CN101516353B - Controlled release oral dosage formulations comprising a core and one or more barrier layers - Google Patents

Controlled release oral dosage formulations comprising a core and one or more barrier layers Download PDF

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Publication number
CN101516353B
CN101516353B CN200780035364.1A CN200780035364A CN101516353B CN 101516353 B CN101516353 B CN 101516353B CN 200780035364 A CN200780035364 A CN 200780035364A CN 101516353 B CN101516353 B CN 101516353B
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preparation
core
preparation according
concentration
acid
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CN101516353A (en
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G·韦尼奥
P·格勒尼耶
A·尼安米斯
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Jagotec AG
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Jagotec AG
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Abstract

Controlled release oral dosage formulations containing one or more active agent, and methods of use thereof, are provided for the once-a-day treatment. The formulation can be in the form of a trilayer tablet containing a core or central layer and one or more barrier layers. The core may contain one or more enteric materials or polymeric materials which modulates the release of the active agent.

Description

The controlled release oral dosage formulations that comprises core and one or more barrier layers
The present invention requires the priority of U.S. Provisional Patent Application that U.S. Provisional Patent Application that the applying date is on August 30th, 2006 number 60/824,043 and the applying date are on August 30th, 2006 number 60/824,054.
Technical field
The present invention relates generally to the field of the controlled release preparation (controlled or modified release) of pharmaceutically active agent.
Background technology
Controlled release preparation refers to such pharmaceutical composition, thus its can with predetermined speed and/or after administration the predetermined time discharge medicine keep needed pharmacological activity within needed a period of time.Such preparation provides medicine to body within the predetermined time period or in predetermined absorption site, thereby for example,, with respect to (rapid release) preparation of routine, can within the longer time period, keep levels of drugs in therapeutic domain.
The dosage form that comprises core (wherein core contains the medicine be scattered in controlled-release material) is the form of welcome production controlled release preparation.The material for this purpose the most often used is hydrophilic material, and hydrophilic polymer for example, once it expand and become colloid with after Physiological Medium contacts.When dosage form is exposed to Physiological Medium, periphery will start hydration and form colloidal stroma.Along with medium osmotic dosage form constantly, the thickness of colloidal stroma increases.Thereby medicine spreads and/or corrode substrate to be released by substrate.Size and geometry by careful selection hydrophilic material and dosage form component can produce a series of needed release rule.But, through after a while, along with the thickness increase of colloidal stroma, the drug level in dosage form reduces, the surface area of dosage form reduces, thereby rate of release reduces.
For a lot of active agents, when this reagent passes gastrointestinal tract, absorption rate or degree are not linear.A lot of active agents have so-called absorbing window.Absorbing window is for describing the term of the such zone of gastrointestinal tract or position, in this zone or position, the absorptance of medicine other gastrointestinal region more effectively or absorption rate higher.Some active agents some zones in gastrointestinal tract are easier to degraded or metabolism than other zone.Therefore, for given active agent, if can enough controlled release forms medicine almost completely be delivered to the specific absorption window, or degraded or the higher zone of metabolism of this active agent preferentially avoided or reduce rate of release in gastrointestinal tract, that will be very useful.In addition, can carry active agent can increase the effect of medicine and/or reduce or eliminate side effect to absorbing window.
Industry has the needs of the controlled release form that provides such, once after described dosage form uses, discharge active agent with low rate at first, but along with the growth rate of release of time increases, with the drug main by dosage form, to be discharged into the gastrointestinal lower end area.Especially, industry has such needs, and a kind of dosage form is provided, and can approximately 5.5 discharge more slowly medicine when following and increases rate of release during in higher pH level in the pH level.
Therefore, target of the present invention is for providing controlled release preparation, and it delays the release of one or more active agents, until said preparation arrives absorbing window, and the method that preparation and use said preparation are provided.
Target of the present invention is for such controlled release form is provided, once, after described dosage form uses, discharge active agent with low rate at first, and, along with the growth rate of release of time increases, with the drug main by dosage form, will be discharged into the gastrointestinal lower end area.
Summary of the invention
This paper describes controlled release preparation and preparation and application thereof for delivery of active agent.In a specific embodiments, preparation comprises active agent and Enteric Materials, is optionally the core of hydrophilic material, and one or more barrier layers optionally.Preparation can any solid oral dosage form for example tablet or capsule sheet (caplet) are used.In a specific embodiments, controlled release preparation is tablet, it comprises core, and (this core comprises the dihydropyridine calcium channel blocker, nisoldipine (Nisoldipine) for example) and Enteric Materials, and on central core or below comprise at least one ，Gai barrier layer, barrier layer and comprise that one or more are easily erosion, that expand and/or become the polymeric material of colloid.In core, the concentration of Enteric Materials is composition weight about 0.1% to about 20%, be preferably about 1% to 15%, more preferably about 5% to 10%.The concentration of one or more polymer in barrier layer be barrier layer weight about 5% to about 90%, be preferably about 50% to about 90%.In preferred specific embodiments, tablet is three layers of tablet, and it contains core and two barrier layers, one on core, one below core.Barrier layer can be identical or different component and thickness.One or more pharmaceutically acceptable additives, excipient or carrier can be contained in core and/or barrier layer.
Core can contain the polymeric material that one or more adjustings (slow down and/or accelerate) discharge active agent.The concentration of polymeric material is about 1% to about 95% of weight.One or more adjuvants also can be contained in central core and/or barrier layer, join together further the to regulate release of active agent of adjuvant and polymeric material.The concentration of adjuvant be composition weight about 1% to about 25%, be preferably about 5% to about 15% of composition weight.
Preparation can carry out coating by one or more controlled release coat, and it further regulates the release of active agent from core.Suitable coating comprises that rapid release coating, taste cover up coating, enteric coatings, slow release or extended release coating and delayed release coat.Dosage form also can be carried out the coating of aesthetic reasons, for example to dosage form, adds color or uses surface finish to dosage form.
Once dosage form, after individuality is used, will descend along gastrointestinal tract along with dosage form, and discharge active agent according to the variation of pH value with the rate of release risen.
The specific embodiment
I. definition
Term " Enteric Materials " refers to normally used material in enteric coatings as used herein.Enteric Materials is almost insoluble in the acid pH level under one's belt, and in intestinal, under higher pH level, dissolves cumulative.
Term " taste is covered up coating " refers to pH dependency coating as used herein, and it is insoluble but solvable under acid pH under one's belt in mouth.
Term " extended release coating " refers to pH dependent/non-dependent material as used herein, and it is as stopping to control the diffusion of medicine from core complex to gastrointestinal fluid.
Term " delayed release coat " refers to pH dependency coating as used herein, its under one's belt under acid pH and small intestinal stage casing to insoluble under the pH of epimere, but solvable at small intestinal hypomere or large intestine epimere.
" C as used herein max" refer to the peak concentration in blood plasma.Unless otherwise, otherwise C maxrefer to the peak concentration of Plasma Ca channel blocker.
" T as used herein max" refer to the time that arrives peak concentration in blood plasma.Unless otherwise, otherwise T maxrefer to the time that arrives Plasma Ca channel blocker peak concentration.
" λ as used herein z" refer to elimination rate constant.
" T as used herein 1/2" refer to the final half-life.
" AUC as used herein lastbut " refer to the area between the time from the time 0 to last quantitative concentrations below concentration-time curve.
" AUC as used herein inf" refer to the area between unlimited from the time 0 to extrapolation below dense blood plasma degree-time graph.
" bioavailability " refers to the active component that absorbs from drug products or speed and the picked-up of active agent as used herein.
" bioequivalence " refers to and discharge on an equal basis identical medicine from two or more drug products or preparation as used herein.This causes from these preparations the absorption of equal speed and degree.
" analog " of compound refers to such compound as used herein, for example, and for example, with similar on another structure but not necessarily isomer (, 5-fluorouracil is the analog of thymus pyrimidine).
" derivant " of compound refers to such compound as used herein, and its compound that can have similar structures from another is produced by one or more steps.Derivant is usually directed to add and/or revise one or more functional groups of parent compound.
" controlled release composition (controlled release elements) " refers to and regulates the material that discharges active agent from preparation as used herein.The controlled release composition can be positioned at core and/or barrier layer.The controlled release composition can be organic or inorganic, natural or synthetic material, include but not limited to the derivant of polymeric material, triglyceride, triglyceride, fatty acid and soap, Pulvis Talci, organic molecule and salt thereof, Pulvis Talci, boric acid and silica gel.
Refer to by market and turn to for " bag heart (coat-core) nisoldipine 40mg tablet " of pharmacokinetics and dose comparison purpose as used herein
Figure G2007800353641D00031
the medicine version, the nisoldipine that it contains the nisoldipine of 8mg and contain 32mg in coating in core.
II. compositions
A. core
I. active agent
Core or central core contain one or more active agents, and this active agent is selected from, and include but not limited to hypnotic, tranquilizer (sedative), psychosis (tranquilizer), anticonvulsant, the loosening all muscles agent, analgesic, antiinflammatory, anesthetis, Anticonvulsants, antiulcer agent, anti-phage agent, antimicrobial, antifungal, cardiovascular drug, diuretic, the cell growth inhibiting agent, anti-tumor agent comprising salmosin, Anti-virus agent, glaucoma reagent, antidepressant, the agent of class sympathetic nerve, Hypoylycemic agents, diagnostic reagent, anti-preparation for treating cough, health reinforcing agent (physic energizers), anti-parkinson reagent, local anesthetic, the muscle contraction agent, antimalaric, hormone reagent, contraceptive, apositia, the arthritis agent, antidiabetic, hypotensive agent, anti-fever reagent, anticholinergic agent, bronchodilators, central nervous system's reagent, inotropic agent, vasodilation, vasoconstrictor, decongestant, hematonic, electrolyte replenisher, antibacterial, parasympatholytic, the parasympathetic nervous analog, Bendectin, the direct stimulation medicine, vitamin, beta blocker, the H-2 blocker, β-2 agonist, counter-stimulus, dressing agent condenses, analeptic, antihormone, Drug Antagonists, the fat regulator, uricosuric excretion reagent (uricosurics), cardiac glycoside, Ergota and derivant thereof, the agent of reducing phlegm, muscle relaxant, antihistamine, Purgative, contrast agent, radiopharmaceutical, developer, anti-allergic agent, or its combination.
Suitable active agent includes but not limited to codeine (codeine), dionin (ethylmorphine), dextromethorphan (dextromethorphan), narcotine (noscapine), pentoxyverine (pentoxiverine), acetylcysteine (acetylcysteine), bromhexine (bromhexine), adrenaline (epinephrine), isoprel (isoprenaline), orciprenaline (orciprenaline), ephedrine (ephedrine), fenoterol (fenoterol), asmaten (rimiterol), Ipratropium Bromured (ipratropium), choline theophyllinate (cholinetheophyllinate), brontyl (proxiphylline), beclomethasone (bechlomethasone), budesonide (budesonide), Deslanoside (deslanoside), digoxin (digoxine), digitoxin (digitoxin), disopyramide (disopyramide), Proscillaridin (proscillaridin), quinindium (chinidine), procainamide (procainamide), mexiletine (mexiletin), Flecainide (flecainide), alprenolol (alprenolol), Propranolol (proproanolol), nadolol (nadolol), pindolol (pindolol), oxprenolol (oxprenolol), labetalol (labetalol), timolol (timolol), Atenolol (atenolol), nitropenthrite (pentaeritrityltetranitrate), Coronary artery ligation (isosorbiddinitrate), single nitro Coronex (isosorbidmononitrate), Buddhist nun's phenol Horizon (niphedipin), aniline (phenylamine), Verapamil (verapamil), cyclandelate (cyclandelar), ronicol (nicotinylalcholhol), yodonicit (inositolnicotinate), PGE1 (alprostatdil), second upper parathyrine (etilephrine), Prenalterol (prenalterol), Dobutamine (dobutamine), dopamine (dopamine), dihydroergotamine (dihydroergotamine), guanethidine (guanetidine), bethanidine (betanidine), ethyldopa (methyldopa), reserpine (reserpine), guanfacine (guanfacine), trimetaphan (trimethaphan), Aprelazine (hydralazine), two hydrazines are piperazine (dihydralazine) too, prazosin (prazosine), diazoxiide (diazoxid), captopril (captopril), nifedipine (nifedipine), Nisoldipine (nisoldipine), Enalapril (enalapril), nitroprusside (nitroprusside), bendroflumethiazide (bendroflumethiaziede), Hydrochioro (hydrochlorthiazide), methychlothiazide (metychlothiazide), polythiazide (polythiazide), chlortalidone (chlorthalidon), hot his azoles (cinetazon), brinaldix (clopamide), baycaron (mefruside), methaqualone (metholazone), bumetanide (bumetanide), ethacrynate (ethacrynacide), spirolactone (spironolactone), amiloride (amiloride), CLOF (chlofibrate), niacin (nicotinicacid), niceritrol (nicheritrol), Brompheniramine (brompheniramine), Cinnarizine (cinnarizine), dexchlorpheniramine (dexchlorpheniramine), clemastine (clemastine), Antazoline (antazoline), cyproheptadine (cyproheptadine), fenazil (promethazine), Cimetidine (cimetidine), ranitidine (ranitidine), ulcerlmin (sucralfat), papaverine (papaverine), moxaverine (moxaverine), atropine (atropin), butylscopolamine (butylscopolamin), the Amy holds in the palm (emepron), glucose pyrrone (glucopyrron), hyoscyamine (hyoscyamine), first piperazine rope draws (mepensolar), epoxytropine tropate (methylscopolamine), Oxyphencyclimine (oxiphencyclimine), propanthaline (probanteline), terodiline (terodilin), folium sennae glucosides (sennaglycosides), cascara sagrada extract (sagradaextract), istizin (dantron), but pyrrole sand pyridine (bisachodyl), picosulfate sodium (sodiumpicosulfat), ethylhydroxyethylcellulose (etulos), diphenoxylate (diphenoxylate), Loperamide (loperamide), salicylazosulfapyridine (salazosulfapyridine), pyrvinium chloride (pyrvin), mebendazole (mebendazol), dimeticone (dimeticon), ferrous fumarate (ferrofumarate), ferrous succinate (ferrosuccinate), 4 half sodium ferrous (ferritetrasemisodium), cyanocobalamin (cyanochobalamine), folic acid heparin (folic acid heparin), heparin co-factor (heparin co-factor), bicoumarin (diculmarole), warfarin (warfarin), streptokinase (streptokinase), urokinase (urokinase), the VIII factor (factor VIII), the IX factor (factor IX), vitamin K (vitamin K), thio-tepa (thiotepa), busulfan (busulfan), Chlorambucil (chlorambucil), endoxan (cyclophosphamid), melophalan (melfalan), BCNU (carmustin), mercaptopurine (mercaptopurin), thioguanine (thioguanin), AZA (azathioprin), cytarabin (cytarabin), vincaleukoblastinum (vinblastin), vincristine (vinchristin), eldisine (vindesin), procarbazine (procarbazine), Dacarbazine (dacarbazine), hexamethylene nitrous knee (lomustin), estramustine (estramustin), Teniposide (teniposide), etoposide (etoposide), cis-platinum (cisplatin), amsacrine (amsachrin), aminoglutethimide (aminogluthetimid), phosphoric acid oestrone (phosphestrol), methoxyl group progesterone (medroxiprogresterone), hydroxyl progesterone (hydroxiprogresterone), megestrol acetate (megesterol), norethindrone (noretisteron), TAM (tamoxiphen), cyclosporine (ciclosporin), domian (sulfisomidine), parasiticin (bensylpenicillin), penicillin Vl phenoxymethylpenicillin (phenoxymethylpenicillin), dicloxacillin (dicloxacillin), cloxacillin (cloxacillin), flucloxacillin (flucloxacillin), ampicillin (ampicillin), Amoxicillin (amoxicillin), Pivampicillin (pivampicillin), Bacampicillin (bacampicillin), Piperacillin (piperacillin), mezlocillin (mezlocillin), Mecillinam (mecillinam), Pivmecillinam (pivmecillinam), cefoxitin (cephalotin), cefalexin (cephalexin), Cefradine (cephradin), cefadroxil (cephadroxil), Cefaclor (cephaclor), cefuroxime (cefuroxim), CTX (cefotaxim), cefotaxime (ceftazidim), Cefoxitin (cefoxitin), AZT (aztreonam), Imipenem (imipenem), cilastatin (cilastatin), tetracycline (tetracycline), Armyl (lymecycline), demeclocycline (demeclocycline), methacycline (metacycline), terramycin (oxitetracycline), power mycin (doxycycline), chloramphenicol (chloramphenicol), spiramvcin (spiramycin), fusidinic acid (fusidic acid), lincomycin (lincomycin), clindamycin (clindamycin), spectinomycin (spectinomycin), rifampin (rifampicin), amphotericin B (amphotericin B), griseofulvin (griseofulvin), nystatin (nystatin), vancomycin (vancomycin), metronidazole (metronidazole), Tinidazole (tinidazole), methoxybenzyl aminopyrimidine (trimethoprim), fluorine promise husky (norfloxacin), salicylazosulfapyridine (salazosulfapyridin), aminosalicylic acid (aminosalyl), different hydrazine hydrochloride (isoniazid), ethambutol (etambutol), furantoin (nitrofurantoin), acidum nalidixicum (nalidixic acid), methenamine (metenamine), chloroquine (chloroquin), HCQ quinoline (hydroxichloroquin), Tinidazole (tinidazol), ketoconazole (ketokonazol), ACV (acyclovir), interferon (interferon), iodoxuridine (idoxuridin), retinol (retinol), thiamines (tiamin), dexpanthenol (dexpantenol), pyridoxol (pyridoxin), folic acid (folic acid), ascorbic acid (ascorbic acid), fertility alcohol (tokoferol), vitamin K1 (phytominadion), fenfluramine (phenfluramin), corticotropin (corticotropin), cosyntropin (tetracosactid), thyrotropic hormone (tyrotropin), growth hormone (somatotropin), Somatrem (somatrem), vasopressins (vasopressin), Diapid (lypressin), minirin (desmopressin), oxytocin (oxytocin), human chorionic gonadtropin (chloriongonadotropin), cortisone (cortison), hydrocortisone (hydrocortison), fludrocortison (fludrocortison), metacortandracin (prednison), prednisolone (prednisolon), Fluoxymesterone (fluoximesteron), first hydrogen testosterone (mesterolon), nandrolone (nandrolon), stanozolol (stanozolol), Oxymetholone (oximetolon), cyproterone (cyproteron), Levothyroxine (levotyroxin), iodine Sai Luoning (liotyronin), propylthiouracil (PTU) (propylthiouracil), Carbimazole (carbimazol), methimazole (tiamazol), dihydrotachysterol (dihydrotachysterol), Alfacalcidol (alfacalcidol), calcitriol (calcitirol), insulin (insulin), orinase (tolbutamid), chlorpropamide (chlorpropamid), first sulphur nitrogen grass urea (tolazamid), Glipizide (glipizid), glibenclamide (glibenclamid), phenobarbital (phenobarbital), Methyprylon (methyprylon), pyridinedione (pyrityldion), Meprobamate (meprobamat), chlordiazepoxide (chlordiazepoxid), diazepam (diazepam), intrazepam (nitrazepam), Oxazepam (oxazepam), clorazepate (dikaliumchlorazepat), Lorazepam (lorazepam), Flunitrazepam (flunitrazepam), alprazolam (alprazolam), midazolam (midazolam), hydroxyzine (hydroxizin), chloromethane sulphur imidazoles (chlomethiazol), propiomazine (propionmazine), alimemazine (alimemazine), chlorpromazine (chlorpromazine), levomepromazine (levomepromazine), acetophenazine (acetophenazine), fluphenazinum (fluphenazine), chloracizin (perphenazine), prochlorperazine (prochlorperazine), triperazine (trifluoperazine), dixyrazine (dixyrazine), thioridazine (thioridazine), pericyazine (periciazin), Chlorprothixene (chloprothixene), pearl chlorine spray assistant (zuclopentizol), fluorine spray assistant (flupentizol), thiothixene (thithixen), haloperole (haloperidol), trimipramine (trimipramin), Opipramol (opipramol), clomipramine (chlomipramin), desipramine (desipramin), lofepramine (lofepramin), amitriptyline (amitriptylin), nortriptyline (nortriptylin), protriptyline (protriptylin), maprotiline (maptrotilin), caffeine (coffein), cinnarizine (cinnarizine), marezine (cyclizine), dramamine (dimenhydinate), meclozine (meclozine), fenazil (prometazine), tietylperazine (thiethylperazine), Metoclopramide (metoclopramide), hyoscine (scopolamine), phenobarbital (phenobarbital), phenytoinum naticum (phenytoine), ethymal (ethosuximide), Primidone (primidone), carbamazepine (carbamazepine), Clonazepam (chlonazepam), Orphenadrine (orphenadrine), atropine (atropine), benzene Sa tropine (bensatropine), Biperiden (biperiden), methixene (metixene), procyclidine (procylidine), left-handed many (levodopa), bromocriptine (bromocriptin), amantadine (amantadine), ambenonium chloride (ambenon), this bright (pyridostigmine) of pyrrole, neostigmine (synstigmine), disulfiram (disulfiram), morphine (morphine), codeine (codeine), spray Ta Youxin (pentazocine), testosterone (buprenorphine), pethidine (pethidine), Phenoperidine (phenoperidine), sweet smell is slave (fentanyl) too, methadone (methadone), pirinitramide (piritramide), Propoxyphene (dextropropoxyphene), Ketobemidone (ketobemidone), acetylsalicylic acid (acetylsalicylic acid), phenazone (phenazone), phenylbutazone (phenylbutazone), apazone (azapropazone), piroxicam (piroxicam), ergotamine (ergotamine), dihydroergotamine (dihydroergotamine), cyproheptadine (cyproheptadine), pizotifen (pizitifen), flumedroxone (flumedroxon), Allopurinol (allopurinol), probenecid (probenecid), gold sulphur fourth sodium (sodiummaurothiomalate), Anranofin (auronofin), penicillamine (penicillamine), estradiol (estradiol), Estradiol Valerate (estradiolvalerianate), estriol (estriol), ethinylestradiol (ethinylestradiol), dihydroprogesterone (dihydrogesteron), lynestrenol (lynestrenol), Medroxyprogesterone (medroxiprogresterone), norethindrone (noretisterone), cyclofenil (cyclophenile), Clomifene (clomiphene), Levonorgestrel (levonorgestrel), mestranol (mestranol), Ornidazole (ornidazol), Tinidazole (tinidazol), econazole (ekonazol), the bent horse azoles (chlotrimazol) of chlorine, natamycin (natamycine), Miconazole (miconazole), sulbentine (sulbentin), metergotamine (methylergotamine), dinoprost (dinoprost), dinoprostone (dinoproston), Misoprostol (gemeprost), bromocryptine (bromocriptine), phenylpropanolamine (phenylpropanolamine), sodium chromoglicate (sodiumchromoglicate), acetazolamide (azetazolamide), dichloroaniline (dichlophenamide), beta carotene (betacarotene), naloxone (naloxone), Calciumlevofolinate (calciumfolinate), particularly clonidine (clonidine), theophylline (theophylline), Dipyridamole (dipyradamol), Hydrochioro (hydrochlorothiazide), hyoscine (scopolamine), Indomethacin (indomethacine), frusemide (furosemide), potassium chloride (potassium chloride), morphine (morphine), brufen (ibuprofen), salbutamol (salbutamol), Terbutaline (terbutalin), and combination.
Active agent can be chirality or achiral.Chiral molecule can be used as single enantiomer, mixture of enantiomers, diastereomer or racemic mixture and exists.Term " stereoisomer " refers to such compound as used herein, and it is comprised of the same atoms with identical skeleton order, but has different atom three-dimensional arrangement, and these atoms can not be replaced mutually.Three dimensional structure is called as configuration.Term " enantiomer " refers to two stereoisomers as used herein, they be each other can not be overlapping mirror image.Term " optical isomer " is of equal value with term " enantiomer " as used herein.Term " diastereomer " refers to two stereoisomers as used herein, and they are not mirror images and can not be overlapping.Term " racemoid ", " racemic mixture " or " racemization modification " refer to the mixture of equivalent enantiomer.Term " chiral centre " refers to the carbon atom that has connected four different groups.The Application standard technology select suitable chiral column, eluant and essential condition with affect separating of a pair of enantiomer be to those skilled in the art know (referring to for example Jacques, J. wait the people, " Enantiomers; Racemates; and Resolutions ", John Wiley and Sons, Inc.1981).
Term " pharmaceutically acceptable salt " refers to the derivant of above listed compound as used herein, and wherein parent compound is by preparing acidity or alkaline addition salts is modified.The acylate that the example of pharmaceutically acceptable salt includes but not limited to mineral or alkaline residue is amine for example; With the organic salt of alkali or acidic residues carboxylic acid for example.Pharmaceutically acceptable salt comprises conventional non-toxic salts or the quaternary ammonium salt of the parent compound of formation, for example or organic acid formed salt inorganic from avirulence.The conventional non-toxic salts of this class comprises that those are derived from mineral acid for example hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid and nitric acid; With from organic acid for example acetic acid, propanoic acid, succinic acid, hydroxyacetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-anilinesulfonic acid., 2-acetate benzoic acid, fumaric acid, toluene sulfonic acide, naphthyl benzenesulfonic acid, Loprazolam, ethane disulfonic acid, oxalic acid and hydroxyethylsulfonic acid. preparation and the salt that takes.
The pharmaceutically acceptable salt of compound can be synthetic by the conventional chemical method from parent compound (it contains alkalescence or acidic moiety).Usually, this class salt can react to prepare in water or in organic solvent or in the two mixture with suitable stoichiometric alkali or acid by the free acid by these compounds or alkali form; Usually, preferred for example diethyl ether, ethyl acetate, ethanol, isopropyl alcohol or acetonitrile of non-aqueous solvent.Can be at Remington ' sPharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p.704 with " Handbook of Pharmaceutical Salts:Properties; Selection, and Use, " P.Heinrich Stahl and Camille G.Wermuth, Eds., Wiley-VCH, Weinheim, find the list of suitable salt in 2002.
Term " pharmaceutically acceptable salt " used as common as this paper refers to those compounds, material, compositions and/or dosage form, they are in the scope of rational medical judgment, be suitable for contacting with human and animal's tissue, match with rational income/relative risk, and there is no unnecessary toxicity, zest, anaphylactic reaction or other problem or complication.
In dosage form, the amount of active agent used will depend on character and the order of severity of stand-by active agent and disease to be treated.The concentration of active agent be generally tablet weight about 0.1% to about 90%, be preferably tablet weight about 0.5% to about 20%, more preferably about 1% of tablet weight to about 10%.Perhaps, the concentration of active agent be generally core weight about 0.1% to about 90%, be preferably core weight about 0.5% to about 20%, more preferably about 1% of core weight to about 10%.
In preferred specific embodiments, active agent is the dihydropyridine calcium channel blocker, for example nisoldipine and derivant thereof, analog or polymorph.Nisoldipine is the yellow crystals material, and it is almost insoluble in water, but solvable in ethanol.The derivant of nisoldipine, such as m-nisoldipine people such as Wang, J. Chrom.B, 835,71-76 has description in (2006).
B. controlled release composition
1. Enteric Materials
Core or central core contain Enteric Materials with the release that postpones one or more active agents until preparation arrives absorbing window.Suitable Enteric Materials includes but not limited to, cellulosic polymer, for example cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate and hydroxypropyl methylcellulose acetate succinate; Polyvinyl acetate phthalate, acrylate copolymer and copolymer, and commercially available methylpropanoic acid olefine resin under (Rohm Pharma) trade name, for example poly-(ethyl acrylate-methyl methacrylate-triethylamine ethyl methacrylate-hydrochlorate) (
Figure DEST_PATH_GSB00001096572200012
rS and
Figure DEST_PATH_GSB00001096572200013
rL) and poly-(ethyl acrylate-methyl methacrylate) (
Figure DEST_PATH_GSB00001096572200014
nE); Alginate esters, alkaline soluble acrylic resin, hydroxypropylmethyl cellulose phthalate, methacrylate-methacrylic acid copolymer, polyvinyl acetate phthalate, styrene maleic acid copolymer etc., and combination.In a specific embodiments, Enteric Materials is cellulose acetate phthalate.The concentration of Enteric Materials be composition weight about 0.1% to about 20%, be preferably composition weight about 1% to about 15%, more preferably about 5% of composition weight to about 10%.
2. hydrophilic material
Core also can contain the hydrophilic material that one or more adjustings (slow down and/or accelerate) active agent discharges.Hydrophilic material can be any material that forms controlled release reagent in dosage form as substrate that is used in known in the art.The example of such material includes but not limited to methylcellulose, sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, crosslinked hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl starch, polymethacrylates, polyvinylpyrrolidone, polyvinyl alcohol, Polyethylene Glycol, methacrylic acid potassium-divinylbenzene copolymer, carboxymethyl cellulose, alginate esters, albumin, gelatin, crosslinked polyvinylpyrrolidone, soluble starch and derivant thereof, polyester, poly-anhydride, polymethyl vinyl ether/acid anhydride copolymer, glucosan, scleroglucan, mannan, beta cyclodextrin and the cyclodextrin derivative that contains straight chain and/or branch polymer chain, and composition thereof.Various types of material mentioned above is commercial, and can for example, by the difference of chemistry-physical features (dissolubility and colloid form), be identified.For example, the erosibility of carboxylic propyl methocel, colloidization and swelliong power can change according to molecular weight and the replacement degree of polymer.Therefore, those skilled in the art can be according to the release rule of desired active agent, but and selects the polymer with same molecular structure different molecular weight and/or viscosity in polymer.In a specific embodiments, core contains
Figure DEST_PATH_GSB00001096572200015
k4M, a kind of hydroxypropyl emthylcellulose, its methoxyl content is that 19-24%, hydroxyl hydroxypropoxyl content are 7-12%, and the outward appearance viscosity of 2308-3755mPa (in 2% aqueous solution, by rotation, measure and obtain) (Colorcon, West Point, PA).
The concentration of hydrophilic material be composition weight about 1% to about 90%, be preferably composition weight about 10% to about 50%, more preferably about 10% to 45% of composition weight.
After Physiological Medium contacts, the core that contains active agent, Enteric Materials and hydrophilic material forms colloidal stroma.Colloidal stroma must have enough intensity so that it keeps its structural intergrity in the process of drug release.While hanging down the pH level under one's belt, Enteric Materials keeps holding.But when dosage form further descends along gastrointestinal tract, the Enteric Materials dissolubility increases, and the hole therefore produced on substrate and passage increase, and the speed that medicine can increase is spread by these holes and passage.Enteric Materials can not expand and/or become colloid in aqueous medium, therefore, and for the not contribution of mechanical strength of colloidal stroma.Importantly, the needed effect of Enteric Materials on rate of release do not offset by the unwanted effect of structural intergrity of ripe in advance destruction colloidal stroma.In order to guarantee can repeat to obtain needed rate of release, preferably, with the hydrophilic material with respect to used, less quantity is used Enteric Materials.Most preferably, the ratio of hydrophilic material and Enteric Materials is about 1.5: 1 to about 10: 1, is more particularly about 1.9: 1 to about 5: 1.
C. barrier layer
Barrier layer is used for the release of active agent contained in central core or core is stoped to one predetermined period.Tablet can contain one or more barrier layers.When existing Shi， barrier layer, two barrier layers can there is identical component or different component and/or identical thickness or different thickness.
In a specific embodiments, polymer one or more expansions, that easily lose and/or the one-tenth colloid is contained on barrier layer.In preferred specific embodiments, polymer expansion, that easily lose and/or the one-tenth colloid is hydroxypropyl emthylcellulose.The weight average molecular weight of hydroxypropyl emthylcellulose is about 1000 to about 4,000,000, more preferably about 2000 to about 2,000,000.In a specific embodiments, barrier layer is contained
Figure G2007800353641D00102
e5, a kind of hydroxypropyl emthylcellulose, its methoxyl content is that 28-30%, hydroxyl hydroxypropoxyl content are 7-12%, and the outward appearance viscosity of the 4.2-6.1mPa measured by rotation (Colorcon, West Point, PA).In another embodiment, barrier layer is contained
Figure G2007800353641D00103
e50, a kind of hydroxypropyl emthylcellulose, its methoxyl content is that 28-30%, hydroxyl hydroxypropoxyl content are 7-12%, and the outward appearance viscosity of the 39-59mPa measured by rotation (Colorcon, West Point, PA).In preferred specific embodiments, a barrier layer is contained
Figure G2007800353641D00104
e5, the second barrier layer is contained
Figure G2007800353641D00105
e50.
Other suitable polymer includes but not limited to, carboxyl ethylene polymer, polyvinyl alcohol, glucosan, scleroglucan, mannan, xanthan gum, alginic acid and derivant thereof, poly-anhydride, polyamino acid, Copolymer of Methyl Vinyl Ether/Maleic Anhydride, carboxymethyl cellulose and derivant, ethyl cellulose, methylcellulose and other cellulosic polymer.
Polymer exists with about 5% to about 90% quantity of barrier layer weight, is preferably about 25% to about 75% of barrier layer weight.
D. other controlled release reagent
One or more adjuvants also can be contained in core layer and/or barrier layer, and based on needed active agent release rule, adjuvant and polymeric material join together to allow the further modification that active agent is discharged.Suitable adjuvant includes but not limited to, glyceryl monostearate, triglyceride derivant, semisynthetic glyceride, castor oil hydrogenated, glyceryl palmitostearate, hexadecanol, polyvinylpyrrolidone, glycerol, ethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, other well known to those skilled in the art natural or synthetic material, and combination.Other suitable adjuvant includes but not limited to, magnesium stearate, stearic acid, Pulvis Talci, sodium benzoate, boric acid, Polyethylene Glycol and silica gel.The concentration of adjuvant be composition weight about 1% to about 25%, be preferably about 5% to about 15% of composition weight.
F. additive, excipient and carrier
Can prepare preparation with pharmaceutically acceptable carrier, described carrier forms by being considered to safe and efficient material, and this material can be used and not bring unwanted side effect biology or undesired interaction to individuality.Carrier be in pharmaceutical formulations except active agent existing all compositions.As this paper usually " carrier " used include but not limited to, plasticizer, diluent, binding agent, lubricant, surfactant, pH adjusting agent, antiplastering aid, disintegrating agent, implant, pigment, coloring agent, stabilizing agent, flavor agent, fluidizer and combination thereof.
Suitable plasticizer includes but not limited to, castor oil hydrogenated, hexadecanol, cetostearyl alcohol, fatty acid, glyceride and triglyceride and derivant thereof, and Polyethylene Glycol and derivant thereof.
Diluent, also referred to as " fill ", be generally essential increase solid dosage forms volume so that can be the compression of tablet or form pearl and granule provides rational size.Suitable diluent includes but not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannose, sorbose, cellulose, microcrystalline Cellulose, Kaolin, sodium chloride, dried starch, hydrolyzed starch, preformation amylopectin, silicon dioxide, titanium oxide, zeopan and powdered sugar.The amount of the active substance discharged at first medicine-feeding period can by the composition of regulating exposed surface and formation hypothallus, by sequencing, this obviously all depends on the main dissolubility of identical activity.
Binding agent is used for adding bond property to solid preparation, and therefore guarantees that tablet or pearl or granule keep complete after dosage form forms.Suitable adhesive material includes but not limited to, starch, the preformation amylopectin, gelatin, sugar (comprises sucrose, glucose, dextrose, lactose and sorbose), Polyethylene Glycol, wax, natural and synthetic natural gum is Radix Acaciae senegalis for example, tragacanth, sodium alginate, cellulose comprises hydroxypropyl emthylcellulose, hydroxypropyl cellulose, ethyl cellulose and aluminium magensium silicate (veegum), and synthetic polymer for example acrylic acid and methacrylic acid copolymer, methacrylic acid copolymer, methylmethacrylate copolymer, methacrylic acid aminoalkyl ester copolymer, poly propenoic acid methacrylic acid and polyvinylpyrrolidone.
Lubricant is for promoting the production of tablet.The example of proper lubrication agent includes but not limited to, magnesium stearate, calcium stearate, stearic acid, behenic acid glycerol, Polyethylene Glycol, Pulvis Talci and mineral oil.
Disintegrating agent is for promoting dosage form disintegrate or " cracking " after using, generally include but be not limited to, starch, carboxylic amylcose acetate sodium, carboxymethyl starch sodium, sodium carboxymethyl cellulose, hydroxypropyl cellulose, preformation amylopectin, clay, cellulose, seaweeds, natural gum or crosslinked polymer be crosslinked PVP (from the polyvidone XL of GAF Chemical Corp) for example.
Stabilizing agent is for suppressing or delaying the medicine decomposition reaction, and decomposition reaction comprises for example, as oxidation reaction.
That surfactant comprises anion, cation, both sexes or non-ionic surfactants.Suitable anion surfactant includes but not limited to, those contain carboxylate radical, sulfonate radical and sulfate ion.The example of anion surfactant comprises chain alkyl sodium sulfonate, potassium, ammonium and alkylaryl sulfonates, for example dodecylbenzene sodium sulfonate; Dialkyl group succinate sodium sulfonate, for example dodecylbenzene sodium sulfonate; Dialkyl group succinate sodium sulfonate, for example two-(2-thio-ethyl (ethylthioxyl))-succinate sodium sulfonate; Alkyl sulfate is sodium lauryl sulphate for example.Cationic surfactant includes but not limited to quaternary ammonium compound for example benzalkonium chloride, benzethonium chloride, cetyl trimethyl ammonium bromide, stearyl dimethyl benzyl ammonium chloride, polyoxyethylene and coconut amine.The example of non-ionic surface active agent comprise ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, tristerin, polyglycine-4-oleate, acrylic acid Pyrusussuriensis sugar ester, sucrose acrylate, PEG-150 laurate, PEG-400 monolaurate, Vinlub 73, polysorbate, polyoxyethylene octyl phenol ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether,
Figure G2007800353641D00121
401, stearyl list Propanolamine and polyethylene glycol hydrogenated tallow amine.The example of the surfactant of both sexes comprises N-dodecyl-β-alanine sodium, N-lauryl-β-imino-diacetic sodium propionate, myristoyl both sexes guanidine-acetic acid salt, lauryl betaine and lauryl thetine.
If necessary, tablet also can contain the complementary material of micro-avirulence for example humidizer or emulsifying agent, dyestuff, pH buffer agent or antiseptic.
F. controlled release coat
The compositions of solid dosage form described herein can be carried out coating by one or more rapid releases and/or controlled release coat, and these coatings are further regulated the release of the active agent in core or central core.Suitable coating includes but not limited to, dissolves in or permeate the coating (being that taste is covered up coating and rapid release coating) of acid medium in stomach; Under one's belt in acid medium insoluble but in small intestinal soluble coating (being enteric coatings) under neutral environment; Insoluble but at small intestinal hypomere or the soluble coating of large intestine epimere (being delayed release coat) to epimere with the small intestinal stage casing under one's belt; And combination.Dosage form also can coating for example add color or use surface finish to dosage form to dosage form because of aesthstic purpose.
1. rapid release coating
The rapid release coating is comprised of polymer, its with after saliva contacts in oral cavity solvable or, insoluble but solvable under low pH under one's belt under the neutral pH in oral cavity.
In mouth, soluble coating can have the characteristic of for example sticking, the absorption with enhanced activity reagent that contacts with the prolongation granule with oral cavity, sublingual gland or other oral surfaces.A lot of adhesion polymer are known and usually are characterized as highdensity carboxylic group.Referring to the U.S. Patent No. 6,235,313 such as people such as Mathiowitz and U.S. Patent No. 5,955,096.
Soluble coating is generally used for providing the characteristic that for example taste is covered up under one's belt.Cationic polymer
Figure G2007800353641D00122
e 100 (Rohm Pharma) is with amino group.Therefore its thin film is insoluble in the neutral medium of saliva, but solvable by forming salt under the sour environment of stomach.The film coating that such thickness is about 10 microns can prevent those bitter in the mouth or distasteful medicine when swallowing or swallow in process orally-dissolvable.Dissolve rapidly under protectiveness thin film acid condition under one's belt, make active agent be released.Coated composition can contain conventional additive, such as plasticizer, pigment, coloring agent, stabilizing agent, fluidizer etc.
2. slow release or extended release coating
Useful coating makes the slow release of active agent or extended release become possibility in the diffusion barrier coating of medicine-above the resin compounded composition granule.Suitable coating material includes but not limited to, cellulosic polymer is cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate and hydroxypropyl methylcellulose acetate succinate for example; Polyvinyl acetate phthalate, acrylate copolymer and copolymer, and
Figure G2007800353641D00131
the acrylic resin of commercially available methacrylic resin, alginate esters, alkali soluble under (Rohm Pharma) trade name, hydroxypropylmethyl cellulose phthalate, methacrylate-methacrylic acid copolymer, polyvinyl acetate phthalate, styrene maleic acid copolymer,
Figure G2007800353641D00132
copolymer under (Rohm Pharma) trade name, for example poly-(ethyl acrylate-methyl methacrylate-triethyl ammonium ethyl methacrylate-hydrochlorate) (
Figure G2007800353641D00133
rS and
Figure G2007800353641D00134
rL) and poly-(ethyl acrylate-methyl methacrylate) (
Figure G2007800353641D00135
nE); And combination.The aqueous dispersions of these polymer can be by trade name
Figure G2007800353641D00136
rS 30D,
Figure G2007800353641D00137
rL30D,
Figure G2007800353641D00138
nE 30D obtains.
These polymer can be used alone, with combination with one another or for example, with plasticizer (, triethyl citrate), pigment and other combinations of substances to change the characteristic of coating.Usually, the main component of coating should be insoluble to and can not see through water.But, may need to add water-soluble substances, methylcellulose for example, change the permeability of coating.
Coating material can be used as the float in waterborne liquid.Coated composition can comprise conventional additives such as plasticizer, pigment, coloring agent, stabilizing agent, fluidizer etc.Plasticizer exists to reduce the fragility of coating usually, and with respect to the polymer dry weight, is about 10 % by weight to 50% weight usually.The example of typical plasticizer includes but not limited to, Polyethylene Glycol, polypropylene glycol, glyceryl triacetate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, Oleum Ricini and acetylated monoglyceride.Stabilizing agent can be used for the granule in the stable dispersion thing.Typical stabilizing agent is for example sorbitan ester, polysorbate and polyvinylpyrrolidone of nonionic emulsifier.Fluidizer is recommended, and for reducing, thin film forms and the viscous effect of dry run, and is generally about 25 % by weight to 100% weight of polymer weight in coating solution.A kind of effective fluidizer is Pulvis Talci.The fluidizer that also can use other is magnesium stearate and glycerol monostearate for example.Also can use for example titanium dioxide of pigment.Also can in coated composition, add for example silicones (for example Simethicone (simethicone)) of a small amount of anti-foam reagent.
3. enteric coatings
Can be according to list of references for example " Pharmaceutical dosage form tablets "; the people such as eds.Liberman (New York; Marcel Dekker; Inc.; 1989); " Remington-The science and practice ofpharmacy ", 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and " Pharmaceutical dosage forms and drug delivery systems ", 6th Edition, the people such as Ansel, (Media, PA:Williams and Wilkins, 1995) prepare the dosage form of enteric coatings.The example of suitable coating material includes but not limited to cellulosic polymer, for example cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate and hydroxypropyl methylcellulose acetate succinate; Polyvinyl acetate phthalate, acrylate copolymer and copolymer,
Figure G2007800353641D00141
commercially available methacrylic resin under (Rohm Pharma) trade name.In addition, coating material can contain conventional carrier for example plasticizer, pigment, coloring agent, fluidizer, stabilizing agent and active surface agent.
III. production method
Can prepare by technology well known in the art by compositions described herein.Can prepare by compression forming by the multilamellar tablet.When compression forming, prepare respectively core and one or more barrier layer, then use multilamellar tablet compressor to be suppressed.Perhaps, can prepare separately core, barrier layer adds as blend, and compressed compositions is to form tablet.
The geometry of dosage form described herein can change according to the type of needed release rule.Its simplest form, dosage form can be comprised of the monolithic core.Perhaps, core can be comprised of one or more layers, contains one or more active substances pharmaceutically in each layer.Such dosage form has description in the people's such as Conte U.S. Patent No. 5,626,874,5,422,123 and 6,027,748.
Perhaps, one or more layers can not contain active agent.Each layer can contain identical or different controlled-release materials and excipient.In another embodiment, dosage form can be the multiparticulates system.Each microgranule can contain identical or different pharmaceutically active substances and identical or different controlled-release material and other adjuvant.In preferred dosage form, core is multilamellar, for example, has two-layerly or three layers, and wherein one or more contain active agent and other layer containing active agent.In particularly preferred specific embodiments, dosage form comprises the core be comprised of three layers, and wherein internal layer contains active agent, and another two skins are not containing active agent.
Preparation can be used technology well known in the art to carry out coating by film coating, at least part of coating core of described thin film.Coating can be used as solid or aqueous suspension or organic solution.The suitable technology for coating includes but not limited to, spray coating, disc type coating, liquid bed coating and compression coating.
IV. application process
Dosage form described herein can be used to treat various cardiovascular disease.Although preferred patient behaves, and usually also can treat any mammal and comprise domestic animal for example Canis familiaris L. and cat.Dosage form is usually Orally administered with the form of tablet or capsule sheet.Dosage form can be used or use with the dosage improved by individually dosed, cumulative dosage, after reaching the specific blood circulation concentration of active agent, is down to than low dosage again.Those skilled in the art can select treatment sequence and determine suitable Dose standard according to bioavailability and the half-life of pharmaceutically active substances to be administered.Those skilled in the art can determine the suitable dosage of material by normal experiment and standard technique with the dosage of getting permission at present to pass through.The interior difference of patient that depends on the seriousness of disease is known in this area and usually adjusts dosage to reach the particular treatment effect in given patient.
For a lot of active agents that disclose, the suitable dosage range of having set up is so that the circulation composition of material maximizes and side effect minimizes.Usually, the amount that active agent can about 0.001 to 100mg/kg body weight is used, and is preferably 0.01 to 10mg/kg, and more preferably 0.1 to 10mg/kg.In the situation that specific calcium channel blocker, the dosage that they can about 0.001 to 100mg/kg patient body weight is used, and is preferably 0.01 to 10mg/kg, and more preferably 0.1 to 1.0mg/kg.The preferred daily dose of calcium channel blocker is about 1-100mg, is preferably 2.5mg to 50mg with Cardiovarscular for example hypertension, angina pectoris and arrhythmia.
Mixture by using Enteric Materials and hydrophilic material is to form controlled release matrix, the technical staff can obtain such release rule, and the initial release that it is characterized by drug substance is slow, along with the time increases, dosage form descends along gastrointestinal tract, according to the variation of pH, causes that rate of release increases.When main dosage that need to be at the low section of gastrointestinal tract release of active agent, such release rule is in demand.The meaning of the low section of gastrointestinal tract is ileum and large intestine.Term " ileum " refers to the 3rd section of small intestinal, and it extends to duodenum and jejunum.Term " large intestine " refers to the position be comprised of caecum, colon, rectum.Term " caecum " refers to the invisible large intestine started from large intestine, and the one end is the ileum opening.
Dosage form described herein can be made into to provide a series of pharmacokinetics release rule, and described release rule is designed to the specific absorption site with the low section of higher rate of release targeting gastrointestinal tract by active agent.Like this, use these dosage forms can be less or eliminate the undesired side effect of a lot of active agents.They also can make active agent effective, although dosage is compared and reduced with the known preparation of those active substances.
Those skilled in the art use the experiment that is no more than normal experiment, will recognize or can determine a lot of equivalents of specific specific embodiments of the present invention described herein.Such equivalent is included by claims.
A. pharmacokinetic parameter
In a specific embodiments, with the calcium channel blocker of same dose in the reference preparation that contains slow release core and rapid release coating (the bag heart) for example nisoldipine compare, compositions described herein provides the bioavailability increased (area below drug plasma concentration-time graph (AUC) is measured).In preferred specific embodiments, with
Figure G2007800353641D00151
in the medicine of same dose compare, compositions provides the bioavailability of the rising of nisoldipine.In another embodiment, the nisoldipine of the dosage that compositions contains minimizing, but show and
Figure G2007800353641D00152
similar pharmacokinetics collection of illustrative plates.
For example,, with 40mg's
Figure G2007800353641D00153
compare the AUC of the three layers of tablet (preparation A) that contain the 40mg nisoldipine lastshow about 16% increase.This shows: in three layers of tablet, the dosage of nisoldipine can reduce about 15%-17%, or 16% (being reduced to 34mg) and the medicine of effective quantity still is provided.Therefore,
Figure G2007800353641D00154
the dose intensity of 10mg, 20mg, 30mg and 40mg can be replaced by dose intensity minimizing, bioequivalent (for example, 8.5mg, 17mg, 25.5mg and 34mg).Owing to obtaining the needed dosage of required therapeutic efficiency, reduce, this can cause lower production cost.
In another embodiment, compositions described herein contains one or more controlled release compositions, and its quantity is for the controlled release of calcium channel blocker can effectively be provided, and under fasted conditions, the dosage said composition based on 40mg provides the T of calcium channel blocker maxaUC for about 9 to about 20 hours and calcium channel blocker lastfor about 48 to about 63 hours * ng/mL.
In the another one specific embodiments, compositions described herein contains one or more controlled release compositions, and its quantity is for the controlled release of calcium channel blocker can effectively be provided, and under fasted conditions, the dosage said composition based on 40mg provides the T of calcium channel blocker maxc for about 9 to about 20 hours and calcium channel blocker maxfor about 2.75 to about 4ng/mL.
Embodiment with reference to following indefiniteness will understand the present invention better.
Embodiment
Three layers of tablet of the nisoldipine that embodiment 1. contains 40mg
Three kinds of different preparations have been prepared, every kind of nisoldipine that contains 40mg.These preparations are called as preparation A, preparation B and formulation C, described in table 1-3.Formulation C is carried out coating with enteric coatings (5% weight increases), and described enteric coatings contains s100 (methacrylic acid copolymer Type B) and the combination of L100 (methacrylic acid copolymer A type).Preparation A and B be with from Colorcon, West Point, PA's
Figure G2007800353641D00163
iI sealing coating carries out coating.
The component of table 1 preparation A
Figure G2007800353641D00164
The component of table 2 preparation B
Figure G2007800353641D00165
Figure G2007800353641D00171
The component of table 3 formulation C
Figure G2007800353641D00172
Figure G2007800353641D00181
Preparation described above is according to the preparation of getting off:
core or central core
1. in the high speed shear agitator, nisoldipine and sodium lauryl sulphate are stirred two minutes.Add lactose monohydrate, polyvidone, methacrylic acid copolymer (Type B) and 2208 type hypromelloses (Methocel K4M) and stir ten minutes in agitator.
2. be dissolved in purified water by polyvidone and add sodium lauryl sulphate to prepare binding soln.Mixture stirs in suitable groove, standing until complete and defoam.
3. add binding soln and stir simply 2 minutes in the high speed shear agitator containing the mixture in 1 in steps.The granule obtained is carried out to kneading and be transferred in the liquid bed dryer, dry until obtain the LOD value below 2.5%.After drying, with the vibration dismembyator, granule is ground.
4., after grinding, half of granule is placed in to dispersator.Add silicon dioxide colloid in blender, then add remaining granule.Mixture is stirred 20 minutes.
5. manually the mixture of magnesium stearate and 5% step 4 is carried out to premixing.Granule in dispersator adds premix and stirs 10 minutes.
barrier layer
1. add lactose monohydrate, Glyceryl Behenate, ferrum oxide (yellow), polyvidone and 2910 type hypromelloses (Methocel E4M) and optional HP-55 in the high speed shear agitator, and stir 6 minutes.
2. to adding about 2 minutes of purified water kneading in the mixture of step 1.
By transfer of granules to the liquid bed dryer, dry until obtain the LOD value below 2.5%.After drying, with the vibration dismembyator, granule is ground.
4., after grinding, half of granule is placed in to dispersator.Add silicon dioxide colloid in blender, then add remaining granule.Mixture is stirred 20 minutes.
5. manually the mixture of magnesium stearate and 5% step 4 is carried out to premixing.Granule in dispersator adds premix and stirs 10 minutes.
in flakes
Central core and barrier layer are loaded into to HATA multilamellar tablet compressor and are suppressed to form three layers of tablet.
film coating (preparation A and B)
What film coating was such applies: increase by 5% weight on the tablet of 563mg.From Colorcon, WestPoint, Pennsylvania obtains
Figure G2007800353641D00191
the II film coating composition.Different coated compositions: 49B97383 is light brown, 49B97382 is light brown, 49B92439 is yellow and 49B97379 is light brown to use 4 kinds.All film coating compositions contain polydextrose FCC, HPMC2910/ hypromellose 3cP, HPMC2910/ hypromellose 6cP, titanium dioxide, HPMC2910/ hypromellose 15cP, Polyethylene Glycol/PEG, yellow iron oxide and Brazil wax.The difference of coated composition is whether there is black iron oxide, red iron oxide and yellow FD& C #5/ tartrazine aluminum lake.Guide according to the manufacturer is carried out coating by tablet.
enteric coatings (formulation C)
1. potassium hydroxide be dissolved in purified water and stir to form the solution of 1N.
2. add Type B methacrylic acid copolymer (Eudragit S100) and stir until dissolve in the purified water whirlpool lentamente.
3. the 1N potassium hydroxide solution of step 1 is joined in the solution of step 2, and stir the mixture gently.
4. add triethyl citrate and stir until the mixture homogeneous in the solution of step 3.
5. use A type methacrylic acid copolymer (Eudragit L100) repeating step 1-4 to form the homogeneous mixture.
6. the solution of step 4 is joined in mixer and slowly and stir.Join in vessel by the solution of step 5 and stir the mixture and continue required a period of time.
7. use Glatt disc type coating device by the coatings coating to the tablet of formulation C.
The Study on relative bioavailability of nisoldipine 40mg extended release tablet under embodiment 2. fasted conditions
The pharmacokinetic parameter of preparation A-C described in embodiment 1 and those parameters of reference preparation (preparation D) are compared.Reference preparation is the nisoldipine of extended release (40mg).
Figure G2007800353641D00193
be bag heart preparation, it is comprised of the core that contains nisoldipine, and this core coating also contains the rapid release coating of nisoldipine.In table 4, provided
Figure G2007800353641D00194
component and concentration thereof.
The target of this single dose, open label, random research under fasted conditions when use to healthy individual, the commercially available reference product of the test formulation (nisoldipine 40mg extended release tablet) described in comparing embodiment 1 and the oral dose of its equivalent (
Figure G2007800353641D00195
40mg extended release tablet) absorption rate and oral administration biaavailability.
Table 4
Figure G2007800353641D00196
component (preparation D)
Composition Coating (mg/ sheet) Core (mg/ sheet) Film coating (mg/ sheet) Add up to (mg) Account for the % by weight of tablet
Nisoldipine 32.0 8.0 40.0 12.27
Polyvinylpolypyrrolidone, NF 5.0 5.0 1.53
Lactose monohydrate, NF 87.5 4.0 91.5 28.07
Magnesium stearate, NF 1.0 0.2 1.2 0.37
Corn starch, NF 10.0 10.0 3.07
Microcrystalline Cellulose, NF 17.2 17.2 5.28
Polyvidone, USP 1.8 1.8 0.55
Sodium lauryl sulphate, NF 0.8 0.8 0.25
Hydroxy propyl cellulose, moderate viscosity, NF 84.5 84.5 25.92
Hydroxy propyl cellulose, low viscosity, NF 63.0 63.0 19.33
Hypromellose, USP 6.6 6.6 2.02
Ferrum oxide, NF (redness) 0.11 0.11 0.03
Ferrum oxide, NF (yellow) 0.99 0.99 0.30
Polyethylene Glycol, NF 2.2 2.2 0.67
Titanium dioxide, USP 1.1 1.1 0.34
Add up to 268.0 47.0 11.0 326.00 100.00
Three nisoldipine 40mg tablet formulations described in comparing embodiment 1 with
Figure G2007800353641D00201
32 health adults participated in this research.31 individualities have completed this research.According to the randomization arrangement, individual in first treatment that period, acceptance distributed, accept other treatment in ensuing period.With interval medication day eluting phase of at least 7 days.For each possible equal individuality of processing sequence random assortment number.Administration by the preparation described in the embodiment 1 of the oral dose under fasted conditions and form.
Within after 1,1.5,2,3,4,6,7.5,9,10.5,12,14,16,18,20,21,23,24,26,28,30,36 of (pre-dose) hour and administration 48 hours before medication, gather blood sample.
The LC-MS-MS program of use experience card is by CEDRA company analysed for plasma sample, and the lower limit of quantitation of nisoldipine is 0.0150ng/mL.Data are stored in Watson LIMS system (Thermo Electron enterprise version 6.4.0.02).
The data that completed all individualities of this research from those all are included in pharmacokinetics and statistical analysis.Use the analysis option of Custom Query Builder that concentration-time data is directly transferred to WinNonlin (enterprise version 4.0, Pharsight, Cary, NC) from Watson.Data are analyzed with noncompartmental method in WinNonlin.In data summary and descriptive statistic, the data of those BLQ (<0.0150ng/mL) concentration-time are treated to 0 (0.00ng/mL).In pharmacokinetic analysis, from the time 0, until first can quantitative concentration be observed, BLQ concentration is treated to 0; BLQ concentration that embed and/or terminal is treated to " loss ".Use complete accurate concentration data to carry out all pharmacokineticss and statistical analysis.
Individual and carry out the calculating of following pharmacokinetic parameter period to each: the peak concentration (C in blood plasma max), arrive the time (T of peak concentration max), elimination rate constant (λ z), final half-life (T 1/2but), the area (AUC between the time from the time 0 to last quantitative concentrations below concentration-time curve last), the area (AUC between unlimited from the time 0 to extrapolation below dense blood plasma degree-time graph inf), and be shown in table 5.Select preparation A further to test.
Be displayed in Table 6 the comparison of the pharmacokinetic parameter of preparation A and reference preparation (preparation D).Table 7 has shown the statistical analysis of non-transformed pharmacokinetic parameter of the nisoldipine of preparation A and reference product (preparation D).
Pharmacokinetics exposure parameter C with 5% significance level to transforming through logarithm max, AUC lastand AUC infcarry out the two one-side t checkout procedures of variation analysis (ANOVA) and Schuirmann.Calculate 90% confidence interval of the difference between test products and reference product.If bioequivalence, in 80%-125%, is declared to have in the lower end of the confidence interval of the parameter transformed through logarithm and upper end.
Pharmacokinetic parameter after the oral nisoldipine of table 6
Figure G2007800353641D00231
The statistical analysis of the non-transformed pharmacokinetic parameter of the nisoldipine of table 7 preparation A and reference product
Figure G2007800353641D00232
The statistical analysis of the system exposure parameter (systemic exposure parameter) transformed through logarithm of the nisoldipine of table 8 test formulation #1 and reference product
Figure G2007800353641D00233
Figure G2007800353641D00241
athe least squares means of test formulation #1 (test) and reference product (reference)
bthe geometric mean of the least squares means of the parameter value based on transforming through logarithm
cratio (%)=geometric mean (test)/geometric mean (reference)
d90% confidence interval
Attention: C max, AUC laststatistical analysis based on n=31, AUC infstatistical analysis based on n=21
The Study on relative bioavailability of the lower nisoldipine 40mg extended release tablet of embodiment 3. feed conditions (fed condition)
The target of this research is preparation A and the market preparation described in comparing embodiment
Figure G2007800353641D00242
food effect.In order to determine the food effect of preparation A and Sular, these two preparations in embodiment 2 pharmacokinetic data under fasted conditions with for referencial use.Recruitment is carried out food effect research from 32 same individualities of embodiment 2.
26 (26) individualities have completed this research.According to the randomization arrangement, individual in first treatment that period, acceptance distributed, accept other treatment in ensuing period.With interval administration day eluting phase of at least 7 days.For each possible equal individuality of processing sequence random assortment number.According to gathering as described in Example 2 and the analyzing blood sample.Table 9 has shown the pharmacokinetic data of preparation A under condition on the feed (processing E) and reference preparation (Sular, 40mg extended release).Table 10 has shown the analysis of the non-transformed pharmacokinetic parameter of the nisoldipine of test formulation A (processing E) and reference product (processing F) under condition on the feed.Table 11 has shown the statistical analysis of the systematic parameter through the logarithm conversion of the nisoldipine of test formulation A (processing E) and reference product (processing F) under condition on the feed.
The statistical analysis of the non-transformed pharmacokinetic parameter of the nisoldipine of test formulation #1 under table 9 feed condition (processing E) and reference product (processing F)
Figure G2007800353641D00243
The statistical analysis of the non-transformed pharmacokinetic parameter of the nisoldipine of test formulation A under table 10 feed condition (processing E) and reference product (processing F)
Figure G2007800353641D00251
The statistical analysis of the system exposure parameter transformed through logarithm of the nisoldipine of test formulation #1 under table 11 feed condition (processing E) and reference product (processing F)
Figure G2007800353641D00252
Three layers of tablet that embodiment 4. contains nisoldipine core and two barrier layers
Table 5 demonstrates the AUC of preparation A lastaUC than the reference preparation of the nisoldipine with same dose lastapproximately high by 17%.This has shown that the dosage of the nisoldipine in preparation A can be reduced about 16% and also still show and the similar pharmacokinetics collection of illustrative plates of reference preparation.
Prepared and contained 8.5,17,25.5 and the preparation of 34mg nisoldipine in the core according to the program described in embodiment 1.The representative of these dosage is than 10mg, 20mg, 30mg and 40mg respectively few about 16%.The composition of each preparation and concentration thereof are shown in table 10-13.
Table 12 nisoldipine multilamellar tablet formulations
Figure G2007800353641D00253
Figure G2007800353641D00261
Figure G2007800353641D00262
Figure G2007800353641D00271
Embodiment 5. low dosages geomatrix (34mg nisoldipine) with
Figure G2007800353641D00273
the bioequivalence of (40mg nisoldipine)
With single dose, open label, random, fourth phase, two processing, two order design iterations crossing research, determine
Figure G2007800353641D00274
(being Geomatrix, the 34mg nisoldipine) with
Figure G2007800353641D00275
the bioequivalence of (40mg nisoldipine).This research and comparison in overnight fast after at least 10 hours, test formulation
Figure G2007800353641D00276
16-E, 34mg tablet (processing E) and reference product absorption rate and the oral administration biaavailability of 40mg tablet (processing F).
research design
This is pivot, single dose, open label, random, fourth phase, two processing, two order design iterations crossing research, wherein 52 (52) individual health adult individualities were arranged at overnight fast after at least 10 hours, accepted the administration of the single dose separated for 4 times of nisoldipine extended release tablet in 4 study periods.Recruit hardy the masculinity and femininity individuality of equal number.The individuality that is successfully completed screening process entered research center eve in medication.Continue to meet and to comprise/to screen out that the individuality of standard is assigned with body number one by one in the morning of medication, number is successfully completed the order of screening process and program based on them, as listed in search procedure.With interval medication day eluting phase of at least 7 days.
Individuality is accepted following treatment 2 times in 2 random order modes 4 treatments period.Test products " is processed E "
Figure G2007800353641D00281
16-E nisoldipine extended release tablet, use with the tablet of a 34mg.Reference product " is processed F "
Figure G2007800353641D00282
the extended release tablet, use with the tablet of a 40mg.
clinical procedure is summed up
At each study period, the selected time in 36 hours before each medication and after each medication is obtained the blood sample of 6mL.Within 48,60 and 72 hours after medication, obtain the blood sample of 2 6mL.Collect the blood sample of 96PK altogether from each individuality, at four study periods that separate, respectively collect 24 samples.
In addition, in screening, foundation level (enter period 1) with finish to dismiss (72 hours processes in period 4) in research, gather blood and also collect urine for clinical laboratory's test (hematochemistry, hematology and urinalysis).In addition, gather the mensuration of blood for hematocrit and hematochrome in the medication of each in period 2,3,4 entered eve, researcher is checked before each medication in three periods.49 (49) individual at least two periods that completed this research in 52 individualities of recruiting.
program for pharmacokinetic analysis collection sample
With containing K 2the vacuum test tube of-EDTA (as antiseptic) (0) and collect blood sample (1x6mL, 2x6mL) in 1.0,2.0,3.0,4.0,5.0,6.0,7.5,9.0,10.5,12.0,14.0,18.0,24.0,26.0,28.0,30.0,36.0,48.0,60.0 and 72.0 hours after each study period medication before medication.
bioanalysis is summed up
The nisoldipine of LC-MS-MS program in CEDRA company analysed for plasma sample of use experience card.Analysis respectively based on to 0.250mL and 1.00mL blood plasma, checking the method is effective for 0.0150 to 10.0ng/mL and 1.00 to 100pg/mL scopes.
pharmacokinetic analysis
To not have the data of 49 individualities of Rogue program to be included in pharmacokinetics and statistical analysis from successfully completing at least two study periods (test, a reference).Three individualities do not complete this research; Sample from these three individualities does not have analyzed.Two individualities have experienced vomiting in research process, and comparative study period that these individualities are determined to be in this extended release nisoldipine preparation, vomiting occurred can not be evaluated.Although obtained and retained concentration-time data in data list, one by one body period 2 (processing E) one by one the data of body in period 4 (processing E) be excluded outside pharmacokinetic analysis series.
Use the analysis option of Custom Query Builder that concentration-time data is directly transferred to WinNonlin enterprise version (4.0, Pharsight company) from Watson.Data are analyzed with noncompartmental method in WinNonlin.In data summary and descriptive statistic, concentration-time data is treated to 0 below quantitative limit (BLQ).In pharmacokinetic analysis, from the time 0, until first can quantitative concentration be observed, BLQ concentration is treated to 0; BLQ concentration that embed and/or terminal is treated to " loss ".Use complete accurate concentration data (not being rounding to 3 significant digits) and actual sample number of times to carry out all pharmacokineticss and statistical analysis.
Carry out the calculating of following pharmacokinetic parameter: the peak concentration (C in blood plasma max), arrive the time (T of peak concentration max), elimination rate constant (λ z), final half-life (T 1/2but), the area (AUC between the time from the time 0 to last quantitative concentrations below concentration-time curve last), the area (AUC between unlimited from the time 0 to extrapolation below dense blood plasma degree-time graph inf).
Pharmacokinetics exposure parameter C with 5% significance level to transforming through logarithm max, AUC lastand AUC infcarry out the two one-side t checkout procedures of linear hybrid effect and Schuirmann.90% confidence interval of computational geometry average (test/reference) ratio.If the lower end of the confidence interval of the parameter transformed through logarithm and upper end in 125%, declare to have bioequivalence in 80%.
Result
Sum up plasma concentration-time data and pharmacokinetic parameter according to processing.Accept each and process because individuality is arranged at two stages, thus according to the descriptive statistic of processing based on 93 to 95 observations.Some individualities observed before medication can be quantitative concentration.But, due to concentration before the medication after given treatment concerning these individualities far away from 5%C maxbelow, thus before all pharmacokinetic analysis have comprised medication concentration and without adjustment.
Pharmacokinetic data and statistical analysis have been shown below in table 13 and table 14.Due to the variation in latter stage in the existence of secondary peak and some individual collection of illustrative plates, in WinNonlin, by logarithm concentration, the linear regression of time data has been assessed to lambda-z (λ z).These data points that are included in calculating are the R based on having maximum adjustment 2the recurrence of value.In whole research process, for all pharmacokinetic analysis, all use λ zthis acquiescence assessment.
Conclusion
Based on ln (C max) for 90% confidence interval of maximum exposure relatively dropping in acceptable 80%-125% limit.Based on ln (AUC last) and ln (AUC inf) 90% confidence interval exposed for more total system drop in acceptable 80%-125% limit.Therefore, test formulation 16-E, 34mg tablet and reference product,
Figure G2007800353641D00292
the 40mg tablet is bioequivalent under fasted conditions.
Table 13 is used test formulation 16-E (Geomatrix, process E) and reference product (Sular, the processing F) pharmacokinetic parameter of nisoldipine afterwards
Figure G2007800353641D00293
Attention: use complete precise information in pharmacokinetic analysis
The statistical analysis of the system exposure parameter of the nisoldipine that table 14 transforms through logarithm, compare test preparation 16-E (Geomatrix processes E) and reference product (Sular processes F)
Figure G2007800353641D00302
athe geometric mean of test formulation (test) and reference product (reference), the least squares means of the parameter value based on transforming through logarithm
bratio (%)=geometric mean (test)/geometric mean (reference)
c90% confidence interval
Fig. 2 has shown and has used test formulation 16-E (Sular Geomatrix-preparation E, 34mg nisoldipine) and reference product (Sular, preparation F, 40mg nisoldipine) the mean concentration time collection of illustrative plates of nisoldipine afterwards.
The bioequivalence of embodiment 6. low dosage Sular Geomatrix (8.5mg nisoldipine) and Sular (10mg nisoldipine)
With single dose, open label, random, fourth phase, two processing, two order design iterations crossing research, determine
Figure G2007800353641D00303
(8.5mg nisoldipine) with
Figure G2007800353641D00304
the bioequivalence of (10mg nisoldipine).This research and comparison in overnight fast after at least 10 hours, test formulation
Figure G2007800353641D00305
16-E, 8.5mg nisoldipine tablet (processing G) and reference product
Figure G2007800353641D00306
absorption rate and the bioavailability of 10mg nisoldipine tablet (processing H).
This is pivot, single dose, open label, random, fourth phase, two processing, two order design iterations crossing research, wherein 52 (52) individual health adult individualities were arranged at overnight fast after at least 10 hours, accepted the administration of the single dose separated for 4 times of nisoldipine extended release tablet in 4 study periods.Recruit hardy the masculinity and femininity individuality of equal number.Continue to meet and to comprise/to screen out that the individuality of standard is assigned with body number one by one in the morning of medication, number is successfully completed the order of screening process and program based on them, as listed in search procedure.With interval medication day eluting phase of at least 7 days.
Individuality is accepted following treatment 2 times in 2 random order modes 4 treatments period.Test products " is processed G "
Figure G2007800353641D00307
nisoldipine extended release tablet, use with the tablet of a 8.5mg.Reference product " is processed H "
Figure G2007800353641D00311
the extended release tablet, use with the tablet of a 10mg.
clinical procedure is summed up
At each study period, the selected time in 36 hours after first 60 minutes of each medication and each medication is obtained the blood sample of a 6mL.Within 48,60 and 72 hours after medication, obtain the blood sample of 2 6mL.Collect the blood sample of 96PK altogether from each individuality, at four study periods that separate, respectively collect 24 samples.49 (49) individual at least two periods that completed this research in 52 individualities of recruiting.
program for pharmacokinetic analysis collection sample
With containing K 2the vacuum test tube of-EDTA (as antiseptic) (0) and collect blood sample (1x6mL, 2x6mL) in 1.0,2.0,3.0,4.0,5.0,6.0,7.5,9.0,10.5,12.0,14.0,18.0,24.0,26.0,28.0,30.0,36.0,48.0,60.0 and 72.0 hours after each study period medication before medication.
bioanalysis is summed up
The nisoldipine of LC-MS-MS program in CEDRA company analysed for plasma sample of use experience card.Analysis respectively based on to 0.250mL and 1.00mL blood plasma, checking the method is effective for 0.0150 to 10.0ng/mL and 1.00 to 100pg/mL scopes.
pharmacokinetic analysis
Will be from successfully completing at least initial two study periods or latter two study period (test, a reference) and do not have the data of 49 individualities of Rogue program to be included in pharmacokinetics and statistical analysis at least.Individual 501 have experienced vomiting in research process.Although obtained and retained concentration-time data in data list, this individuality be determined to be in all study periods be can not assess and be excluded outside the vomiting generation pharmacokinetic data series in period.
Use the analysis option of Custom Query Builder that concentration-time data is directly transferred to WinNonlin enterprise version (edition 4 .0, Pharsight company) from Watson LIMS.Data are analyzed with noncompartmental method in WinNonlin.In data summary and descriptive statistic, the data of concentration-time are treated to 0 below quantitative limit (BLQ).In pharmacokinetic analysis, from the time 0, until first can quantitative concentration be observed, BLQ concentration is treated to 0; BLQ concentration that embed and/or terminal is treated to " loss ".Use complete accurate concentration data (not being rounding to 3 significant digits) and actual sample number of times to carry out all pharmacokineticss and statistical analysis.
Carry out the calculating of following pharmacokinetic parameter: the peak concentration (C in blood plasma max), arrive the time (T of peak concentration max), elimination rate constant (λ z), final half-life (T 1/2but), the area (AUC between the time from the time 0 to last quantitative concentrations below concentration-time curve last), the area (AUC between unlimited from the time 0 to extrapolation below dense blood plasma degree-time graph inf).
Pharmacokinetics exposure parameter C with 5% significance level to transforming through logarithm max, AUC lastand AUC infcarry out the two one-side t checkout procedures of linear hybrid effect process and Schuirmann.90% confidence interval of computational geometry average (test/reference) ratio.If the lower end of the confidence interval of the parameter transformed through logarithm and upper end in 125%, declare to have bioequivalence in 80%.
Result
Sum up plasma concentration-time data and pharmacokinetic parameter according to processing.Accept each and process because individuality is arranged at two stages, thus according to the descriptive statistic of processing based on 96 or 94 observations.Shown mean concentration-time data in Fig. 3.Shown below the result of pharmacokinetic data and statistical analysis in table 15 and table 16.
Conclusion
Based on ln (C max) for 90% confidence interval of maximum exposure relatively dropping in acceptable 80%-125% limit.Based on ln (AUC last) and ln (AUC inf) 90% confidence interval exposed for more total system drop in acceptable 80%-125% limit.Therefore, test formulation Geomatrix 8.5mg tablet and reference product Sular10mg extended release tablet are bioequivalent under fasted conditions.
Table 15 is used test formulation 16-E (Geomatrix, process A) and reference product (Sular, the treatments B) pharmacokinetic parameter of nisoldipine afterwards
Figure G2007800353641D00321
The statistical analysis of the system exposure parameter of the nisoldipine that table 16 transforms through logarithm, compare test preparation 16-E (Geomatrix processes A) and reference product (Sular, treatments B)
Figure G2007800353641D00322
Should be appreciated that, disclosed method is not limited to described specific methodology, program and reagent, because these can change.Also should be appreciated that its purpose of term used herein is only in order to describe specific specific embodiments, rather than, in order to limit scope of the present invention, scope of the present invention is only limited by the claims of enclosing.
Unless otherwise, otherwise all technology used herein and scientific terminology have the implication with common the understood same meaning of the technical staff of disclosed technical field that the present invention belongs to.

Claims (23)

1. a multilamellar controlled-release solid oral formulations, said preparation comprises:
(a) comprise one or more active agents, as one or more hydrophilic materials of substrate and the core of one or more Enteric Materials, the ratio of wherein said hydrophilic material and Enteric Materials is 1.5: 1 to 10: 1; With
(b) comprise one or more expansions, easy erosion or two or more barrier layers that become the polymer of colloid, one on core, another is below core;
Wherein, after individuality is used, along with preparation descends along gastrointestinal tract, active agent is released with cumulative speed for the variation of pH.
2. preparation according to claim 1, the ratio of wherein said hydrophilic material and Enteric Materials is 1.9: 1 to 5: 1.
3. preparation according to claim 1, wherein said one or more active agents are calcium channel blocker.
4. preparation according to claim 1, the concentration of wherein said one or more active agents is weight of formulation 0.1% to 90%.
5. preparation according to claim 1, the concentration of wherein said one or more active agents is weight of formulation 0.5% to 20%.
6. preparation according to claim 1, the concentration of wherein said one or more active agents is weight of formulation 1% to 10%.
7. preparation according to claim 1, wherein said one or more Enteric Materials are selected from cellulose acetate phthalate, alginate esters, alkaline soluble acrylic resin, hydroxypropylmethyl cellulose phthalate, methacrylate-methacrylic acid copolymer, polyvinyl acetate phthalate, styrene maleic acid copolymer, or its combination.
8. preparation according to claim 1, the concentration of wherein said one or more Enteric Materials is core weight 0.1% to 20%.
9. preparation according to claim 1, the concentration of wherein said one or more Enteric Materials is core weight 1% to 15%.
10. preparation according to claim 1, the concentration of wherein said one or more Enteric Materials is core weight 5% to 10%.
11. preparation according to claim 1, wherein said one or more hydrophilic materials are selected from polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, methylcellulose, hydroxypropyl emthylcellulose, the hydroxypropyl cellulose that polymethacrylates is crosslinked, sodium carboxymethyl cellulose, carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, carboxymethyl starch, polyester, poly-anhydride, polymethyl vinyl ether/acid anhydride copolymer, Polyethylene Glycol, methacrylic acid potassium-divinylbenzene copolymer, polyvinyl alcohol, glucosan, scleroglucan, mannan, soluble starch, alginate esters, albumin, gelatin, beta cyclodextrin, the cyclodextrin that contains straight chain and/or branch polymer chain, and composition thereof, and combination.
12. preparation according to claim 1, wherein said one or more hydrophilic materials exist with 1% to 90% of core weight.
13. preparation according to claim 12, wherein said one or more hydrophilic materials exist with 10% to 45% of core weight.
14. preparation according to claim 1, polymer wherein said one or more expansions, that easily lose or the one-tenth colloid is selected from hydroxypropyl emthylcellulose, carboxyl ethylene polymer; Polyvinyl alcohol; Glucosan, scleroglucan; Mannan; Xanthan gum; Alginate esters; Poly-anhydride; Polyamino acid; Copolymer of Methyl Vinyl Ether/Maleic Anhydride; Carboxymethyl cellulose; Ethyl cellulose, methylcellulose, or its combination.
15. preparation according to claim 1, wherein said one or more expansions, easily erosion and/or to become the concentration of the polymer of colloid be 5% to 90% of barrier layer weight.
16. preparation according to claim 15, wherein said one or more expansions, easily erosion and/or to become the concentration of the polymer of colloid be 25% to 75% of barrier layer weight.
17., according to claim 15 or the described preparation of 16 any one, wherein said polymer is hydroxypropyl emthylcellulose.
18. preparation according to claim 1, wherein said core and/or barrier layer also comprise one or more excipient, described excipient is selected from plasticizer, binding agent, lubricant, surfactant, pH adjusting agent, antiplastering aid, disintegrating agent, implant, coloring agent, stabilizing agent, flavor agent, fluidizer or its combination.
19. preparation according to claim 1, the form that wherein said preparation is tablet or capsule sheet.
20. preparation according to claim 1, wherein said central core and/or barrier layer also comprise one or more and further regulate the adjuvant that active agent discharges, described adjuvant is selected from glyceryl monostearate, triglyceride, semisynthetic glyceride, castor oil hydrogenated, glyceryl palmitostearate, hexadecanol, polyvinylpyrrolidone, glycerol, ethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, magnesium stearate, stearic acid, Pulvis Talci, sodium benzoate, boric acid, Polyethylene Glycol, silica gel, or its combination.
21. preparation according to claim 1, said preparation also comprises one or more and regulates the coating material that active agent discharges.
22. preparation according to claim 21, wherein said one or more coating materials are selected from the rapid release coating, taste is covered up coating, sustained release coating, enteric coatings, or its combination.
23. a calcium channel blocker is used for the treatment of the purposes in the preparation of cardiovascular disease in production, wherein said preparation is multilamellar controlled-release solid oral formulations, and said preparation comprises:
(a) comprise calcium channel blocker, as one or more hydrophilic materials of substrate and the core of one or more Enteric Materials, the ratio of wherein said hydrophilic material and Enteric Materials is 1.5: 1 to 10: 1; With
(b) comprise one or more expansions, easy erosion or two or more barrier layers that become the polymer of colloid, one on core, another is below core;
Wherein, after individuality is used, along with preparation descends along gastrointestinal tract, calcium channel blocker is released with cumulative speed for the variation of pH.
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