CN101553211B

CN101553211B - Drug delivery systems comprising solid solutions of weakly basic drugs

Info

Publication number: CN101553211B
Application number: CN2007800408343A
Authority: CN
Inventors: 戈皮·文卡特什; 卢吉·博尔特里; 伊塔洛·科隆博; 赖金旺; 弗拉维奥·弗拉比亚尼; 卢吉·马佩利
Original assignee: Eurand America Inc
Current assignee: Adare Pharma Solutions Inc
Priority date: 2006-08-31
Filing date: 2007-08-29
Publication date: 2012-01-04
Anticipated expiration: 2027-08-29
Also published as: ZA200901366B; CN101553211A

Abstract

The present invention is directed to pharmaceutical compositions and dosage forms comprising TPR beads, wherein said TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, and a TPR coating comprising a water insoluble polymer and an enteric polymer, wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 [mu]g/mL at pH 6.8.

Description

Include the drug delivery system of weakly basic drugs solid solution

Cross reference to related applications

This application claims the priority for being filed in August, 2006 U.S. Provisional Application of 31 days 60/841,760 and 60/841,893, they are hereby incorporated by reference for all purposes herein.

Technical field

(modified-release) composition, and the method for preparing the composition are discharged the present invention relates to the regulation that bioavilability is improved.Solid dispersions (solid dispersion) of the composition of the present invention comprising at least one active pharmaceutical ingredient and time-controlled release (timed pulsatile releas) are coated.

Background technology

Many medicines are when in absorption site or most effective when location proximate is utilized with constant rate of speed absorbing.The absorption for the medicine being so utilized generally facilitates the expectation plasma concentration for causing maximum efficiency and minimum toxic side effect.But, due to the physicochemical properties of the complexity of absorption process, many related compound variables (compositional variable) of influence medicine rate of release from formulation and medicine itself, it is typically difficult to develop the oral Pharmaceutical dosage forms for delivering the medicine for expecting plasma concentration with constant rate of speed.For example, when the pharmaceutical dosage form of oral administration is through remarkable alimentary canal, medicine should discharge from formulation, and absorbing site or absorbed in the form of a solution from stomach and intestine (GI) road absorbing location proximate.Formulation and medicine thus are limited by the pH of change during gastrointestinal transit, i.e. pH is changed to pH from about 1.2 (the stomach pH during fasting) and is up to 4.0 (after feeds) or about 7.4 (bile pH is 7.0-7.4 and intestines pH is 5 to 7).In addition, formulation (such as can change in the transhipment time of alimentary canal various pieces with the size and leading local condition of formulation along the permeability of intestines and stomach；The property of lumenal contents, such as pH, surface tension, volume, wriggling and buffer capacity；And the change after dietary intake) and significant changes.Influenceing medicine (drug substance) physicochemical properties of itself of plasma concentration includes its pK_a, solubility and crystal energy (crystalline energy), and for example many particle (multiparticulate) formulations recombination property, include the size or specific surface area etc. of medicine-containing particle.Therefore, it is typically what is be difficult to constant speed release medicine.

In addition, alkaline drug and acidic drug show the solubility distribution that pH is relied on, the solubility The intensity of variation being distributed in physiological pH range is more than 2 orders of magnitude.Wherein, the medicine for being most difficult to prepare is alkaline compound, its (such as with 50 μ g/mL or smaller solubility) almost insoluble in pH ＞ 5, and need high dose (such as 10mg or bigger optimal daily dose) effectively to treat.Under so high dosage, after the pH environment in stomach and intestine (Gl) road is entered, the medicine of some dissolutions may be precipitated, unless absorption rate is faster than drug release rate.Alternatively, medicine can be maintained under supersaturated solution state, for instance, it is known that the state has benefited from bile salt present in alimentary canal and lecithin, medicine maintains the supersaturated level that the order of magnitude is far above aqueous solubilities.However, supersaturated solution may be precipitated, and evidence show the redissolution of medicine and absorption then may be with slower speed generations.In order to solve these problems, different methods has been developed to increase the solubility of weakly basic drugs, and these methods for example introduce organic acid to form sour additive compound, or use solid dispersions or solid solution (solid solution).

However, the above method is not entirely satisfactory because the solubility of medicine with medicine itself physicochemical properties and prepare the method for pharmaceutical preparation and change.For example, some weakly basic drugs such as nifedipine or Lercanidipine (lercanidipine) do not show the increase of significant solubility in unsaturated organic acid solution, and solid dispersions tend to provide undesirable medicine after oral administration and discharged immediately (immediate release).

The composition of the present invention makes alkalescent medicine, and (such as the pKa of described medicine is less than 14, it needs high dose to maintain target plasma concentration) delivering be improved, and the insoluble drug release distribution of the composition is suitable to dosage regimen once a day.

The content of the invention

In one embodiment, the present invention relates to the pharmaceutical composition for including TPR pearls, wherein the TPR pearls include the solid dispersions of at least one active pharmaceutical ingredient and at least one solubilized polymer (solubility-enhancing polymer)；And TPR is coated, the TPR, which is coated, includes insoluble polymer and enteric polymer；Wherein described active pharmaceutical ingredient includes alkalescent active pharmaceutical ingredient of the solubility when pH is 6.8 no more than 100 μ g/mL.

In another embodiment, the present invention relates to the method for preparing pharmaceutical composition, methods described includes active pharmaceutical ingredient or enough solubilized polymer being dissolved in medicinal solvent；Medicinal solvent is removed from the solution of active pharmaceutical ingredient and solubilized polymer, the particle of solid dispersions of the active component in the solubilized polymer is consequently formed；Insoluble polymer and enteric polymer are dissolved in medical coating solvent, TPR Coating Solutions are consequently formed；With the TPR Coating Solutions to described solid Body dispersion is coated, and is consequently formed TPR pearls, and the TPR pearls are included in the TPR formed on the solid dispersions and are coated.

Brief description of the drawings

Fig. 1 illustrates the section (cross-section) of an embodiment for the TPR pearls of the present invention.

Fig. 2 illustrates the pH- solubility distribution of following medicine：(a) ondansetron hydrochloride (ondansetronhydrochloride), (b) Carvedilol (carvedilol), (c) Dipyridamole (dipyridamole) and (d) Clonazepam (clonazepam)；

Fig. 3 illustrates the turbidity distribution of the solid solution/solid dispersions of (A) Lercanidipine hydrochloride (lercanidipine HCl) and the solid solution/solid dispersions of (B) nifedipine.

Fig. 4 illustrates (A) polymorph I, (B) the polymorph II of Lercanidipine hydrochloride and the intrinsic dissolution rate (IDR) of (C) amorphous substance (drug-polymer solid solution).

Fig. 5 illustrates the x-ray diffractogram of powder shape of Lercanidipine hydrochloride and (A) Kollidon VA 64 or Lercanidipine hydrochloride and the solid dispersions of (B) Methocel E5 formation.

Fig. 6 illustrates the x-ray diffractogram of powder shape of nifedipine and (A) Kollidon VA 64 or nifedipine and the solid dispersions of (B) Methocel E5 formation.

Fig. 7 illustrates TPR and is coated the influence that composition discharges to medicine from TPR pearls described in embodiment 4.

Fig. 8 illustrates the influence that medicine carrying capacity (i.e. 10% medicine carrying capacity is compared with 5% medicine carrying capacity) discharges to medicine from TPR pearls described in embodiment 3.

Fig. 9 is illustrated compared with the embodiment 4D similar TPR pearls prepared from 25-30 mesh sugar ball, the influence that granularity (particle size) discharges to medicine from the embodiment 3B TPR pearls being coated in 60-80 mesh sugar balls using the ratio of 10% medicine carrying capacity and 15% weight as 45/40 Eudragit RL/L coatings.

Figure 10 illustrates TPR and is coated the influence that composition discharges to medicine from the TPR pearls of embodiment 5.

Figure 11 is illustrated from the insoluble drug release distribution in the Lercanidipine hydrochloride TPR pearls containing Kollidon VA 64 and tartaric acid of embodiment 8.

Figure 12 illustrates TPR and is coated the influence that composition and thickness discharge to medicine from the TPR pearls of embodiment 10.

Embodiment

The present invention relates to pharmaceutical composition, described pharmaceutical composition includes the combination of following two systems： The solid dispersions of at least one active pharmaceutical ingredient and at least one solubilized polymer, and the time-controlled release (TPR) comprising insoluble polymer and enteric polymer is coated, wherein the active pharmaceutical ingredient includes alkalescent active pharmaceutical ingredient of the solubility when pH is 6.8 no more than 100 μ g/mL.Compared with the release profile derived from conventional composition (wherein alkalescent active pharmaceutical ingredient is not coated with existing in the form of solid dispersions and/or lacking TPR), the combination that alkalescent active pharmaceutical ingredient solid dispersions and TPR are coated is there is provided improved release profile.For example, by the way that to suitably being handled comprising at least one TPR compositions being coated, it was about constant in 12-18 hours that can make rate of release, or relative to solubilized polymer is used alone, can make the time delay for reaching maximum release rate.

Term " solid dispersions " or " solid solution " refer to the substantially unbodied active pharmaceutical ingredient being dispersed in polymer substrate (polymeric matrix), and/or more specifically refer to that at least one active pharmaceutical ingredient and at least one crystallization are suppressed (crystallization-inhibiting) polymer and substantially disperseed in the case of solid-state with molecular forms.Term " substantially amorphous " refers to that the active pharmaceutical ingredient less than 40% forms single crystalline phase (crystalline phase) in the polymer matrix.In other embodiments, " substantially amorphous " refers to form single crystalline phase in the polymer matrix less than 30%, less than 20%, less than the 10%, active pharmaceutical ingredient less than 5% or less than 1%.In other words, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% active pharmaceutical ingredient is in amorphous state (amorphous state).Term " substantially scattered with molecular forms " refers to that the active pharmaceutical ingredient less than 40% forms single crystalline phase in the polymer matrix, and remaining active pharmaceutical ingredient is dissolved in polymer substrate.In other embodiments, " substantially scattered with molecular forms " refers to form single crystalline phase in the polymer matrix less than 30%, less than 20%, less than the 10%, active pharmaceutical ingredient less than 5% or less than 1%.The solid dispersions of the present invention include the combination of the active pharmaceutical ingredient of " substantially with molecular forms scattered " and " substantially amorphous " in the polymer matrix, condition be no more than 40% active pharmaceutical ingredient and be no more than 30% in some embodiments, form single crystalline phase in the polymer matrix no more than 20%, no more than the 10%, active pharmaceutical ingredient no more than 5% or no more than 1%.

Term " active pharmaceutical ingredient " can be exchanged with term " medicine (drug) ", " medicine " etc. and used.Term " weakly basic drugs active component " used in this application and any specific medicine include the mixture of alkali, pharmaceutical salts, polymorph (polymorph), stereoisomer, solvate, ester and above-mentioned form.In one embodiment, the alkalescent active pharmaceutical ingredient in the present composition can refer to the compound that pKa is less than 14.In another embodiment, the solubility of the alkalescent active pharmaceutical ingredient is no more than about 100 μ g/mL when pH is 6.8.In another embodiment, the alkalescent is lived Property drug ingedient include at least one basic nitrogen atom.In another embodiment, the pKa of the alkalescent active pharmaceutical ingredient is less than 14, and its solubility is no more than about 100 μ g/mL when pH is 6.8.In another embodiment, the pKa of the alkalescent active pharmaceutical ingredient is less than 14, and it includes at least one basic nitrogen atom.In another embodiment, the pKa of the alkalescent active pharmaceutical ingredient is less than 14, and its solubility is no more than about 100 μ g/mL when pH is 6.8, and it includes at least one basic nitrogen atom.

Term " solubilized polymer " or " crystallization suppresses polymer " used herein refers to water-soluble polymer, and the water-soluble polymer can for example form the solid dispersions such as application-defined weakly basic drugs in solubilized polymer by the following method under suitable concentration：Medicine and polymer are dissolved in same solvent system first, solvent is then removed under suitable condition.During the storage, transport and commercial distribution of the composition containing solubilized polymer and the solid dispersions of weakly basic drugs, the weakly basic drugs are substantially maintained molecule discrete form or amorphous form.

Term used herein " discharges " (IR) and refers to that the release of active pharmaceutical ingredient in one hour after administration composition is greater than about 75% immediately, and in other embodiments greater than about 85%.The amount of release can in vivo or in vitro measure and (use conventional USP methods described herein).

Term " IR pearls " refers to the particle with releasing properties immediately comprising active pharmaceutical ingredient.IR pearls may include any kind of particle containing active constituents of medicine, the particle of solid dispersions of such as active pharmaceutical ingredient in solubilized polymer or the inert core being coated with solid dispersions of the active pharmaceutical ingredient in solubilized polymer.IR pearls also include the particle for containing solid dispersions and being further coated with sealant (sealant) or protective layer, and the particle has such as releasing properties immediately described herein.

Term " rapid dispersion particulate (rapidly dispersing microgranule) " used herein refers to agglomerative particle (agglomerated particle), and the agglomerative particle includes the elementary particle (primary particle) containing sugar alcohol (such as PEARLITOL 25C) and/or sugared (such as lactose) and disintegrant.

Term " lag time film coating (lag-time membrane coating) ", " lag time polymer coating (lag-time polymer coating) ", " time-controlled release (TPR) film coating ", " TPR polymer coatings " or " TPR coatings " can in this application be exchanged and used, and they refer to the coating comprising insoluble polymer and enteric polymer.

Term " time-controlled release (TPR) pearl " or simple " TPR pearls " refer to be coated the particle being coated with TPR comprising active pharmaceutical ingredient.In some embodiments, TPR pearls refer to be coated the IR pearls being coated with TPR, and weakly basic drugs active component discharges the sustained release distribution being characterised by after of short duration lag time from the TPR pearls prepared according to certain embodiments of the invention.

Term " lag time " refers to a period of time, during this period of time discharge less than about 10%, more specifically less than about 5%, more specifically substantially 0% active pharmaceutical ingredient, and being up to about the lag time of 4 hours can be coated to realize by the TPR of the present invention, and the TPR is coated the combination comprising water-insoluble and enteric polymer (such as Eudragit RL and L polymer).

Term " solubility regulation organic acid (solubility-modulating organicacid) " used herein or " organic acid " refer to water-soluble pharmaceutically acceptable organic acid, and the organic acid can increase dissolution rate and/or dissolution degree of the active pharmaceutical ingredient in the aqueous solutions of organic acids.

Term " rate of release " refers to the amount that medicine discharges from composition in vitro or in vivo in the unit interval.The unit of amount is typically expressed as example accounting for the percentage (%) of accumulated dose.

Term " blood plasma distribution ", " plasma concentration ", " C_max" or " C_min" concentration of the medicine in subject's blood plasma is intended to refer to, it is typically expressed as quality/unit volume, typically nanograms/milliliter (ng/mL).

Term " therapeutically effective amount " refers to provide the amount of the active pharmaceutical ingredient required for desired pharmacological outcomes.In practice, therapeutically effective amount can on a large scale change with the order of severity of illness, the age of subject and desired therapeutic effect.

Solid dispersions and TPR of the pharmaceutical composition of the present invention comprising at least one active pharmaceutical ingredient and at least one solubilized polymer are coated.

Refer to Fig. 1 and specific embodiments of the present invention are described in further detail.Fig. 1 illustrates TPR pearls 10.Inert particle core 18; suppress the unformed layer 16 of polymer (also referred to as solubilized polymer) and solubilized organic acid comprising weakly basic drugs, crystallization; protective seal coatings 14, and lag time (also referred to as TPR or pulse release) are coated 12 and constitute TPR pearls 10.

Suitable activity drug ingedient for pharmaceutical composition of the present invention includes weakly basic drugs.In one embodiment, the pKa value of the active pharmaceutical ingredient is less than 14.In another embodiment, the solubility of the active pharmaceutical ingredient is no more than about 100 μ g/mL when pH is 6.8.In another embodiment, the elimination half-life period of the active pharmaceutical ingredient is about 3 hours or longer.In another embodiment, the solubility of the active pharmaceutical ingredient is no more than 50 μ g/mL when pH is 6.8.In another embodiment, the ratio of the solubility (in units of mg/mL) when the optimal daily dose (in units of mg) of the active pharmaceutical ingredient is 6.8 with pH is at least 100.In another embodiment, the pKa value of the active pharmaceutical ingredient is less than 14, and its solubility is no more than about 100 μ g/mL when pH is 6.8, and its elimination half-life period is about 3 hours or longer.In another embodiment, the solubility of the active pharmaceutical ingredient is no more than about 100 μ g/mL when pH is 6.8, and the ratio of the solubility (in units of mg/mL) of its optimal daily dose (in units of mg) and pH when be 6.8 is extremely Few 100.In another embodiment, the solubility of the active pharmaceutical ingredient is no more than about 50 μ g/mL when pH is 6.8, and the ratio of solubility (by mg/mL in units of) of its optimal daily dose (in units of mg) when with pH being 6.8 is at least 100.

The non-limiting examples of all kinds of suitable active pharmaceutical ingredients include but is not limited to antalgesic (analgesic), antihypertensive, anxiolytic, the solid medicine (anticlotting agent) of anti-freezing, anticonvulsive drug, antidiabetic, hypoglycemic agent (blood glucose-lowering agent), decongestant (decongestant), antihistamine, anti-inflammatory agent, antitussive (antitussive), antineoplastic (antineoplastic), β-blocking agent, antirheumatic drug, antiphlogistic (anti-inflammatory), antipsychotic drug (antipsychotic agent), cognition enhancer (cognitive enhancer), antiatherosclerotic, antiadipositas drug (anti obesity agent), Alibra (anti-impotence agent), anti-infectious agent, somnifacient, antiparkinsonism medicine, anti- alzheimer disease medicine, antidepressants, antiviral agent, glycogen phosphorylase inhibitors, cholestery ester transfer protein inhibitors, CNS (central nervous system) excitant, dopamine-receptor stimulant, antiemetic (anti-emetic), gastrointestinal drug, psychotropic drugs, opioid agonist (opioid agonist), opioid antagonists (opioid antagonist), antiepileptic, histamine H₂Antagonist, antasthmatic, smooth muscle relaxant and skeletal muscle relaxant.

The instantiation of antalgesic includes paracetamol, rofecoxib, celecoxib, morphine, codeine, Oxycodone, hydrocodone, diamorphine (diamorphine), pethidine, C16H25NO2, buprenorphine (buprenorphene)；Antihypertensive includes prazosin, nifedipine, Lercanidipine, Amlodipine, Trimazosin and Doxazosin；The instantiation of anxiolytic includes hydroxyzine hydrochloride, Lorazepam, buspirone hydrochloride (buspirone hydrochloride), pazepam, chlorine nitrogen

, Meprobamate, Oxazepam, trifluoperazine hydrochloride, dipotassium chlorine nitrogen

(clorazepate dipotassium), diazepam；The instantiation of the solid medicine of anti-freezing includes Abciximab (abciximab), eptifibatide (eptifibatide), tirofiban (tirofiban), lamifiban (lamifiban), clopidogrel, ticlopidine, bicoumarin (dicumarol), heparin and warfarin；The instantiation of anticonvulsive drug includes phenobarbital, mephobarbital, Clobazam (clobazam), Clonazepam, chlorine nitrogen

(clorezepate), diazepam, midazolam, Lorazepam, Felbamate (felbamate), carbamazepine (carbamezepine), Oxcarbazepine (oxcarbezepine), sabril (vigabatrin), progabide (progabide), Tiagabine (tiagabine), Topiramate (topiramate), Gabapentin, Pregabalin (pregabalin), Ethotoin (ethotoin), phenytoinum naticum (phenytoin), mephenytoin (mephenytoin), Fosphenytoin (fosphenytoin), paramethadione (paramethadione), trimethadione (trimethadione), ethadione (ethadione), beclamide (beclamide), Primidone (primidone), brivaracetam, Levetiracetam (levetiracetam), seletracetam, ethymal (ethosuximide), phensuximide (phensuximide), mesuximide (mesuximide), acetazolamide, easypro thiazine (sulthiame), methazolamide (methazolamide), Zonisamide (zonisamide), Lamotrigine, ethyl phenacemide (pheneturide), phenacemide, valpromide and Valnoctamide (valnoctamide)；The instantiation of antidiabetic includes Repaglinide (repaglinide), Nateglinide (nateglinide), melbine (metformin), insoral (phenformin), Rosiglitazone (rosiglitazone), Pioglitazone (pioglitazone), troglitazone (troglitazone), Miglitol (miglitol), acarbose (acarbose), exanatide, vildagliptin and sitagliptin (sitagliptin)；The instantiation of hypoglycemic agent includes orinase, Acetohexamide, tolazamide (tolazamide), glibenclamide (glyburide), Glimepiride (glimepiride), gliclazide (gliclazide), Glipizide (glipizide) and chlorpropamide (chlorpropamide)；The instantiation of decongestant includes pseudoephedrine, phyenlephrinium (phenylephrine) and oxymetazoline (oxymetazoline)；The instantiation of antihistamine includes mepyramine (mepyramine), Antazoline (antazoline), diphenhydramine, carbinoxamine (carbinoxamine), doxylamine (doxylamine), clemastine (clemastine), dramamine (dimenhydrinate), pheniramine (pheniraminc), chlorphenamine, dexchlorpheniramine (dexchlorpheniramine), Brompheniramine (brompheniramine), triprolidine (triprolidine), Cyclizine (cyclizine), chlorcyclizine (chlorcyclizine), hydroxyzine, meclozine (meclizine), fenazil, temaril, cyproheptadine (cyproheptadine), azatadine and Ketotifen；The instantiation of antitussive includes dextromethorphan (dextromethorphan), coscopin (noscapine), dionin and codeine；The instantiation of antineoplastic includes Chlorambucil, lomustine (lomustine), Tubulozole (tubulazole) and echinomycin (echinomycin)；The instantiation of anti-inflammatory agent includes betamethasone, prednisolone, aspirin, piroxicam, valdecoxib, Carprofen (carprofen), celecoxib, fluorine ratio and coughs up fragrant and (+)-N- { 4- [3- (4- fluorophenoxies) phenoxy group] -2- cyclopentene-l- bases }-N- hydroxycarbamides；The instantiation of β-blocking agent includes timolol (timolol) and Nadolol (nadolol)；The instantiation of antitussive includes dextromethorphan (dextromethorphan), coscopin (noscapine), dionin, theobromine and codeine；The instantiation of antineoplastic includes D actinomycin D, actinomycin D, Doxorubicin, daunorubicin, epirubicin (epirubicin), bleomycin, plicamycin (plicamycin) and mitomycin；The instantiation of β-blocking agent includes alprenolol, carteolol, levobunolol (levobunolol), mepindolol (mepindolol), metipranolol (metipranolol), Nadolol, oxprenolol (oxprenolol), penbutolol (penbutolol), pindolol (pindolol), Propranolol, Sotalol (sotalol), timolol, acebutolol (acebutolol), atenolol, betaxolol, Bisoprolol, esmolol, metoprolol, Nebivolol (nebivolol), Carvedilol, celiprolol (celiprolol), labetalol and butaxemine；The instantiation of antirheumatic drug includes adalimumab (adalimumab), imuran (azathioprine), chloroquine, HCQ, cyclosporin, Beracilline, Etanercept (etanercept), sodium aurothiomalate (sodium aurothiomalate), Anranofin (auranofin), infliximab (infliximab), leflunomide, methopterin, minocycline (minocycline), SASP (sulfasalazine)；The instantiation of anti-inflammatory agent includes steroid and nonsteroidal anti-inflammatory agent (steroidal and nonsteroidal anti-inflammatory drug),Such as hydrocortisone,Metacortandracin,Prednisolone,Methylprednisolone,Dexamethasone,Betamethasone,Fluoxyprednisolone (triamcinolone),Beclomethasone (beclomethasone),Aldosterone (aldosterone),Paracetamol,amoxiprin,Benorylate (benorilate),Diflunisal (diflunisal),faislamine,Diclofenac,Aceclofenac (aceclofcnac),Acemetacin (acemetacin),Bromfenac (bromfenac),Etodolac (etodolac),Indomethacin,Nabumetone (nabumctonc),Sulindac (sulindac),Tolmetin (tolmetin),Carprofen,Ketorolac (ketorolac),Mefenamic acid (mefenamic acid),Phenylbutazone,The hydrazone of Ah Zhas third,Analgin (metamizole),Oxyphenbutazone (oxyphenbutazone),Sulfinpyrazone (sulfinprazone),Piroxicam,Lornoxicam (lornoxicam),Meloxicam (meloxicam),Tenoxicam (tenoxicam),Celecoxib,Etoricoxib (etoricoxib),Lumiracoxib (lumiracoxib),Parecoxib (parecoxib),Rofecoxib,Valdecoxib and numesulide；The instantiation of antipsychotic drug includes Iloperidone (ilopcridone), Ziprasidone (ziprasidone), Olanzapine (olanzapine), thiothixene hydrochloride (thiothixene hydrochloride), fluspirilene (fluspirilene), Risperidone (risperidone) and penfluridol (penfluridole)；The instantiation of cognition enhancer includes ampakine (ampakine)；Antiatherosclerotic, the instantiation of cardiovascular drug and/or gemfibrozil includes Atorvastatin calcium (atorvastatin calcium), cerivastatin (cerivastatin), Fluvastatin (fluvastatin), Lovastatin (lovastatin), mevastatin (mevastatin), Pitavastatin (pitavastatin), Pravastatin (pravastatin), rosuvastatin (rosuvastatin) and Simvastatin (simvastatin)；The instantiation of antiadipositas drug includes dexadrine (dexadrine), Dexfenfluramine (dexfenfluramine), fenfluramine (fenfluramine), Phentermine (phentermine), orlistat (orlistat), acarbose and Rimonabant (rimonabant)；The instantiation of Alibra includes silaenafil (sildenafil) and sildenafil citrate (sildenafilcitrate)；The instantiation of anti-infectious agent such as antimicrobial, antiviral agent, antiprotozoal agent (antiprotozoal), anthelmintic (antihelminthic) and antifungal (antifungal agent) include carindacillin sodium (carbenicillin indanyl sodium), bacampicillin hydrochloride (bacampicillin hydrochloride), Troleandomycin (troleandomycin), Doxycycline Hyclate (doxycycline hyclate), ampicillin, benzyl penicillin, azithromycin (azithromycin), terramycin (oxytetracycline), minocycline (minocycline), erythromycin (erythromycin), CLA (clarithromycin), spiramvcin (spiramycin), ACV (acyclovir), nelfinavir (nelfinavir), virazole (virazole), benzalkonium chloride (benzalkonium chloride), Chlorhexidine (chlorhexidine), econazole (econazole), terconazole (terconazole), Fluconazole (fluconazole), voriconazole (voriconazole), griseofulvin (griseofulvin), metronidazole (metronidazole), thiabendazole (thiabendazole), oxfendazole (oxfendazole), Mo Luntaier (morantel), sulfamethoxazole (cotrimoxazole)；The instantiation of somnifacient includes alfaxalone (alfaxalone) and Etomidate (etomidate)；The instantiation of antiparkinsonism medicine includes levodopa (levodopa), bromocriptine (bromocriptine), Pramipexole (pramipexole), Ropinirole (ropinirole), pergolide (pergolide) and selegiline (selegiline)；Anticholinergic drug (anticholinergic) such as benzhexol (trihexyphenidyl), benztropine mesylate (benztropine mesylate), procyclidine (procyclidine), Biperiden (biperiden) and Ai Puba piperazines (ethopropazine)；Antihistamine such as diphenhydramine and dorphenadrine；With amantadine (amantadine)；The instantiation of anti-alzheimer disease medicine includes donepezil (donepezil), rivastigmine (rivastigmine), galanthamine (galantamine), Tacrine (tacrine)；The instantiation of antibiotic includes minocycline,Rifampin,Erythromycin,Naphthlazole (nafcillin),Cephazoline (cefazolin),Imipenem (imipenem),AZT (aztreonam),Gentamicin (gentamicin),Sulfamethoxazole (sulfamethoxazole),Vancomycin (vancomycin),Ciprofloxacin (ciprofloxacin),TMP (trimethoprim),Metronidazole,Clindamycin (clindamycin),telcoplanin,Mupirocin (mupirocin),Azithromycin,CLA (clarithromycin),Ofloxacin (ofloxacin),Lomefloxacin (lomefloxacin),Norfloxacin (norfloxacin),Acidum nalidixicum (nalidixic acid),Sparfloxacin (sparfloxacin),Pefloxacin (pefloxacin),Amifloxacin (amifloxacin),Enoxacin (enoxacin),Fleraxacin (fleroxacin),ternafloxacin,Tosufloxacin (tosufloxacin),Clinafloxacin (clinafloxacin),Sulbactam (sulbactam),Clavulanic acid (clavulanic acid),Amphotericin B (amphotericin B),Fluconazole (fluconazole),Itraconazole (itraconazole),Ketoconazole (ketoconazole),Nystatin (nystatin)；The instantiation of antidepressants includes Isocarboxazid (isocarboxazid), nardil (phenelzine), parnitene (tranylcypromine)；The instantiation of antiviral agent includes Zidovudine (azidovudine) (AZT), Didanosine (didanosine) (dideoxyinosine (dideoxyinosine)) (ddI), d4T, zalcitabine (double deoxidation cytimidines (dideoxycytosine)) (ddC), NVP (nevirapine), Lamivudine (lamivudine) (epivir) (3TC), inverase (saquinavir) (Invirase), Ritonavir (ritonavir) (Norvir), indinavir (indinavir) (Crixivan), Delavirdine (delavirdine) (Rescriptor))；The instantiation of glycogen phosphorylase inhibitors includes [R- (R^*S^*)] the chloro- N- of -5- [2- hydroxyls -3- { methoxymethylamino group } -3- oxos -1- (phenyl methyl) propyl group -1H- indole 2-carboxamides and the chloro- 1H- indole-2-carboxylic acids of 5- [(1S)-benzyl-(2R)-hydroxyl -3- ((3R, 4S)-dihydroxy-pyrrolidin-1-yl) -3- oxopropyls] acid amides；The instantiation of cholestery ester transfer protein inhibitors includes [2R, 4S] 4- [(3, 5- bis- (trifluoromethyl)-benzyl)-methoxycarbonyl-amino] -2- ethyl -6- trifluoromethyls -3, 4- dihydro -2H- quinoline -1- carboxylic acid, ethyl esters, [2R, 4S] 4- [acetyl group-(3, 5- bis- (trifluoromethyl)-benzyl)-amino] -2- ethyl -6- trifluoromethyls -3, 4- dihydro -2H- quinoline -1- carboxylic acid isopropyls, [2R, 4S] 4- [(3, 5- bis- (trifluoromethyl)-benzyl)-methoxycarbonyl-amino] -2- ethyl -6- trifluoromethyls -3, 4- dihydro -2H- quinoline -1- carboxylic acid isopropyls；The anti-depressant instantiations of CNS include caffeine and methylphenidate (methylphenidate)；The instantiation of dopamine-receptor stimulant includes Cabergoline (cabergoline) and Pramipexole；The instantiation of antiemetic includes Dolasetron (dolasetron), Granisetron (granisetron), Ondansetron (ondansetron), Tropisetron (tropisetron), palonosetron (palonosetron), domperidone (domperidone), droperidol (droperidol), dramamine (dimenhydrinate), haloperole (haloperidol), chlorpromazine, fenazil, prochlorperazine (prochlorperazine), Metoclopramide (metoclopramide) and alizapride (alizapride)；The instantiation of gastrointestinal drug includes Loperamide (loperamide) and Cisapride (cisapride)；The instantiation of psychotropic drugs includes chlorpromazine (chlorpromazine), thioridazine (thioridazine), prochlorperazine, haloperole, alprazolam (alprazolam), amitriptyline (amitriptyline), biphenylacetone (bupropion), buspirone (buspirone), chlorine nitrogen

, Citalopram (citalopram), Clozapine (clozapine), diazepam, Prozac (fluoxetine), fluphenazinum (fluphenazine), Fluvoxamine (fluvoxamine), hydroxyzine, Lorazepam, loxapine (loxapine), Mirtazapine (mirtazapine), Molindone (molindone), Nefazodone (nefazodone), nortriptyline (nortriptyline), Olanzapine (olanzapine), Paxil, nardil, Quetiapine (quetiapine), Risperidone (risperidone), Sertraline (sertraline), thiothixene (thiothixene), parnitene, Trazodone (trazodone), Venlafaxine (venlafaxine) and Ziprasidone (ziprasidone)；The instantiation of opioid agonist includes Hydromorphone (hydromorphone), fentanyl (fentanyl), methadone (methadone), morphine, Oxycodone and Oxymorphone (oxymorphone)；The instantiation of opioid antagonists includes naltrexone (naltrexone)；The instantiation of antiepileptic includes sodium vedproate (sodium valproate), nitrazepam (nitrazepam), phenytoinum naticum (phenytoin)；Histamine H₂The instantiation of antagonist includes famotidine (famotidine), nizatidine (nizatidine), Cimetidine (cimetidine), ranitidine (ranitidine)；The instantiation of antasthmatic includes salbutamol (albuterol), Menglusitena (montelukast sodium)；The instantiation of smooth muscle relaxant includes nicorandil (nicorandil), Iloperidone (iloperidone) and Clonazepam；The instantiation of skeletal muscle relaxant includes diazepam, Lorazepam, C-34647 Ba (baclofen), Cali is general many (carisoprodol), Chlorzoxazone (chlorzoxazone), cyclobenzaprine (cyclobenzaprine), Dantrolene (dantrolene), metaxalone (metaxalone), Orphenadrine (orphenadrine), Pancuronium Bromide (pancuronium), Tizanidine (tizanidine), bentyl (dicyclomine), clonidine (clonidine) and Gabapentin.All said medicines are all construed as including the neutral form and its pharmaceutical salts, solvate, ester and prodrug of the medicine.

As described above, the solubility of some medicines is pH dependences, and its solubility can be increased by adding organic acid.However, as shown in table 1 below and 2 and Fig. 2, adding the solubility of organic acid only minimal effect other medicines.

Table 1 lists the increase of weakly basic drugs solubility in organic acid buffer liquid (referring also to Fig. 2).It can determine that three different groups.A group medicines representated by ondansetron hydrochloride show that alkalescent active matter solubility in the buffer solution containing trace fumaric acid is dramatically increased.For example, solubility of the Ondansetron in the buffer solution only containing 0.05mg/mL fumaric acid is about 26mg/mL, when concentration of the fumaric acid in buffer solution increases to 5mg/mL, above-mentioned solubility remains unchanged.In the B groups representated by Dipyridamole, Carvedilol and Iloperidone, the solubility of weakly basic drugs increases with the increase of acid concentration.In the C groups representated by Clonazepam, the influence of organic acid is very limited amount of, i.e. the incrementss of solubility are typically smaller than 3 times.For example, Clonazepam is respectively about 11.6 and 6.9 μ g/mL for the solubility in 2.3 and 6.8 buffer solution (fumaric acid containing higher concentration and low concentration respectively) in pH.

Table 1：Solubility of the weakly basic drugs in organic acid

Fumaric acid Concentration (mg/mL)	Start pH	Terminate pH	Ondansetron hydrochloride In fumaric acid Solubility (mg/mL)	Start pH	Dipyridamole In fumaric acid Solubility (mg/mL)
						5	2.13	2.01	26.9	2.98	6.24
2.5	2.26	2.14	27.0	3.42	1.80
						1	2.48	2.40	26.1	3.68	0.93
0.25	2.79	2.75	26.2	3.88	0.65
						0.05	3.19	3.49	26.0	4.33	0.27
0.01	3.64	4.05	26.1	4.71	0.13
						0.0025	4.15	4.33	26.1	6.28	0.006

Table 2：Solubility of the nifedipine in buffer solution

In an embodiment of pharmaceutical composition of the present invention, the active pharmaceutical ingredient is nifedipine.In another embodiment, the active pharmaceutical ingredient is Lercanidipine.It should be understood, however, that the scope of the present invention is not limited to any specific active pharmaceutical ingredient.

The suitable solubilized polymer that can be used in the pharmaceutical composition of the present invention includes but is not limited to polyvinylpyrrolidone (polyvinylpyrrolidone) (PVP or PVP (povidone)), the copolymer (such as Kollidon VA 64) of vinyl acetate/ethylene base pyrrolidones, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hydroxypropyl methylcellulose (hypromellose)), HPMC-AS (hydroxypropyl methylcellulose acetate succinate, HPMCAS), polyethylene glycol oxide (polyethylene oxide), polyethylene glycol and cyclodextrin.

Type and amount to solubilized polymer are selected, to make the combination of active pharmaceutical ingredient and solubilized polymer to form solid dispersions as defined herein.Some solubilized polymer that can be used for preparing solid solution/solid dispersions are typically used as adhesive.However, the solid dispersions in order to provide active pharmaceutical ingredient, the ratio of solubilized polymer and active pharmaceutical ingredient is generally significantly greater than the ratio of polymer adhesive in traditional drug formulations (polymeric binder) and active pharmaceutical ingredient.In traditional drug formulations, the ratio of polymer adhesive and active pharmaceutical ingredient is typically smaller than 1/9, e.g., from about 1/50 to about 1/20.In one embodiment, the ratio of solubilized polymer and active pharmaceutical ingredient is 9/1 to 1/6 (by weight) in solid dispersions.In another embodiment, the ratio of solubilized polymer and active pharmaceutical ingredient is about 3/1 to about 1/3 (by weight) in solid dispersions.In another embodiment, the ratio of solubilized polymer and active pharmaceutical ingredient is about 2/1 to about 1/2 (by weight) or about 1/1 in solid dispersions.

The solid dispersions can be existed by the form of particle (such as particle (granule), piller (pellet), pearl (bead)), or alternatively, the solid dispersions can layer be layed onto in inert core.For example, active pharmaceutical ingredient and solubilized polymer can be dissolved in medicinal solvent (or mixture of solvent), it is then applied in inert core.Remove after solvent, the solid dispersions are configured to the coating in inert core.Any medicinal inert material can be used as inert core, the sugar ball (sugar sphere) that is for example distributed with suitable particle size or pearl is (for example

), cellulose balls, silica spheres etc., e.g., from about 20-25 mesh to 35-40 mesh sugar ball, it is used to prepare the coating pearl being incorporated into capsule preparations, and sugar ball or cellulose balls with the narrow size distribution of about 50-100 purposes, and it is used to prepare the coating pearl being incorporated into ODT preparations.The thickness and active pharmaceutical ingredient of solid dispersions layer and the relative quantity of solubilized polymer can be adjusted, to provide the active pharmaceutical ingredient of therapeutically effective amount.For example, the inert core covered with the solid dispersions of active pharmaceutical ingredient layer can be containing 2% to about 50% weight active pharmaceutical ingredient (relative to the gross weight for being coated the inert core for having medicine).

The solid dispersions in pharmaceutical composition of the present invention are coated into (such as U.S.6, the TPR described in 627,223 is coated, and is incorporated herein by reference for all purposes) with the TPR comprising insoluble polymer and enteric polymer to be coated.The TPR is coated the release of adjustment active pharmaceutical ingredient, to provide the active pharmaceutical ingredient for the treatment level of significance for continuing 12-24 hours in the blood plasma of patient.In some embodiments, the TPR is coated the lag time (such as at most about four hours) that the hangover of active pharmaceutical ingredient can be made of short duration.In addition, (such as at most about 12 hours, the at most about 18 hours or at most about 24 hours) period that the TPR coatings can last extension provides the medicine of lasting treatment level.

Suitable insoluble polymer includes the copolymer (such as Eudragit NE, RS, RS30D, RL or RL30D) with quaternary amines of cellulose derivative (such as ethyl cellulose), polyvinyl acetate (Kollicoat SR30D, derived from BASF), the neutral copolymer based on ethyl acrylate and methyl methacrylate, acrylate and methacrylate.

It is insoluble during the low ph level that enteric polymer exists under one's belt but relatively solvable during higher pH levels present in enteron aisle.Suitable enteric polymer includes the EUDRAGIT L100 and shellac (shellac) of cellulose esters (such as Cellacefate (cellulose acetate phthalate), Hydroxypropyl Methylcellulose Phathalate (hydroxypropyl methylcellulose phthalate)), polyvinyl acetate phthalate (polyvinyl acetate phthalate), the pH sensitivity of acid substitution.Commercially available enteric polymer is the enteric polymer for the trade name " Eudragit " (such as Eudragit L100, S100, L30D) that Rhom Pharma are manufactured, from Eastman The enteric polymer of Chemical Co. trade name Cellacefate (Cellacefate) enteric polymer, the enteric polymer of trade name Aquateric (aqueous dispersion of Cellacefate) from FMC Corp. and the trade name Aqoat (aqueous dispersion of HPMC-AS) from Shin Etsu K.K..

The ratio of insoluble polymer and enteric polymer can be changed to about 9/1 (by weight) from about 1/9 during TPR is coated.In one embodiment, the ratio of insoluble polymer and enteric polymer can be changed to about 4/1 from about 1/4, or can be changed to about 3/1 (by weight) from about 1/3.The gross weight of enteric coating (enteric coating) can account for the about 5-50% of TPR pearl gross weights.In one embodiment, the gross weight that the TPR on TPR pearls is coated accounts for about 10% to about 25% weight of TPR pearl gross weights.

Enteric polymer and insoluble polymer for forming TPR coatings can be plasticized.Representative example available for the suitable plasticizers being plasticized to TPR coatings includes the sour tri-n-butyl (acetyltri-n-butyl citrate) of glyceryl triacetate (triacetin), tributyl citrate, triethyl citrate, acetyl triethyl, diethyl phthalate, castor oil, dibutyl sebacate, monoglyceride (acetylated monoglyceride) of acetylation etc. or their mixture.Plasticizer can account for about 3 to 30% that TPR is coated gross weight when it is present.In one embodiment, plasticizer accounts for about the 10 to 25% of TPR coating gross weights.The type and amount of plasticizer depend on the property (total solids content for being for example also based on solvent based on water, being also based on based on solution in dispersion and coated systems) of the property and coated systems of insoluble polymer and enteric polymer in TPR layers.

In addition to solid dispersions (including at least one active pharmaceutical ingredient and at least one solubilized polymer) and TPR coatings, pharmaceutical composition of the invention can also include extra medicinal ingredient or excipient.Example for the appropriate excipients of composition or formulation of the invention includes filler, diluent, glidant, disintegrant, adhesive, lubricant etc..Other pharmaceutical excipients include acidulant (acidifyingagent), basifier (alkalizing agent), preservative, antioxidant, buffer, chelating agent, colouring agent, complexing agent (complexing agent), emulsifying agent and/or solubilizer, flavouring and spices (perfume), wetting agent (humectant), sweetener, wetting agent (wetting agent) etc..

The example of suitable filler, diluent and/or adhesive include lactose (lactose of such as spray drying, alpha-lactose, beta lactose,

, various ranks

Or

), microcrystalline cellulose (various ranksMing

Or), hydroxypropyl cellulose, L- hydroxypropyl celluloses (low substituted), hydroxypropyl methyl cellulose (HPMC) (such as Shin-Etsu.Ltd Methocel E, F and K, Metolose SH, such as 4, the SH of Methocel E and Metolose 60 of 000cps ranks, the Methocel of 4,000cps ranks The F and SH of Metolose 65, 4, 000, 15, 000 and 100, the Methocel K of 000cps ranks, and 4.000, 15, 000, 39, 000 and 100, the SH of Metolose 90 of 000 rank), methyl cellulose polymers (such as Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethyl cellulose, sodium carboxymethylcellulose, carboxylic methylene (carboxymethylene), carboxymethyl hydroxyethyl cellulose and other cellulose derivatives, sucrose, agarose, sorbierite, mannitol, dextrin, maltodextrin (maltodextrin), starch or converted starch (including farina, cornstarch and rice starch), calcium phosphate (such as basic calcium phosphate, calcium monohydrogen phosphate, Dicalcium Phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc..

The instantiation of diluent is included such as calcium carbonate, Bibasic Calcium Phosphate (dibasic calciumphosphate), three alkali calcium phosphates (tribasic calcium phosphate), calcium sulfate, microcrystalline cellulose, powdered cellulose, glucan, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbierite, starch, pregelatinized starch, sucrose, sugar.

The instantiation of disintegrant includes such as alginic acid or alginate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other cellulose derivatives, Ac-Di-Sol (croscarmellosesodium), Crospovidone (crospovidone), polacrilin potassium (polacrilin potassium), primojel (sodium starch glycolate), starch, pregelatinized starch, CMS (for example

With

) etc..The instantiation of adhesive is included such as Arabic gum, alginic acid, agar, calcium carrageenan (calcium carrageenan), sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose (liquid glucose), guar gum (guar gum), hydroxypropyl methyl cellulose, methylcellulose, pectin, PEG, polyethylene glycol oxide, PVP, pregelatinized starch.

The instantiation of glidant and lubricant includes stearic acid, magnesium stearate, calcium stearate or other Metallic stearates, talcum, wax and glyceride, light mineral oil, PEG, behenate (glyceryl behenate), cataloid, hydrogenated vegetable oil, cornstarch, fumaric acid stearyl alcohol ester sodium salt (sodium stearyl fumarate), polyethylene glycol, alkyl sodium sulfate ester (alkyl sulfate), sodium benzoate, sodium acetate etc..

Other excipient are included such as flavouring, colouring agent, odor mask (taste-masking agent), pH adjusting agent, buffer, preservative, stabilizer, antioxidant, wetting agent, moisture regulator (humidity-adjusting agent), surfactant (surface-active agent), suspending agent, sorbefacient (absorption enhancing agent), release regulator (agents for modified release).

Antioxidant is used to improve the long-term chemical durability of amorphous solid solution/solid dispersions, it includes such as ascorbic acid, ascorbyl palmitate (ascorbyl palmitate), Butylated Hydroxyanisole (butylatedhydroxyanisole), Butylated Hydroxytoluene (butylated hydroxytoluene), hypophosphorous acid, monothioglycerol (monothioglycerol), potassium metabisulfite (potassium metabisulfite), propylgallate, sodium sulfoxylate formaldehyde (sodium formaldehyde sulfoxylate), sodium pyrosulfite (sodiummetabisulfite), sodium thiosulfate, sulfur dioxide, tocopherol (tocopherol), tocopherol acetate (tocopherol acetate), hemisuccinic acid tocopherol (tocopherol hemisuccinate), TPGS or other Tocopheryl derivatives etc..

In addition, the pharmaceutical composition of the present invention can also include pharmaceutically acceptable organic acid.The pharmaceutically acceptable organic acid can improve or adjust the release profile (speed and degree of such as release) of active pharmaceutical ingredient.The suitable pharmaceutically acceptable organic acid that can be used in the present compositions includes but is not limited to citric acid, fumaric acid, aspartic acid, tartaric acid and butanedioic acid.In some embodiments, the solid dispersions of active pharmaceutical ingredient and solubilized polymer include at least one pharmaceutically acceptable organic acid, and the amount of the pharmaceutically acceptable organic acid accounts for the about 10-90% of solid dispersions weight.In other embodiments, the amount of organic acid accounts for the 25-75% weight of solid dispersions.

The composition of the present invention can also include one or more extra coatings (such as protectiveness or sealant, compressible coating (compressible coating), enteric layer, taste mask layer).For example; the extra coatings (or multiple coatings layer) may include that one or more protectiveness or sealing are coated (or multiple coatings); the protectiveness or sealing, which are coated, includes such as Opadry Clear or Pharmacoat 603 (hydroxypropyl methyl cellulose coated composition); or hydroxypropyl cellulose, or ethyl cellulose.The protectiveness or sealing coating can be coated on solid dispersions and TPR be coated between or be coated in TPR coating, or sealing is coated for multiple protective, for example, be coated between solid dispersions and TPR coatings and be coated in TPR coatings.The extra coatings (or multiple coatings layer) may also include compressible coating, and the highly plasticized ethyl cellulose or the layer of hydroxypropyl cellulose being for example coated on IR pearls, taste masking IR pearls or TPR pearls, those described above pearl include solid dispersions.

Other embodiments of pharmaceutical composition of the present invention may include one or more enteric layers, and the enteric layer includes one or more enteric polymers described herein.Optional enteric layer can be coated between solid dispersions and TPR coatings, and/or be coated in TPR coatings.

The pharmaceutical composition of the present invention may include any combinations of protective layer or sealant, compressible coating and enteric layer, and the combination provides desired working properties and insoluble drug release is distributed.

The pharmaceutical composition of the present invention can be configured to various peroral dosage forms, such as capsule (such as gelatin Capsule or HPMC capsules), tablet or Orally disintegrating tablet (orally disintegrating tablet, ODT).The difference of tablet and ODT formulations is that tablet is intended to completely swallow and the rapid dispersion after stomach is reached, and ODT fater disintegrations when with saliva contacts in oral cavity, forms the soft and smooth suspension of easy-to-swallow particle.

In some embodiments, formulation of the invention only includes TPR pearls.In other embodiments, formulation of the invention can include the blend of release (IR) pearl and TPR pearls (TPR pearls i.e. as here depicted) immediately.IR pearls are comprising active pharmaceutical ingredient the solid dispersions in solubilized polymer, and substantially release active pharmaceutical ingredient (such as release >=75% of medicine upon administration in about 60 minutes) immediately.IR pearls can include the solid dispersions " layer covers " of the particle or active pharmaceutical ingredient of solid dispersions in solubilized polymer to the particle (as described in the present application) in inert core.IR pearls also can optionally include one or more protective layers or selection layer (select layer).Then IR pearls can be converted into TPR pearls by adding TPR to be coated.

When the formulation of the present invention includes the blend of IR pearls and TPR pearls, the IR pearls can be uncoated, be optionally coated and be coated with sealing or protectiveness, and/or be optionally coated with taste mask layer.The taste mask layer may include such as U.S. Patent application 11/213,266,11/248,596 and 11/256, and above-mentioned application is hereby incorporated by reference by any taste masking composition described in 653 herein.Specifically, suitable taste mask layer includes one or more medicinal insoluble polymers and one or more pore formers (pore forming agent).Non-limiting examples for the suitable medicinal insoluble polymer of taste mask layer include such as ethyl cellulose, cellulose acetate, cellulose acetate-butyrate, polyvinyl acetate and methacrylate polymers (such as Eudragit RL, RS, NE and 30D).The non-limiting examples of suitable pore former include sodium chloride, calcium carbonate, calcium phosphate, Calciofon (calciumsaccharide), calcium succinate, calcium tartrate, ferric acetate, iron hydroxide, ferric phosphate, magnesium carbonate, citrate of magnesia, magnesium hydroxide, magnesium phosphate, polyvinylpyrrolidone, Crospovidone, Eudragit E100, Eudragit EPO and their mixture.The ratio of insoluble polymer and pore former is about 95/5 to about 50/50 in taste mask layer, or is about 85/15 to about 65/35 in some embodiments.About the 5% to about 50% of IR pearl gross weights of coating can be accounted for by being coated on the amount of the taste mask layer of IR pearls, and about the 10% to about 50% of the IR pearl gross weights of coating is accounted in some embodiments.

When the formulation of the present invention includes the blend of IR pearls and TPR pearls, the ratio of IR pearls and TPR pearls is about 1/9 to about 5/5, is about 1/4 to about 1/1 (by weight) in some embodiments.

When the pharmaceutical composition of the present invention is configured into ODT formulations, the composition also includes disintegrant.The disintegrant can be in the form of rapid dispersion particulate, and the particulate includes at least one disintegrant And at least one sugar alcohol and/or sugar.The non-limiting examples of suitable disintegrant include Crospovidone (PVPP), starch, cellulose, sodium starch glycolate and sodium carboxymethylcellulose.The non-limiting examples of sugar alcohol include arabite, antierythrite (erythritol), lactitol, maltitol, mannitol, sorbierite and xylitol.The non-limiting examples of suitable sugar include lactose, sucrose and maltose.

The ratio of disintegrant and sugar alcohol and/or sugar is about 1/99 to about 10/90 in rapid dispersion particulate, is about 5/95 (by weight) in some embodiments.

The pastille pearl (pearl containing solid solution being coated) that is coated in ODT formulations and the ratio of rapid dispersion particulate are about 1/9 to 1/1, are about 1: 4 to about 1: 2 in some embodiments.

Because ODT formulations fater disintegration in the oral cavity of patient, ODT organoleptic attribute (organoleptic property) is important Consideration.For example, ODT should be configured to " mouthfeel (mouthfeel) " and taste property provided." mouthfeel " describes product how are you feeling today in mouth.In order to obtain " mouthfeel " of no chiltern sense, the particle mean size of the TPR pearls, rapid dispersion particulate and optional IR pearls should be 400 μm or smaller, be in some embodiments 300 μm or smaller, and be 200 μm or smaller in other embodiments.In one embodiment, include the rapid dispersion particulate (particle i.e. comprising disintegrant and sugar alcohol and/or sugar, form rapid dispersion particulate together with the disintegrant and sugar alcohol and/or sugared agglomeration) the particle mean size of elementary particle be 30 μm or smaller, it is 25 μm or smaller in other embodiments, and is 20 μm or smaller in other embodiments.

In one embodiment, the ODT formulations comprising the present composition include such as TPR pearls described herein and rapid dispersion particulate.The ODT formulations can also include extra excipient, such as compression aid (compression aid) (such as microcrystalline cellulose) and/or extra disintegrant (it can be identical or different with the disintegrant in rapid dispersion particulate).The ODT formulations may also include lubricant (such as magnesium stearate), or when being suppressed in outside lubricated dies system (externally lubricated die system), may not include lubricant.In one embodiment, ODT formulations of the invention were disintegrated when with saliva contacts in oral cavity in about 60 seconds, formed the easy-to-swallow suspension of " mouthfeel " that has had.In another embodiment, ODT formulations of the invention were disintegrated when with saliva contacts in oral cavity in about 30 seconds, formed the easy-to-swallow suspension of " mouthfeel " that has had.

In one embodiment, TPR pearls in formulation (such as tablet, ODT or capsule) can include inert core, the inert core is coated with the solid dispersions of medicine and solubilized polymer, then it is coated, and is optionally coated with one or more sealants or enteric layer with TPR layers.

When IR pearls are present in formulation (such as tablet, ODT or capsule), formulation (such as tablet, ODT or capsule) in IR pearls can include inert core, the inert core is coated with the solid dispersions of medicine and solubilized polymer, and is optionally coated with sealant described herein and/or taste mask layer.Above-mentioned pearl also is used as preparing " intermediate " of TRP pearls-when being coated with TPR layers to IR pearls, and IR pearls are converted into TPR pearls.

Alternatively, IR pearls can be prepared as follows：Form the particle of solid dispersions, for example pass through spray drying, " bulk (bulk) " or the solid dispersions of larger particles form are ground, or one or more pharmaceutical excipients (such as filler, adhesive, disintegrant) are pelletized together with solid dispersions, (extrude) and nodularization (spheronize) are optionally then extruded to obtained particle.Then the IR particles/pearl/piller is coated with TPR layers and is translated into TPR pearls.

The formulation of the present invention may include one or more different types of TPR pearls (such as the TPR pearls with different TPR layers TPR pearls or with sealant and/or enteric layer various combination).For example, different lag time features and/or different rate of release features can be shown with different TPR layers TPR pearls, thus make formulation that there are different overall drug release characteristics.Formulation including different type TPR pearls also can optionally include IR pearls, to provide the feature that some discharge immediately.For example, in one embodiment, formulation includes the mixture of IR pearls and the 2nd TPR pearls group once a day, the IR pearls include the active pharmaceutical ingredient that elimination half-life period is about 7 hours, and the IR pearls allow to discharge immediately, and the lag time of the 2nd TPR pearls group is at most about 4 hours, and the 2nd TPR pearls group provides the sustained drug release profile for the delay for lasting about 12-20 hours, and the effective plasma concentration of maintaining treatment in about 18-24 hours.

Solid solution or solid dispersions of the active pharmaceutical ingredient in solubilized polymer can be prepared as follows：Active pharmaceutical ingredient and solubilized polymer are dissolved in the mixture of medicinal solvent or solvent.Then the solution of active pharmaceutical ingredient and solubilized polymer is dried in following condition, the condition promotes the formation of solid solution of the active pharmaceutical ingredient in solubilized polymer.As described above, solubilized polymer phase has relatively high level for active pharmaceutical ingredient, this advantageously forms the solid dispersions disperseed with molecular forms.In addition, solid dispersions also may be formed：For example by spray drying from the solution of active pharmaceutical ingredient and solubilized polymer rapid solvent removal, such as the solution of active pharmaceutical ingredient and solubilized polymer is coated to (forming layer is covered with the pearl of medicine) in inert core using fluidized bed coating (fluidizedbed coating).Alternatively, solid dispersions also can be prepared as follows：For example active pharmaceutical ingredient is dissolved in the melt of solubilized polymer by polymer extrusion molding (polymer extrusion method) (such as being mixed in double screw extruder (twin screwextruder))., can be optional if being necessary to obtain suitable granularity (such as the granularity for being less than 400 μm for ODT formulations) The particle of solid dispersions is milled (to reduce granularity), or the granulation (such as rotogranulation (rotogranulation) or first pelletize extrude nodularization (extrusion-spheronization) again) in the presence of appropriate excipients.Solid dispersions also formable " microplate (mini-tablet) " for 1-2mm diameters, for example, shape by the following method：The particle (optionally together with excipient (such as compression aid, lubricant)) of solid dispersions is suppressed using the circle of appropriate size drift (roundbeveled punch) of splaying.

In one embodiment, the solid dispersions are prepared as follows：Solubilized polymer, weakly basic drugs and optional other pharmaceutical excipients (such as adhesive, diluent, filler) are pelletized in high shear granulator (high-shear granulator) or fluidised bed granulator (fluid bed granulator) (such as GlattGPCG granulators), and granulation forms agglomerate.Also the wet feed (wet mass) from high shear granulator can be extruded and nodularization, obtains spheroidal particle (piller).

When solid dispersions are prepared by solvent treatment method discussed above, the medicinal solvent can be the mixture of single solvent or solvent.The non-limiting examples of suitable solvent include water, ketone such as acetone, alcohol such as ethanol and their mixture (such as aqueous acetone, 95% ethanol).

After preparation, solid dispersion particles (solid dispersions, layer such as the drug/polymer of spray drying are covered with the pearl of medicine, the solid dispersions through granulation, microplate) can optionally be coated (such as Pharmacoat with protective seal^TM603 orClear) it is coated.

The solid dispersion particles prepared as described above can be described as IR and (discharge) pearl or IR particles immediately, because above-mentioned pearl or particle can substantially discharge active pharmaceutical ingredient immediately if being administered in this form.Then the IR pearls prepared as described above or IR particles are coated with TPR Coating Solutions, the TPR Coating Solutions include the insoluble polymer and enteric polymer being dissolved in medicinal solvent.Any suitable coating method (such as fluidized bed coating) can be used and is coated to be coated with TPR.

In some embodiments, it is desirable that, in addition to TPR is coated, a variety of coatings are also coated on IR pearls or IR particles.For example, in some embodiments, the IR pearls are coated with enteric coatings (such as comprising at least one enteric polymer described herein being dissolved in medicinal solvent) first, are dried to remove coating solvent, are then coated and are coated with above-described TPR.In other embodiments, the IR pearls are successively coated with following coating：Enteric polymer is coated, TPR is coated and the second enteric polymer is coated.In other embodiments, the IR pearls are successively coated with following coating：First TPR is coated, enteric polymer is coated and the 2nd TPR is coated, wherein first and second TPR coatings are independent identical or different.In other embodiments, sealant (as here depicted) is coated onto IR pearls, is then coated with TPR coatings and/or enteric polymer bag Clothing layer.In other embodiments, sealant can be coated with after coating TPR coatings and/or enteric polymer coatings.

In the pharmaceutical dosage form of the mixture containing TPR pearls and IR pearls, the IR pearls can be coated with taste mask layer.For example, any suitable packaging technique (such as fluidized bed coating or coacervation (coacervation)) can be used, any IR pearls described herein are coated with the solution comprising medicinal solvent, insoluble polymer and optional pore former.

Then pharmaceutical dosage form can be prepared from TPR pearls, such as, by the way that TPR pearls is tabletted, TPR pearls and disintegrant (such as rapid dispersion particulate) are pressed into ODT, or use conventional method TPR pearl capsule charges.These pharmaceutical dosage forms can optionally containing extra excipient and as here depicted IR pearls.In one embodiment, it is using external lubrication tablet press machine (externally lubricated tabletpress) that the composition and optional additional excipients of the present invention and/or IR pearls is tabletted.In another embodiment, composition, fater disintegration particulate, optional additional excipients and/or the IR pearls of the present invention are pressed into ODT.

Pharmaceutical dosage form comprising the present composition lasts the active pharmaceutical ingredient of 12-18 hours release treatment levels of significance, for example as shown in fig.7-12.Various dissolution test methods can be used to evaluate the composition of the present invention or the insoluble drug release distribution of formulation in vitro, the dissolution test method such as (hanging basket of American Pharmacopeia device 1, rotating speed is 100rpm) or device 2 (agitating paddle, rotating speed is 50rpm) and two benches dissolving-out method (then test is tested for 2 hours in 900mL pH is 6.8 solution (being obtained by adding 200mL pH adjusting agents) first in 700mL 0.1N HCl (hydrochloric acid)).Medicine/acid to the sample that is gathered with selected interval is carried out HPLC and determined with being released through for time.

In one embodiment, when by American Pharmacopeia (USP) dissolving-out method using two benches dissolution medium (first in 0.1N HCl carry out 2 hours then pH for 6.8 buffer solution in tested) to test dissolution when, composition of the invention lasts the plasma concentration at least about providing therapeutically effective active pharmaceutical ingredient in 12 hours.

In order to evaluate the release in vitro distribution pattern realized once a day required for plasma concentration profile, it is usually carried out modeling and gropes (modeling exercise)：Using the pharmacokinetic parameter of medicine, software program WinNonlin is used^TMStandard Edition 2.1 or equivalent procedures (such as Gastro

), single chamber first-order model (it is assumed that first order kinetics (assuming first orderelimination kinetics)) of the fitting with lag time.Then using the model slightly made an amendment previously set up by basic parameter input to another program i.e. Stella versions 6.01.Different release in vitro distributions are obtained, and desired release in vitro is obtained from target once a day release profile by deconvoluting (deconvolution) (medium, target and quick) distribution.

Following non-limiting examples illustrate to show one or more insoluble drug releases " pulse " and show the capsule formulation of default delay drug release (delayed-onset).Can by adjust TPR layers amount or thickness and optionally the number and type of regulation additional layer (such as enteric layer or sealant) and after vitro drug release distribution or formulation are administered orally corresponding plasma concentration profile in vivo be designed to provide desired distribution, so as to reach maximum therapy efficiency and improve patient compliance (such as by providing formulation once a day).The formulation of the present invention makes insoluble drug release distribution be improved, and the improved insoluble drug release distribution makes drug plasma concentration maintain following level, and the side effect that the level makes the insoluble drug release distribution to regular dosage form related is minimized.

Embodiment 1

Turbidimetry

Concentrated solution (0.5mg/ml) (3mL) of the Lercanidipine hydrochloride in acetone is added in 200mL cushioning liquid (pH 6.0), the cushioning liquid contains Kollidon VA 64, Methocel E5 (hydroxypropyl methylcellulose), polyethylene glycol (PEG 6000), cyclodextrin or the PF of Kollidon 14 (polyvinylpyrrolidone), and the ratio of medicine and polymer by weight is 1: 2., it is evident that drug solution shows improved stability from Fig. 3 A, the danger that the conjugate base of Lercanidipine hydrochloride is crystallized thus is strongly reduced.

Intrinsic dissolution rate (Intrinsic Dissolution Rate) measurement

Intrinsic dissolution rate is determined for two kinds of different polymorphs and amorphous substance (such as 1: 2 solid solution of amorphous drug and Lercanidipine hydrochloride and Methocel E5 1: 2 solid solution and Lercanidipine hydrochloride and Kollidon VA 64) of Lercanidipine hydrochloride.Data are shown in Figure 4.The polymorph of crystallization shows poor dissolution rate and dissolution degree, and solid solution shows significantly higher dissolution rate and dissolution degree.

Powder x-ray diffraction

Lercanidipine hydrochloride and Methocel E5 (hydroxypropyl methylcellulose) that ratio is 1: 1 and the Lercanidipine hydrochloride that ratio is 1: 2 and Methocel E5 (hydroxypropyl methylcellulose) are dissolved in methylene chloride-methanol (1 to 1, v/v in solvent mixture), solution drying to residual solvent levels is then less than 1% (w/w).Similarly, Lercanidipine hydrochloride and Kollidon VA 64 1: 1 co-precipitate (co-precipitate) and Lercanidipine hydrochloride and Kollidon VA 64 1: 2 co-precipitate are prepared.Obtain the x-ray diffractogram of powder shape of all four samples.XRD (X-ray diffraction) figure of the solid solution of Lercanidipine-Kollidon VA 64 is shown in Figure 5, and its displaying ratio is almost completely free setting for 1: 2 Lercanidipine hydrochloride and Kollidon VA 64 solid solution.

Embodiment 2

Turbidimetry

Concentrated solution (0.5mg/ml) (3mL) of the nifedipine in acetone is added in 200mL cushioning liquid (pH 6.0), contain Kollidon VA 64, Methocel E5 (hydroxypropyl methylcellulose), polyethylene glycol (PEG 6000), cyclodextrin or Kollidon 14PF (polyvinylpyrrolidone) in the cushioning liquid, the ratio of nifedipine/polymer by weight is 1: 2.Nifedipine/polymer solution is monitored with the transmission (transmittance) of time, as shown in Figure 3 B.Relatively stable solution shows that transmission is slower with the decay of time, and this is due to that nifedipine is more slowly crystallized from solution.Methocel E5, Kollidon VA 64 and the PF of Kollidon 14 show stronger stabilization.

Powder x-ray diffraction

The following nifedipine for preparing nifedipine/Methocel ratios for 1: 1 and 1: 2 and MethocelE5 (hydroxypropyl methylcellulose) two kinds of co-precipitates：In the mixture that nifedipine and Methocel are dissolved in methylene chloride-methanol (1: 1, v/v), solution drying to residual solvent levels is then less than 1% (w/w).Nifedipine and Kollidon VA 64 1: 1 and 1: 2 co-precipitate (co-precipitate) are also prepared for using identical method.All four samples are analyzed by powder x-ray diffraction；The XRD shape of the solid solution of nifedipine-Kollidon VA 64 is shown in Figure 6.For 1: 1 co-precipitate, spike present in XRD shape shows that nifedipine exists in crystalline form.For 1: 2 co-precipitate, wide relatively undistinguishable XRD shape shows that nifedipine is almost completely amorphous, and shows that nifedipine forms solid dispersions in Kollidon VA 64.

Embodiment 3

3A：Nifedipine IR pearls (nominal nifedipine carrying capacity is 10%)

In the 72.5/22.5/5 mixtures that Kollidon VA 64 (800g) are added slowly to 95% ethanol/acetone/water (4930g/1530g/340g), it is stirred vigorously simultaneously until dissolving, is then slowly added into nifedipine (400g) until dissolving.Glatt GPCG 3 are filled with 2584g 25-30 mesh sugar balls, and the Glatt GPCG3 are equipped with the pillar height Wurster inserts of 7 " bottom sprays/8 ", 20mm distribution gaps (partition gap), air distribution plate (air-distribution plate) B (250 μm of sieves), 1.0mm nozzle bores (nozzle port), 1.5 bar atomization air pressures and 3.2mm internal diameter tubes.About 40g talcums are homogenized in nifedipine/polymer solution, accumulation of static electricity (static build-up) is minimized.Solids content was sprayed in sugar ball for the nifedipine solution of 15% weight with the spray rate of 8-17g/ minutes, export the breeze door piece (outlet flap) is that (air velocity is about 85-115m to about 60-80%³/ hour), while maintaining product temperature at about 36-40 DEG C.Obtained layer is covered with into the pearl of nifedipine (being in batches 3724g) to dry about at 40 DEG C in Glatt equipment 45 minutes, minimize the level of residual solvent in product.Available pearl (600-1200 μm) is obtained, yield is 98.5%.

It is 2% (being coated the weight relative to uncoated pearl weight) to provide coat weight for the 2800g layers of pearl for being covered with nifedipine

Clear protective seal is coated (by weight containing 8% solid；Product temperature：37-41℃；Spray rate：5-12g/ minutes), then it is further dried in Glatt equipment at 40 DEG C about 45 minutes, removes residual solvent/moisture.Compared with the target efficiency of 10% nifedipine, measured efficiency is 9.81% (% nifedipines).

3B：(TPR is coated nifedipine TPR pearls：Ratio is 45/40/10/5 EudragitRL/Eudragit L/TEC/ talcums)

What is prepared as described in 3A above there is nominal medicine carrying capacity to be coated by the following method for 10% nifedipine IR pearls (700g)：Solids content of the EudragitRL/Eudragit L/TEC/ talcums that spraying ratio is 45/40/10/5 in the acetone/ethanol that ratio is 45/55 is the solution (talcum is suspended in solution using Ultraturrex homogenizers) of 10% solid, obtains the coating (being sampled when coat weight is 5%, 10% and 15%) of at most 20% weight.

The TPR Coating Solutions are prepared as follows：Eudragit RL polymer is added slowly in solvent mixture under agitation first, settled solution is obtained.Next, being successively slowly added to Eudragit L polymer and plasticizer (triethyl citrate or " TEC ") and it is dissolved in solution.Talcum is individually homogenized in solvent mixture, is then added in the polymer and plasticizer of dissolving.TPR Coating Solutions are coated on nifedipine IR pearls using Glatt GPCG 1, the Glatt GPCG 1 are equipped with 4 " bottom spray Wurster inserts, 20mm distribution gaps, air distribution plate B (250 μm of sieves), 1.0mm nozzle bores, 1.5 bar atomization air pressures, 3.2mm internal diameter tubes and the special filter bags of T165P.With the spray rate spraying TPR Coating Solutions of 4-11g/ minutes, export the breeze door piece was about 20-30% (air velocity is about 2.0-2.5m/s), and product temperature is 35-38 DEG C.The pearl of coating is dried 45 minutes in Glatt at 40 DEG C, excessive residual solvent is removed.Dry pearl is sieved, removes the pearl (double) (i.e. two or more pearls are coated and adhered to each other by TPR) (if formation) of any dimerization.Efficiency and the insoluble drug release distribution for the TPR pearls for the use of HPLC evaluation of methodology coat weights being about 5% and 15%.

3C：Nifedipine IR pearls (nominal nifedipine carrying capacity is 5% weight)

The nifedipine IR pearls that nominal medicine carrying capacity is 5% weight are prepared according to the method described in 3A above.64 layers of 190g nifedipines and 380g Kollidon VA are overlayed in 3154g 25-30 mesh sugar balls.The efficiency of measurement is defined as 4.81% nifedipine (compared with the nominal efficiency of the theory of 5% nifedipine).

3D：Nifedipine TPR pearls (are coated：Ratio is 40/45/10/5 Eudragit RL/L/TEC/ talcums)

According to the operation described in 3B above, the TPR Coating Solutions for the Eudragit RL/Eudragit L/TEC/ talcums for being 45/40/10/5 with ratio in Glatt GPCG 1 are coated to the nifedipine IR pearls (700g) that the nominal nifedipine carrying capacity prepared as described in 3C above is 5%, and coating level is 5% weight, 10% weight, 15% weight and 20% weight.Efficiency and the insoluble drug release distribution for the TPR pearls for the use of HPLC evaluation of methodology coat weights being about 5% and 15%.

Embodiment 4

4A：Nifedipine IR pearls (60-80 mesh sugar ball)

According to similar to the operation described in 3A above, nifedipine/Kollidon VA 64 1: 2 solution is sprayed in 60-80 mesh sugar balls in Glatt GPCG 3, nifedipine IR pearls are thus prepared (nominal nifedipine carrying capacity is 10% weight).

4B：(TPR is coated nifedipine TPR pearls：Ratio is 35/50/10/5 EudragitRL/Eudragit L/TEC/ talcums)

The nifedipine IR pearls (700g) prepared as described in 4A above are carried out as follows coating：According to the operation described in 3B above, 35/50/10/5 solution of Eudragit RL/EudragitL/TEC/ talcums of being sprayed in Glatt GPCG 1, coat weight is 20%, is then dried 10 minutes at 40 DEG C in Glatt, removes excessive residual solvent.Dry pearl is sieved, removes the pearl (if formation) of any dimerization.It is distributed using HPLC evaluation of methodology coat weight for the efficiency and insoluble drug release of 5%, 10% and 15% TPR pearls.

4C：(TPR is coated nifedipine TPR pearls：Ratio is 40/45/10/5 EudragitRL/Eudragit L/TEC/ talcums)

The nifedipine IR pearls (700g) prepared as described in 4A above are carried out as follows coating：According to 40/45/10/5 solution of EudragitRL/Eudragit L/TEC/ talcums of similar to the operation described in 3B above, being sprayed in Glatt GPCG 1, coat weight is 20%.

4D：(TPR is coated nifedipine TPR pearls：Ratio is 45/40/10/5 EudragitRL/Eudragit L/TEC/ talcums)

The nifedipine IR pearls (700g) prepared as described in 3B above are carried out as follows coating：According to similar to the operation described in 2A above, 45/40/10/5 solution of spraying Eudragit RL/EudragitL/TEC/ talcums in Glatt GPCG 1, coat weight is 20%, is then dried 10 minutes at 40 DEG C in Glatt, removes excessive residual solvent.The use of HPLC evaluation of methodology coat weight is 15% It is distributed with the efficiency and insoluble drug release of 20% TPR pearls.

The insoluble drug release distribution of

embodiment

3 and 4

Fig. 7 shows that TPR is coated the influence that composition discharges to nifedipine from the TPR pearls of embodiment 4.The content of enteric polymer (Eudragit L) increases the rate of release of nifedipine during increase TPR is coated.Fig. 8 shows the influence that nifedipine carrying capacity discharges to nifedipine from the TPR pearls of embodiment 3.Nifedipine carrying capacity increases to 10% from 5% reduces the rate of release of nifedipine.Fig. 9 is shown is coated the influence of granularity in the case of composition and coat weight identical to medicine release from embodiment 3B and 4D TPR pearls (be respectively 25-30 mesh or 600-700 μm and 60-80 mesh or 170-250 μm) in TPR.Less embodiment 4D pearl shows faster nifedipine release.

Embodiment 5

5A：Model drug IR pearls (medicine carrying capacity is 10%)

By PVP (PVP K29/32,128.2g) it is added slowly in 95% ethanol/acetone/water that ratio is 72.5/22.5/5, content is 6% solid, while being stirred vigorously until dissolving, is then slowly added into the alkalescent analog (128.2g) of Lamotrigine until dissolving.Glat GPCG 3 are filled with 1000g 25-30 mesh sugar ball (Chris Hansen), and the Glatt GPCG 3 are equipped with the pillar height Wurster inserts of 6 " bottom sprays/8 ", 20mm distribution gaps, air distribution plate D (200 mesh sieve), 1.0mm nozzle bores, 1.0 bar atomization air pressures and 14mm single heads pipe (single-head tubing).Sugar ball is coated with the spray rate of 8mL/ minutes with drug solution, export the breeze door piece is 28-30% (air velocitys：3.6-4.2m/s；Pressure：10.5-8Pa), while maintaining product temperature at about 32.5-33.5 DEG C.Layer is covered with the pearl of medicine and then is coated with Pharmacoat 603 protective seal and is coated, and coat weight is 2%, is then dried about 10 minutes in Glatt equipment, removes residual solvent/moisture.Then the pearl being coated is sieved by 20-30 mesh sieves.

5B：(TPR is coated model drug TPR pearls：Ratio is 50/35/15 EC-10/HP-55/TEC)

The IR pearls (1000g) prepared as described in 4A above are carried out as follows coating：Solution (7400/822.2 of the EC-10/HP-55/TEC that spraying ratio is 50/35/15 in the acetone/water that ratio is 90/10；7.5% solid), coat weight at most about 40% weight (being sampled when coating level is about 20%, 25%, 30% and 35%).EC-10 (ethyl cellulose, Ethocel Premium 10cps, derived from DowChemicals, 333.3g) is added slowly in the acetone/water that ratio is 90/10, be no less than 30 minutes while continuing to stir, until dissolving.Then HP-55 (hydroxypropyl methyl cellulose, derived from Shin Etsu, 233.3g) and TEC (100g) are added in EC-10 solution, until dissolving.TPR Coating Solutions are coated with Glatt GPCG 3, the Glatt GPCG 3 are equipped with the pillar height Wurster inserts of 6 " bottom sprays/8 ", 20mm Distribution gap, air distribution plate D (200 mesh sieve), 0.8mm nozzle bores, 1.0 bar atomization air pressures, 14mm single heads pipe and the special filter bags of PB3%.TPR Coating Solutions were sprayed on IR pearls with the spray rate of 10-15mL/ minutes, export the breeze door piece is about 28% (air velocity：3.4-3.8m/s；Pressure：7-7.5Pa), while maintaining product temperature at about 32-34 DEG C, excessive residual solvent was then removed with mutually synthermal drying 10 minutes in Glatt.Dry pearl is sieved, removes the pearl (if formation) of any dimerization.

5C：Model drug TPR pearls (are coated：Ratio is 35/50/15 EC-10/HP-55/TEC)

According to the operation similar with being described above, the IR pearls (1000g) prepared as described in 5A above are coated with 35/50/15 EC-10/HP-55/TEC TPR Coating Solutions, coat weight is 20%, 25%, 30%, 35% and 40%.

5D：Model drug TPR pearls (are coated：Ratio is 60/25/15 EC-10/HP-55/TEC)

According to the operation similar with being described above, the IR pearls (1000g) prepared as described in 4A above are coated with 60/25/15 EC-10/HP-55/TEC TPR Coating Solutions, coat weight is 5%, 10%, 15% and 20%.

Figure 10, which is shown, is coated the influence that composition and/or coating level discharge to medicine from the TPR pearls with identical medicine carrying capacity of embodiment 5.The speed that the content of enteric polymer increases to 50% weight from 25% weight and causes medicine to be discharged from TPR pearls during TPR is coated is dramatically increased.

Embodiment 6

6A：Nifedipine IR pearls (fumaric acid of nifedipine/VA 64/)

Nifedipine IR pearls prepare as follows：Using with similar operation described above, ratio is layed onto in 25-30 mesh sugar balls for 1/2/1 solution layer of the fumaric acid of nifedipine/VA 64/ in ethanol/acetone/water in Glatt GPCG3, nominal nifedipine carrying capacity is 10% weight.

6B：Nifedipine IR pearls (are coated：Eudragit RL/L/TEC/ talcums)

Use the operation similar with being described above, it is coated with 35/50/10/5 Eudragit RL/Eudragit L/TEC/ talcums TPR and the IR pearls (700g) prepared as described in 6A above is coated, coat weight is at most 30% (being sampled when coating level is 10%, 15%, 20% and 25%).It is distributed using HPLC evaluation of methodology coat weight for the efficiency and insoluble drug release of 15% and 20% TPR pearls.

6C：Nifedipine TPR pearls (dual coating)

In fluidized-bed coating machine (fluid bed coater) is GPCG 1, the IR pearls (700g) prepared as described in 6A above are coated with the inside enteric coatings comprising 85/10/5EudragitL/TEC/ talcums, coat weight is 10%.Eudragit L100 are added slowly in ethanol, are stirred vigorously until dissolving (about 90 minutes).Then TEC (triethyl citrate) is added slowly in solution until dissolving, then The talcum of suspension is added under continuous stirring.Then these enteric coatings pearl ratios are coated for the TPR layers of 35/50/10/5 Eudragit RL/Eudragit L/TEC/ talcums, and coat weight is at most 30% (being sampled when coating level is 10%, 15%, 20% and 25%).Carry out applying layers using with similar operation described above and treatment conditions.It is distributed using HPLC evaluation of methodology TPR coat weights for the efficiency and insoluble drug release of 15% and 20% TPR pearls.

Embodiment 7

7A：Nifedipine IR pearls (aspartic acids of nifedipine/VA 64/)

Nifedipine IR pearls prepare as follows：Use the operation similar with being described above, the solution of aspartic acids of nifedipine/VA 64/ that ratio is 1/2/1 in ethanol/acetone/water that ratio is 72.5/22.5/5 is coated onto 25-30 mesh sugar balls in Glatt GPCG3, the nominal nifedipine carrying capacity for 10% weight is obtained.Because aspartic acid is insoluble in Coating Solution, it is homogenized in coating solvent using Ultraturrex homogenizers, is then added in nifedipine and Kollidon VA 64 solution and further homogenizes.

7B：Nifedipine TPR pearls (are coated：Ratio is 35/50/15 RL/L-55/TEC)

Use the operation similar with being described above, the nifedipine IR pearls (700g) prepared as described in 7A above are coated for 35/50/10/5 EudragitRL/Eudragit L/TEC/ talcums with ratio, coat weight is at most 30% (being sampled when coating level is 10%, 15%, 20% and 25%).It is distributed using HPLC evaluation of methodology coat weight for the efficiency and insoluble drug release of 15% and 20% TPR pearls.

Embodiment 8

8A：Lercanidipine hydrochloride IR pearls (tartaric acid of Lercanidipine/VA 64/)

Lercanidipine hydrochloride (93g) is added slowly in ethanol (4808g), stirring is until dissolving.Then Kollidon VA 64 (186g) and tartaric acid (21g) are successively slowly added to until dissolving.Glatt GPCG 1 are filled with 2100g 30-35 mesh sugar balls (2322g), and the Glatt GPCG 1 are equipped with 6 " bottom spray pillar height Wurster inserts, 200mm distribution gaps, air distribution plate C (50 mesh sieve), 0.8mm nozzle bores and 1.5 atomization air pressures.Sugar ball is coated with the tartaric acid Coating Solutions of Lercanidipine/VA 64/, and its method is as follows：Sprayed with the spray rate of 11g/ minutes, export the breeze door piece is 45-50% (air velocitys：90-105m³/ hour), while maintaining product temperature at about 32-34 DEG C.The pearl that Lercanidipine is covered with to layer with Opadry Clear protective seal coating is coated, and coat weight is 2%, is then dried about 15 minutes at 45 DEG C in Glatt equipment, removes residual solvent/moisture, is then sieved by 25 mesh sieves.

8B：Lercanidipine TPR pearls (are coated：The EC-10/HP-55/DEP that ratio is 1: 4: 1)

The Lercanidipine hydrochloride IR pearls (930g) prepared as described in 8A above are carried out as follows coating：Use the operation similar with being described above; solution of the EC-10/HP-55/DEP for being 1/4/1 with ratio in Glatt fluidization granulators (fluid granulator) in the acetone/water that ratio is 98/2 is sprayed to the IR pearls, and coat weight is 27%.The composition that gained TPR is coated is 16.4%EC-10,65.6%HP-55 and 18%DEP (diethyl phthalate).

8C：Lercanidipine TPR pearls (double-layer coatings)

Eudragit L100 are added slowly in ethanol, are stirred vigorously until dissolving (about 90 minutes).Then TEC (triethyl citrate) is added slowly in solution, until dissolving, the talcum of suspension then be added under continuous stirring.Then the inside enteric coatings of the 74.1/7.4/18.5 Eudragit L100/TEC/ talcums prepared as described above are applied on the IR pearls prepared as described in 8A above, coat weight is at most 20%.Then the operation similar with described in 8B above is used, obtained enteric coatings IR pearls are coated with 16.4/65.6/18 EC-10/HP-55/DEP TPR Coating Solutions, coat weight is 10%.

8D：Lercanidipine TPR pearls (three layers of coating)

Using the operation similar with being described above, 80/20HP-55/DEP inside enteric coatings are applied on the IR pearls prepared as described in 8A above, coat weight is 20%.Then according to the operation similar with being described above, enteric coatings pearl is coated with 16.4/65.6/18 EC-10/HP-55/DEP TPR Coating Solutions, coat weight is 25%.Then use and be coated with similar operation described above, the outer enteric coatings for the Eudragit S100/TEC/ talcums for being further 74.1/7.4/18.5 with ratio by these pearls.The outer enteric coatings are prepared as follows：Eudragit S100 are added slowly in ethanol, while being stirred vigorously until dissolving (about 90 minutes).Then TEC (triethyl citrate) is added slowly in Eudragit S100, until dissolving, the talcum of suspension then be added under continuous stirring.Using dual stage process (then test is tested for 2 hours in the case where pH is 6.8 i.e. first in 0.1N HCl and 0.3% Tween 80), the insoluble drug release distribution to embodiment 8B, 8C and 8D TPR pearls carries out dissolution test.The result of dissolution test is shown in Figure 11.

Embodiment 9

9A：Nifedipine IR pearls (tartaric acid of nifedipine/VA 64/)

Nifedipine IR pearls prepare as follows：Ratio is layed onto in the solid sugar balls of 25-30 for 1/2/1 solution layer of the tartaric acid of nifedipine/VA 64/ in ethanol/acetone/water in Glat GPCG 3, nominal nifedipine carrying capacity is 10% weight.

9B：Nifedipine TPR pearls (are coated：Ratio is 35/50/15 RL/L-55/TEC)

The nifedipine IR pearls (1000g) prepared as described in 9A above are carried out as follows coating：Use the operation similar with being described above; it is coated in Glatt fluidization granulators with ratio for 35/50/15 EudragitRL/Eudragit L/TEC, coat weight is at most 30% (being sampled when coating level is 10%, 15%, 20% and 25%).

Embodiment 10

10A：IR pearls (medicine carrying capacity is 16.67%)

PVP (PVP K29/32,666.7g) is added slowly in the ethanol/acetone that ratio is 16.6/83.4, while being stirred vigorously until dissolving.Iloperidone (333.3g) is slowly added to until dissolving.Then the operation similar with being described above is used, 25-30 mesh sugar ball (1000g) is coated with drug solution (8.17% solid) in Glatt GPCG 3.The pearl that medicine is covered with to layer with Pharmacoat 603 protective seal coating is coated, and coat weight is 2%.IR pearls are dried about 10 minutes in a device, removes residual solvent/moisture, is then sieved, remove the pearl (if formation) of dimerization.

10B：TPR pearls (dual coating：The EC-10/HP-55/TEC that ratio is 45/40/15 is on HP-55/TEC)

The IR pearls (1800g) prepared as described in 10A above are coated by enteric coatings solution in the acetone/water that ratio is 95/5 of HP-55/TEC that spraying ratio is 80/20, coat weight is 8%.Then use and similar operation described above, TPR Coating Solutions (7.5% solid) of the EC-10/HP-55/TEC for being 45/40/15 with ratio in Glatt GPCG 3 in the acetone/water mixture that ratio is 90/10 is coated to enteric coatings pearl (850g), coat weight is at most 50% (being sampled when coating level is 20%, 30% and 40%), then dried 10 minutes at about 50 DEG C in Glat, remove excessive residual solvent, then sieved, remove the pearl (if formation) of any dimerization.

10C：TPR pearls (dual coating：The EC-10/HP-55/TEC that ratio is 30/55/15 is on HP-55/TEC)

The enteric coatings pearl (530g) prepared as described in 10B above is carried out as follows coating：Use the operation similar with being described above, TPR Coating Solutions (7.5% solid) of the EC-10/HP-55/TEC that ratio of being sprayed in Glatt GPCG 3 is 30/55/15 in the acetone/water that ratio is 90/10, coat weight is at most 50% (being sampled when coating level is 20%, 30% and 40%).It is shown in from the representative drugs release profile in the TPR pearls being coated with two kinds of difference TPR components/levels in Figure 12.

Claims

1. a kind of pharmaceutical composition, it includes time-controlled release pearl, wherein the time-controlled release pearl includes：

Solid dispersions of at least one active pharmaceutical ingredient at least one solubilized polymer；And

Time-controlled release is coated, and the time-controlled release, which is coated, includes insoluble polymer and enteric polymer；

Wherein described active pharmaceutical ingredient is selected from nifedipine or hydrochloride Lercanidipine；

Wherein described solubilized polymer is selected from polyvinylpyrrolidone, copolymer, hydroxypropyl methyl cellulose, polyethylene glycol oxide, polyethylene glycol and the cyclodextrin of vinyl acetate/ethylene base pyrrolidones；

Wherein described insoluble polymer is selected from the polymer or copolymer, the polymer of polyvinyl acetate or copolymer, cellulose acetate, cellulose acetate-butyrate, ethyl cellulose, the neutral copolymer based on ethyl acrylate and methyl methacrylate and their mixture with quaternary amines of methacrylate；

Wherein described enteric polymer is selected from the sensitive EUDRAGIT L100s and Hydroxypropyl Methylcellulose Phathalate of pH；

Insoluble polymer and the part by weight of enteric polymer are 9: 1 to 1: 9 during wherein described time-controlled release is coated；

The part by weight of wherein described active pharmaceutical ingredient and the solubilized polymer is 6: 1 to 1: 9.

2. the pharmaceutical composition of claim 1, wherein the composition lasts the plasma concentration for providing the therapeutically effective active pharmaceutical ingredient at least 18 hours.

3. the pharmaceutical composition of claim 1, wherein the time-controlled release is coated the triethyl citrate for also including 3% weight to 30% weight compared with the gross weight that the time-controlled release is coated.

4. the pharmaceutical composition of claim 1, wherein the solid dispersions of the active pharmaceutical ingredient and solubilized polymer are coated in inert core.

5. the pharmaceutical composition of claim 4, wherein the solid dispersions also include pharmaceutically acceptable organic acid, the organic acid is selected from fumaric acid, aspartic acid and tartaric acid.

6. the ratio by mass of the pharmaceutical composition of claim 5, wherein organic acid and active pharmaceutical ingredient is calculated as 4/1 to 1/9.

7. the pharmaceutical composition of claim 4, wherein the time-controlled release pearl includes the release pearl immediately for being coated and being coated with time-controlled release；And

The pearl of release immediately includes the inert core being coated with the solid dispersions.

8. the pharmaceutical composition of claim 7, wherein the time-controlled release pearl is also comprising the enteric coatings being coated on the solid dispersions；

The enteric coatings account at most the 40% of the time-controlled release pearl gross weight；And

The time-controlled release pearl provides the lag time of 1-4 hours.

9. the pharmaceutical composition of claim 7, wherein the time-controlled release pearl is also comprising the enteric coatings being coated in the time-controlled release coating；

The time-controlled release pearl provides the lag time of at most 4 hours.

10. the pharmaceutical composition of claim 7, wherein the time-controlled release pearl is also comprising the first enteric coatings being coated on the solid dispersions；With

It is coated on the second enteric coatings that the time-controlled release is coated；

Wherein described first and second enteric coatings each account at most the 40% of the time-controlled release pearl gross weight；And

The time-controlled release pearl provides the lag time of at most 4 hours.

11. the pharmaceutical composition of claim 7, it includes the combination of release pearl and time-controlled release pearl immediately, wherein the part by weight of release pearl and time-controlled release pearl is 1: 9 to 5: 5 immediately.

12. the pharmaceutical composition of claim 1, wherein the composition is the Orally disintegrating tablet comprising time-controlled release pearl and Fast Stripping particulate；

The particle mean size of wherein described time-controlled release pearl and Fast Stripping particulate is no more than 400 μm；

Particle of the Fast Stripping particulate comprising at least one disintegrant and sugar alcohol and/or sugar, the particle mean size of the particle is no more than 30 μm.

13. the pharmaceutical composition of claim 7, it is comprising time-controlled release pearl, Fast Stripping particulate and discharges pearl immediately, wherein the part by weight of release pearl and time-controlled release pearl is 10: 90 to 50: 50 immediately.

14. the pharmaceutical composition of claim 13, wherein the pearl of release immediately also includes the taste mask layer being coated on the solid dispersions；And

Wherein described taste mask layer includes insoluble polymer, or the taste mask layer includes insoluble polymer and water-soluble or gastric solubility pore former.

15. the pharmaceutical composition of claim 13, wherein

The pearl of release immediately is also coated comprising sealing, and the sealing is coated comprising the hydroxypropyl methylcellulose being coated on the solid dispersions；

The solubilized polymer is selected from the copolymer and polyvinylpyrrolidone of vinylpyrrolidone/vinyl acetate；

The time-controlled release is coated the copolymer of the sensitive methacrylic acid-methyl methacrylate of copolymer and pH comprising medicinal methacrylate/methyl methacrylate, and the part by weight of described two copolymers is 9: 1 to 1: 9；

The weight that the time-controlled release is coated accounts at most the 50% of the time-controlled release pearl weight.

16. preparing the method for the pharmaceutical composition of claim 1, methods described includes：

The active pharmaceutical ingredient and enough solubilized polymer are dissolved in medicinal solvent；

The medicinal solvent is removed from the solution of active pharmaceutical ingredient and solubilized polymer, the particle of solid dispersions is consequently formed, the solid dispersions include the active pharmaceutical ingredient and solubilized polymer disperseed with molecular forms；

Insoluble polymer and enteric polymer are dissolved in medical coating solvent, time-controlled release Coating Solution is consequently formed；

The particle of solid dispersions is coated with the time-controlled release Coating Solution；

The coating solvent is removed, time-controlled release pearl is consequently formed, the time-controlled release pearl is included in the time-controlled release formed on the particle of solid dispersions and is coated；

Wherein described enteric polymer is selected from the sensitive EUDRAGIT L100s and Hydroxypropyl Methylcellulose Phathalate of pH.

17. the method for claim 16, wherein the solution of active pharmaceutical ingredient and solubilized polymer is coated onto inert core, then forms the solid dispersion particles by removing the medicinal solvent, is consequently formed and discharges pearl immediately；

The pearl of release immediately is coated with the time-controlled release Coating Solution, time-controlled release pearl is consequently formed.

18. the method for claim 17, methods described also includes：

At least one disintegrant is pelletized together with least one sugar alcohol and/or at least one sugar, Fast Stripping particulate is consequently formed；

The time-controlled release pearl is mixed with the Fast Stripping particulate；

The mixture is suppressed, Orally disintegrating tablet is consequently formed.

19. the method for claim 17, methods described also includes：

To the time-controlled release pearl, release pearl and the Fast Stripping particulate are mixed immediately；

The mixture is suppressed, Orally disintegrating tablet is consequently formed.