylate of 20 to 40 weight %, preferably 25 to 35 weight %, particularly preferred 18 to 22 weight %, and
Higher than the methacrylic acid fourth of 10 to 30 weight %, preferably 15 to 25 weight %, particularly preferred 18 to 22 weight % Ester,
Wherein the monomer composition by selection so that the glass transition temperature of the copolymer be 55-70 DEG C, it is excellent Select 59-66 DEG C, it is 60-65 DEG C particularly preferred.
In this regard, glass transition temperature refers to according to ISO 11357-2, the neutral temperature T of trifle 3.3.3mg.Not Under the conditions of adding plasticizer, residual monomer content (REMO) is lower than 100ppm, and the rate of heat addition is 10 DEG C/min and in nitrogen atmosphere Under, it measures.
Copolymer preferably substantially arrive fully comprising 90,95 or 99 to 100 weight %, in the range of the above-mentioned amount Methacrylic acid, methyl acrylate, ethyl acrylate and butylmethacrylate monomer.
However, it is possible to be additionally present of a small amount of range 0 to 10 weight %, the other of such as 1 to 5 weight % can Carry out alkenes copolyreaction monomer, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, Vinyl pyrrolidone, ethylene propylmalonic acid, styrene, vinyl alcohol, vinyl acetate and/or its derivative, without necessarily damaging Evil fundamental character.
The preparation of anion (methyl) acrylate copolymer
The radical polymerization that anion (methyl) acrylate copolymer can pass through monomer with this field per se known manner Conjunction is produced (for example, with reference to 0 704 208 A2 of EP 0 704 207 A2 and EP).Copolymer of the invention can be with this field Per se known manner is made by the free-radical emulsion polymerization reaction in water phase preferably in the presence of anion emulsifier It is standby, for example, being carried out by 2 135 073 the method for DE-C.
If can be by forming initiator and the appropriate tune there are also for adjusting not diluted molecular weight in free radical The conventional method of the radical polymerization of the continous way or discontinuous (batch process) under conditions of agent is saved with solution polymerization process, logical It crosses pearl polymerisation method or copolymer is prepared with emulsion polymerization.Average molecular weight Mw (weight, such as by measurement solution viscosity come Determine) it can be in the range of such as 80 000 to 1 000 000 (g/mol).It is preferred that in water phase, in water soluble starter and The emulsion polymerization carried out in the presence of (preferred anionic) emulsifier.
It, can be by rolling, squeezing out, be granulated or thermal cutting obtains the polymerization of solid form in the case where bulk polymerization Object.
Bulk polymerization of (methyl) acrylate copolymer according to this field per se known manner by free radical, solution Polymerization, pearl polymerisation or emulsion polymerization are obtained.They must be processed by grinding appropriate, dry or spray process reaches Particle size range of the invention.This can be carried out by simply rolling the piller for being extruded and cooling down or carrying out thermal cutting.
It can be to be advantageous, in terms of the mixture with other powder or liquid using powder.For manufacturing powder The suitable device at end is well known to those skilled in the art, such as air jet mill, peg type disc grinder (pinned disc Mills), multicell is ground.If applicable, it is also possible to including suitable sifting step.Suitable mill for industrial mass It is the opposite jet mill (opposed jet mill) (Multi No.4200) for example to be worked with about 6 bars of gauge pressure.
Part neutralizes
Anionic polymer can partially or even wholly be neutralized with alkali.Suitable alkali is in 0 088 951 A2 of EP Those of or clearly mentioned in WO 2004/096185, or by those of its derivative.Specifically: sodium hydroxide solution, hydrogen Potassium oxide solution (KOH), ammonium hydroxide or organic base such as triethanolamine, sodium carbonate, potassium carbonate, sodium bicarbonate, phosphorus Sour trisodium, trisodium citrate or ammonia or the amine such as triethanolamine or three (methylol) aminomethanes of physiology tolerance.In addition Suitable cation organic base is basic amino acid histidine, arginine and/or lysine.
More granule medicament forms
The pharmaceutical composition of controlled release of the invention can have pellet form, be comprised in more granule medicament form examples As compressed tablets, capsule, pouch, effervescent tablet or reconstitutable powder form in.
Table coating and bottom coating
The pharmaceutical composition of controlled release of the invention can be further coated with bottom coating and/or table coating.
Bottom coating can be located between core and the coatings (control layer) for controlling pharmaceutically active substance release.Bottom coating can have There is making the substance of core that possibility is incompatible each other to separate with the substance of control layer.Bottom coating is substantial to release characteristic Do not influence.Bottom coating is preferably substantially water solubility, for example, it may include the object of such as hydroxypropyl methyl cellulose (HPMC) Matter is as film forming agent.The average thickness of bottom coating is very thin, for example, being no more than 15 microns, preferably more than 10 microns.
Table coating is preferably also substantially water-soluble.Table coating, which can have, makes medicament forms with color or protection drug shape Formula effect moisture-proof during exempting from such as storage affected by environment.Table coating may include adhesive, such as water-soluble polymer is as more Sugar or HPMC or sugar compounds such as sucrose.In addition table coating can contain a small amount of drug excipient such as pigment or lubricant.Table packet Clothing is on release characteristic essentially without influence.
Expression base coating and table coating are well known to those skilled in the art.
The method for preparing medicament forms of the invention
The pharmaceutical composition of controlled release of the invention can pass through medicine such as below with this field per se known manner Learn conventional process to be produced: direct pressing, dry, wet or agglomerated grain compacting and subsequent full circle, wet granulation or dry method are made Grain or directly pill or by powder-stuck (powder stratification) to without active constituent globule or neutral core (blank core) or It is coated on particle containing active constituent and by spraying process or by fluidized bed prilling applying polymer.
Excipient/usual additive
In addition core also contains figuration respectively in the manner known to persons skilled in the art other than active pharmaceutical ingredient Agent or usual additive.Other excipient is not crucial for the present invention.
Coatings are made in addition to polymeric blends, non-porous inert lubricant, neutral cellulosic cpd and emulsifier Can also in addition to contain excipient or usual additive except basis in the manner known to persons skilled in the art respectively. However if excipient is comprised in coatings, they are always different from necessary ingredient, and necessary ingredient is that polymer is mixed Close object, non-porous inert lubricant, neutral cellulosic cpd and emulsifier.(namely polymer is mixed with necessary ingredient Close object, non-porous inert lubricant, neutral cellulosic cpd and emulsifier) it compares, excipient in addition is for the present invention For be not crucial.Other excipient does not contribute advantageous invention effect.Preferably, with the dry weight of total coatings It counts, the amount of other excipient is lower than 5 weight %, more preferably less than 2 weight % in coatings.It is most preferably not another in coatings Outer excipient.
The usual excipient of pharmacy, also referred to as usual additive, is added into preparation of the invention, preferably exists occasionally It is added into during the production of particle or powder.All excipient or usual additive used necessarily toxicology always certainly It is acceptable and can particularly to the calm strategical vantage point of patient be used for drug.
The usual excipient of pharmacy is that those skilled in the art are known for the usage amount and application of drug coating or coating 's.The example of possible usual excipient or additive is releasing agent, pigment, stabilizer, antioxidant, pore-forming in pharmacy Agent, penetrant, gloss agent, aromatic substance and flavoring agent.They are used as processing aid and are intended to ensure reliable and reproducible Production process and good long-term storing stability or they other advantageous property is realized in medicament forms. They are added into polymer formulations before processing and can influence the permeability of coating, when in place possible with this Point is as other control parameter.
Pigment:
As previously mentioned, pigment can be used in coatings, play the role of non-porous inert lubricant, to promote to be resistant to The influence of ethyl alcohol.If additionally incorporating pigment as not having contributive excipient to the present invention, coating can be added them into Table above layer is coated to provide certain color.Play the role of non-porous inert lubricant in coatings or as to this hair The bright pigment for not having contributive excipient is usually certainly nontoxic and is suitable for pharmacy purpose.About this point, also refer to, Such as: Deutsche Forschungsgemeinschaft, Farbstoffe f ü r Lebensmittel, Harald, Boldt Verlag KG,Boppard(1978)；Deutsche Lebensmittelrundschau 74, No.4, page 156 (1978)； Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980。
The example of pigment is orange, carmine lake, the colored pigment based on aluminium oxide or azo dyes, sulfonic acid dye, Orange S (E110, C.I.15985, FD&C Yellow 6), indicarminum (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), quinoline yellow (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 brilliant green (E 142, C.I.44090, FD&C Green S).
E digital representation and EU number related pigment.It about this point, also refers to: " Deutsche Forschungsgemeinschaft,Farbstoffe für Lebensmittel,Harald Boldt Verlag KG, Boppard(1978)；Deutsche Lebensmittelrundschau 74, No.4, page 156 (1978)； Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980.FD&C number is related to institute in the following Approval number describing, being used for by U.S. Food and Drug Administration (FDA) approval in food, drug 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 can also be plasticizer.Plasticizer can be advantageously added into coatings.Usual amounts are to be based on Such as 0 to 50 weight % of the weight of (methyl) acrylate copolymer of coatings, preferably 5 to 20 weight %.It is preferred that not to Coatings add plasticizer.
Plasticizer can influence the function of polymeric layer, according to the difference of type (lipophilicity or hydrophily) and additional amount It is different.Plasticizer reduces glass transition temperature and carrying out Physical interaction with polymer and promotes to form a film, according to addition Amount it is different and different.Suitable substance usually there is the molecular weight between 100 to 20 000 and in the molecule containing one or Multiple hydrophilic radicals such as hydroxyl, ester group or amino.
The example of suitable plasticizer is citric acid alkyl esters, glyceride, alkyl phthalates, decanedioic acid alkyl Ester, sucrose ester, Isosorbide Dinitrate, diethyl sebacate, dibutyl sebacate and polyethylene glycol 200 are to 12 000.Preferably Plasticizer is triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS).In addition it will mention To be the esters for being at room temperature usually liquid, such as citrate, phthalic acid ester, sebacate or castor oil.It is excellent Choosing uses the ester of citric acid and decanedioic acid.
Plasticizer is added into preparation to carry out in known manner, that is, is added directly into aqueous solution or in mixture Grape berry after be added.It is also possible to the mixture using plasticizer.
Neutral cellulosic cpd is added in coating
By polymeric blends (compound i) and ii)) dry weight in terms of, coatings additionally comprise 1 to 35 weight %, preferably The cellulosic cpd of at least one neutrality of 2-30 weight %, most preferably 5-25 weight %.Neutral cellulosic cpd is A kind of cellulose derivative of neutrality and the ethylether or methyl ether that may be preferred that cellulose.Most preferably, neutral Cellulosic cpd is hydroxyethyl cellulose or hydroxypropyl methyl cellulose (HPMC).
Emulsifier is added in coating
Seem to improve the resistance to of pharmaceutical composition indirectly the inventors discovered that adding one or more emulsifying agents in coating By property.Speculate that presence of the detergent in sprayed suspension promotes film forming procedure and become more completely.More complete film is seemingly Film is formed by more tolerant to the influence of ethyl alcohol than being free of a certain amount of emulsifier in coating.A certain amount of emulsifier is free of in coating Being formed by film is considered as than being formed by film little more hole in the presence of emulsifier.Therefore, emulsifier was forming a film Effect in journey, although not yet really understanding, it may be possible to be similar to the effect for being different from that coated pellets are carried out with solidification process. More, it is surprising that whether including ethyl alcohol in medium all seemingly to release characteristic itself without negative effect or change Change.
Therefore, by polymeric blends (compound i) and ii)) dry weight in terms of, the pharmaceutical composition of controlled release of the invention Object can additionally comprise at least one emulsifier of 2 to 20 weight %, preferably 5-15 weight %, preferably nonionic emulsifier.
Preferred emulsifier is the polyoxyethylene deriv of Isosorbide Dinitrate.
Most preferably, detergent is polyoxy-ethylene sorbitan monoleate (polyethylene glycol anhydro sorbitol list oil Acid esters, CAS registration number 9005-65-6, such as80)。
Improved storage stability
, it is surprising that steady for storing when cellulosic cpd or emulsifier to be individually used in pharmaceutical composition It is qualitative not influence.In this case, storage stability is still acceptable, it means that is still left some room for improvement.However, When cellulosic cpd to be used together with emulsifier, storage stability becomes much better, and can be referred to as excellent.
Using
The pharmaceutical composition of the dependent controlled release of pH of the invention can be used for reducing after oral due to simultaneously or with The risk of the enhancing release for the active pharmaceutical ingredient for being included brought by the beverage (misuse) containing ethyl alcohol is absorbed afterwards.
Embodiment
Method
Model drug
Metoprolol is used as model drug to be studied.
Dissolution research
According to USP 28-NF23, general rules<711>, dissolution, to be tested, first 2 hours pH 1.2 simulate the gastric juice, Then in the buffer medium of pH 6.8.
Dissolve out parameter:
Device: USP I type (basket method)
RPM:100/min
Temperature: 37.5 ± 0.5 DEG C
Dissolve out volume: 500ml.
It takes out volume: manually taking out 5ml using pipette, do not supplement medium
Detection mode: HPLC
Dissolution medium 1:
Simulate the gastric juice pH 1.2 (European Pharmacopoeia=EP)
Dissolution medium 2:
Simulate the gastric juice pH 1.2 (European Pharmacopoeia=EP) contains 40% (v/v) ethyl alcohol
Dissolution medium 3:
Phosphate buffered saline (PBS) pH 6.8 (European Pharmacopoeia=EP)
Dissolution medium 4:
The phosphate buffered saline (PBS) pH 6.8 of alcohol containing 40%v/v, the KH of EP-0.9g2PO4, the K of 1.8g2HPO4, The NaCl of 7.65g uses the alcohol of 540ml demineralised water and 360ml.
Copolymer
NEBe by the methyl methacrylate of the ethyl acrylate and 70 weight % of 30 weight % from The copolymer being made of base polymeric unit.
FSIt is the methyl acrylate and 10 weights of methyl methacrylate by 25 weight %, 65 weight % Measure the copolymer of the free radical polymerization unit composition of the methacrylic acid of %.
Preparation prepares details
In the fluidized bed processing unit (plant) using bottom spray, by 1700-2000 microns of cores (sugar ball, blank capsule core) Load metoprolol.Polyvinylpyrrolidone (K25) it is used as adhesive.The core of 900g blank capsule core is used Be bonded in 80g adhesive (K25 the 270g metoprolol coating in).
Film coating suspension preparation:
It willDispersion mixes in the suitable container for applying gentle agitation.Applying high shear force will moisten Lubrication prescription and different polymer are dissolved or dispersed in water.
Lubricant-suspension is poured into and applies gentle agitationIn dispersion.In entire coating process Middle stirring is lasting to be carried out.
Coating process:
In fluid unit, under suitable conditions, i.e., in about 10-20g film coating suspension/minute/kilogram core Under spray rate and about 25-28 DEG C of bed temperature, the piller with medicine layer is coated with different film coating suspensions.It is wrapping After clothing, piller is fluidized 1 hour in fluidized bed processing unit (plant) at 50 DEG C.The talcum of micronization is used as excipient.Coated pellets With about 3000 microns of average diameter.
Storage stability
The deviation of release characteristic after before storage is with f2When value is expressed as 50 or more but is less than 60 similitude, it is believed that Storage stability is acceptable.The deviation of release characteristic after before storage is with f2When value is expressed as 60 to 100, it is believed that storage Stability is good.

Claims (16)

  1. The pharmaceutical composition of the dependent controlled release of 1.pH, it includes:
    Core, it includes the active pharmaceutical ingredients of at least one non-opium drug, and wherein core controls drug by least one The coatings coating of composition release,
    Wherein coatings include the polymeric blends of following substance:
    I) in terms of the dry weight of polymeric blends, at least one water-insoluble of 70~90 weight %, substantially neutral alkene Quasi polymer or copolymer, it is the methyl methacrylate of ethyl acrylate by 20~40 weight %, 60~80 weight % With 0~(methyl) acrylate of neutral or substantial neutrality for being formed lower than the acrylic or methacrylic acid of 5 weight % Copolymer, and
    Ii) in terms of the dry weight of polymeric blends, at least one anionic polymer or copolymer of 10~30 weight %, It is insoluble and at least solvable in the range of 7.0~pH of pH 8.0 in buffer medium lower than pH 4.0, it is by 10~30 weights Measure the methacrylic acid composition of the methyl methacrylate of %, the methyl acrylate of 50~70 weight % and 5~15 weight % (methyl) acrylate copolymer,
    It is characterized in that, non-porous inert lubricant of the coatings in addition containing 140~220 weight %, 1~35 weight % At least one emulsifier of at least one neutral fibre element compound and 1~25 weight %, all with the dry weight of polymeric blends Meter, wherein the neutral fibre element compound is hydroxypropyl methyl cellulose or hydroxyethyl cellulose, the non-porous inertia profit Lubrication prescription is talcum or stearate compound, and the emulsifier is the polyoxyethylene deriv of Isosorbide Dinitrate.
  2. 2. the pharmaceutical composition of the dependent controlled release of the pH of claim 1, it is characterised in that the inert lubricant is hard Resin acid calcium or magnesium stearate.
  3. 3. the pharmaceutical composition of the dependent controlled release of the pH of claims 1 or 2, it is characterised in that the emulsifier is poly- second Oxygroup Sorbitan Monooleate.
  4. 4. the pharmaceutical composition of the dependent controlled release of the pH of claims 1 or 2, it is characterised in that according to USP paddle method, 100rpm, under conditions in vitro of the pH 6.8 through buffering, in the medium for being added and being added without 40% (v/v) ethyl alcohol, the drug Composition has the property that
    When active pharmaceutical ingredient discharges under the conditions of being added without 40% (v/v) ethyl alcohol reaches the degree lower than 20%, adding Enter the difference of the rate of release under the conditions of 40% (v/v) ethyl alcohol no more than corresponding under the conditions of being added without 40% (v/v) ethyl alcohol ± the 15% of release value,
    When active pharmaceutical ingredient discharges under the conditions of being added without 40% (v/v) ethyl alcohol reaches 20~80% degree, adding Enter the difference of the rate of release under the conditions of 40% (v/v) ethyl alcohol no more than corresponding under the conditions of being added without 40% (v/v) ethyl alcohol ± the 30% of release value.
  5. 5. the pharmaceutical composition of the dependent controlled release of the pH of claims 1 or 2, it is characterised in that active pharmaceutical ingredient is Mei Tuo The pharmaceutically acceptable salt of Luo Er or metoprolol.
  6. 6. the pharmaceutical composition of the dependent controlled release of the pH of claims 1 or 2, it is characterised in that the pharmaceutical composition is to be wrapped It is contained in the form of the piller in more granule medicament forms.
  7. 7. the pharmaceutical composition of the dependent controlled release of the pH of claim 6, it is characterised in that more granule medicament forms It is compressed tablets, capsule, pouch or reconstitutable powder form.
  8. 8. the pharmaceutical composition of the dependent controlled release of the pH of claim 6, it is characterised in that more granule medicament forms It is effervescent tablet.
  9. 9. the pharmaceutical composition of the dependent controlled release of the pH of claims 1 or 2, it is characterised in that the pharmaceutical composition has bottom Coating and/or table coating.
  10. 10. the pharmaceutical composition of the dependent controlled release of the pH of claims 1 or 2, it is characterised in that the pharmaceutical composition is with total The form for the coated pellets that average diameter is 100~5000 microns exists.
  11. 11. the pharmaceutical composition of the dependent controlled release of the pH of claim 10, it is characterised in that the coated pellets it is total Average diameter is 100~700 microns.
  12. 12. the pharmaceutical composition of the dependent controlled release of the pH of claim 10, it is characterised in that the coated pellets it is total Average diameter is 1400~5000 microns.
  13. 13. the pharmaceutical composition of the dependent controlled release of the pH of claim 12, it is characterised in that with the poidometer of core, coating Layer exists with the amount of at least 30 weight %.
  14. 14. the pharmaceutical composition of the dependent controlled release of the pH of claims 1 or 2, it is characterised in that adding or do not adding The releasing degree of active constituent is 10% or more in simulate the gastric juice pH 1.2 in 2 hours in the case where 40% ethyl alcohol (v/v) It is low.
  15. 15. the pharmaceutical composition of the dependent controlled release of the pH of claims 1 or 2, it is characterised in that after reduction orally ingestible By subsequently or simultaneously absorbing the enhancing for the active pharmaceutical ingredient for being included brought by the beverage containing ethyl alcohol or reducing release Risk.
  16. 16. the method for preparing the pharmaceutical composition of the dependent controlled release of pH of one of claim 1~15, this method is with known Mode is made by direct pressing, dry, wet or agglomerated grain compacting and subsequent full circle, wet granulation or non-slurry pelletizing or directly Ball or by being integrated to powder stratification on the globule without active constituent or neutral core or particle containing active constituent It is coated with by spraying process or by fluidized bed prilling applying polymer.
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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Citations (1)

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CN1382051A (en) * 1999-08-27 2002-11-27 南方研究所 Injectable bupernorphine microparticle compositions and their use

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US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US20030118641A1 (en) * 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
DE102005024614A1 (en) * 2005-05-25 2006-11-30 Röhm Gmbh Use of polymer blends for the production of coated drug forms and drug form with polymeric blend coating
DE102006051020A1 (en) * 2006-10-26 2008-04-30 Evonik Röhm Gmbh Use of enteric (meth)acrylate copolymers in controlled-release oral pharmaceutical dosage forms as drug matrix formers to reduce the effect of ethanol-induced release rate increase or decrease in vitro

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CN1382051A (en) * 1999-08-27 2002-11-27 南方研究所 Injectable bupernorphine microparticle compositions and their use

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