CN105287434A

CN105287434A - Ethanol influence-resistant controlled-release medicine composition adopting coating containing neutral vinyl polymers and excipients

Info

Publication number: CN105287434A
Application number: CN201510876092.4A
Authority: CN
Inventors: H·巴尔; T·弗尔斯特; G·雷恩纳; M·古特沙尔克
Original assignee: Evonik Roehm GmbH
Current assignee: Roehm GmbH Darmstadt
Priority date: 2009-03-18
Filing date: 2009-03-18
Publication date: 2016-02-03

Abstract

The invention relates to a controlled-release medicine composition which comprises a core containing medicine active ingredients, wherein the core is coated with a coating layer with ethanol resistance, and the coating layer with ethanol resistance has the effect of endowing the medicine active ingredients with release characteristic ethanol influence resistance. The coating layer with ethanol resistance contains a mixture of at 70wt% of a polymer part (a) and an excipient part (b), wherein the polymer part (a) is composed of water-insoluble and basically-neutral vinyl polymers or vinyl copolymers; the excipient part (b) is composed of the following excipients: 100-250wt% of non-porous inert lubricant (b1), 1-35wt% of cellulose compound (b2), 0.1-25wt% of emulsifying agent (b3), and 0.1-30wt% of added plasticizer (b4) or 0.1-30wt% of plasticizer (b4) capable of replacing the (b3); and the excipients of the excipient part (b) are respectively calculated based on the dry weight of the polymer part (a).

Description

Adopt the controlled release pharmaceutical compositions with resistance to influence of ethanol of the coating containing neutral vinyl polymers and excipient

The divisional application of the Chinese patent application 200980158104.2 that to be denomination of invention be the application " adopting the controlled release pharmaceutical compositions with resistance to influence of ethanol of the coating containing neutral vinyl polymers and excipient ".

Invention field

The present invention relates to the controlled release pharmaceutical compositions field with resistance to influence of ethanol.

Technical background

The abuse that US2003/0118641A1 describes for reducing the oral pharmaceutical form comprising extractible opioid misapplies possible method.In the method, should hinder especially and be extracted by the reactive compound of conventional domestic solvent means, described solvent is as the 0.01HCl in the alcohol of isopropyl alcohol, Little water., Fructus Vins wine vinegar, hot water or peroxide, dilution.Advise reactive compound and substrate-formation polymer and ion exchange material such as styrene-divinylbenzene polymer formulation with micronised form.Described ion exchange material is the key improving the function hindering reactive compound to extract.Described substrate-formation polymer is obviously used as the texturizing agent of medicated core.A queue of possible material by clearly for substrate-formation polymer, especially also comprises polymethacrylate.Preferred substrate-forming agent is C ₁-C ₆-hydroxy alkyl cellulose.

US2004/0052731A1 describes medicament forms, is particularly suitable for OPIOIDS reactive compound, and its abuse misuse that should reduce as the improper result used may.Lipophilic active chemical variants and water insoluble additive combine by suggestion, such as fatty acid or crosslinked water-soluble polysaccharides.

US2005/0163856A1 describes and had by the method for the patient of pain, described medicament forms to reduce as dissolving in a solvent and the abuse misuse possibility of the improper result used afterwards with the medicament forms treatment containing oxycodone.In this respect, described reactive compound should be by the substrate being selected from lower group-formation polymer formulation: hydroxypropyl-cellulose, hydroxypropyl emthylcellulose or hydroxyethyl-cellulose.

WO2006/094083A1 describes the medicament forms with controlled release venlafaxine (venlafaxine) characteristic.In order to be decreased through the abuse misuse possibility of adding ethanol, described reactive compound is integrated into the substrate of the cross linked polymer (such as xanthan gum) of gelation.Hydrophobic polymer can be added further as additive, especially polymethacrylates.

WO1994/022431A1 describes the oral drug preparation for the morphine containing treatment effective dose used.It is made up of the granule of at least 50 particle diameters respectively had in 0.7 to 1.4mm scope.Each granule has the core of the morphine salt including barrier layer coating.Described barrier layer comprises the water-msoluble ingredients that at least one is selected from lower group: ethyl cellulose, by the copolymer of the Lipase absobed of acrylic or methacrylic acid and native paraffin, and plasticizer, by substantially irrelevant with the pH of 1.0 to 7.0 scopes coating barrier layer in order to provide drug release.The morphine serum concentrations obtained at least 12 hours after the single dose using described preparation is at least 50% of maximum serum-concentration.

US2007/053698 discloses the method that sustained release uses opioid, described opioid includes but not limited to hydromorphone (hydromorphone) and oxycodone (oxycodone), the method with regard to the common digestion of aqueous alcohol with regard to present the character of improvement.

Problem andsolution

So that the pharmaceutical composition of the patten's design release of active ingredients of release characteristic can be reappeared.This should cause can wishing and reliable blood level feature, and it should provide best therapeutic effect.If blood levels is too low, described active component does not cause enough therapeutic effect.If blood levels is too high, this can cause poisonous effect.In both of these case, the non-optimal blood levels of active component may be dangerous and therefore should be avoided for patient.Problems existing is, the ideal ratio supposed for the release of active component during designer drug compositions can by patient and ethanol or containing the relevant general living habit of the beverage of ethanol, unconscious or be changed by addictive behavior.In these cases, the described medicament forms being in fact only water-bearing media design is exposed to the strong or weak medium containing ethanol extraly.Since much more more and more healthy authoritative institution such as theFoodandDrugAdministration (FDA) pays close attention to alcohol problems, in the near future resistance to alcohol repellency may be important registration requirement.

Since not all patient know take in simultaneously controlled release drug form and containing the beverage of ethanol risk or do not follow and maybe can not follow suitable warning, sincere advice or suggestion, task is that design controlled release pharmaceutical compositions is to make their binding mode as small as possible by the impact that ethanol exists.

Or coating or the standard pharmaceutical composition usually not resistance to ethanol without coating.Problem of the present invention is to provide the controlled release pharmaceutical compositions of the impact of resistance to ethanol.The means adopted should be general for existing controlled release pharmaceutical compositions and be enforceable and not their optimized release characteristic of material alterations.The means adopted should be also general and enforceable for the design of new controlled release pharmaceutical compositions and be applicable to the active constituents of medicine of wide region.

Described problem and theme are solved by following controlled release pharmaceutical compositions, and described controlled release pharmaceutical compositions comprises:

Core containing (one or more) active constituents of medicine,

Wherein said core is endowed resistance to alcohol repellency coatings coating, described coatings has the effect of following release characteristic of giving active constituents of medicine, described release characteristic be added with 40% (v/v) ethanol according in the buffer medium of USP in pH1.2 and/or the impact of resistance to ethanol under the conditions in vitro of pH6.8.

Wherein the impact of resistance to ethanol represents with compared with release characteristics determined in the same media of ethanol, and under the impact of the medium containing 40% ethanol, release characteristics accelerates be no more than 20% and delay to be no more than 20%.

Wherein give polymer moieties that resistance to alcohol repellency coatings comprises at least 70 % by weight a) with excipient part b) mixture, wherein

Described polymer moieties a) is made up of water-insoluble, basic neutral polyvinyl or ethylenic copolymer,

And excipient part b) be made up of following excipient:

B1) the non-cellular inert lubricant of 100 to 250 % by weight,

B2) cellulosic cpd of 1 to 35 % by weight,

B3) emulsifying agent of 0.1 to 25 % by weight is with additional or alternative in b3),

B4) plasticizer of 0.1 to 30 % by weight,

Wherein excipient part b) excipient calculate based on polymer moieties dry weight a) respectively.

From there is given activity composition and wishing the given core of release characteristic, technical staff can use described polymer moieties a) and excipient part b) component regulate in the medium with ethanol between the balance accelerated and delay with make have ethanol and without the medium of ethanol in as much as possible close to desired release characteristic.As further adjustment means, technical staff can also apply the thickness giving resistance to alcohol repellency coatings.

Pharmaceutical composition

Term pharmaceutical composition according to the present invention should make broad understanding.This term comprises the high-level pharmaceutical composition that needs to tackle the examination & approval of healthy authoritative institution and has lower approval requirements or do not need to have the pharmaceutical composition of specific examination & approval, such as so-called medical treatment device or dietetic product.

Controlled release pharmaceutical compositions

Controlled release pharmaceutical compositions represents that comprising the acceptable film with pharmacy forms polymer and the optionally pharmaceutical composition of the active pharmaceutical ingredient of acceptable excipient with pharmacy, the wherein reproducible release characteristic of pharmaceutical composition display pH dependency or non-TCP friendly flow.The example of controlled release pharmaceutical compositions is the pharmaceutical composition, enteric coating pharmaceutical composition, the pharmaceutical composition of pulse release or the pharmaceutical composition of sustained release that at once discharge.

Active constituents of medicine dissolubility classification in water or in ethanol

The present invention relates to and classify according in this USP pharmacopeia reference table active constituents of medicine quoted dissolubility in water or in ethanol:

Classification	Solvent part (between 15 DEG C and 25 DEG C) that a solute needs
		Fairly soluble	Be less than 1
Yi Rong's	1 to 10
		Solvable	More than 10 to 30
Slightly molten	More than 30 to 100
		Sl. sol.	More than 100 to 1000
Very slightly soluble	More than 1000 to 10000
		Insoluble in fact	More than 10000

Example:

Sl. sol. active constituents of medicine is categorized as according to the dissolubility that controlled release pharmaceutical compositions of the present invention is used in ethanol, as opioid, such as morphine sulfate, or OPIOIDS antagonist, such as naloxone.Dissolubility in its water is preferably categorized as solvable.

Slightly molten active constituents of medicine is categorized as, as diltiazem according to the dissolubility that controlled release pharmaceutical compositions of the present invention is used in ethanol (diltiazem), metoprolol or theophylline.Dissolubility in its water in this case can easily molten to sl. sol. scope.

Be used for dissolubility in ethanol according to controlled release pharmaceutical compositions of the present invention and be categorized as insoluble in fact active constituents of medicine, as mesalazine (mesalazine).Dissolubility in its water is very slightly soluble in this case but can solvable to very slightly soluble scope.

Active substance

Any active substance is suitable in theory according to multilayer dosage forms of the present invention.Information about conventional pharmaceutical goods can find in handbook is as GermanRedList or MerckIndex.

The medicine used within the scope of the invention be intended in human or animal's body surface or body with

1. cure, alleviate, prevent or detect disease, disease, somatic damage or sufferer;

2. identify disease, condition or function or the mental status;

3. substitute the active substance or the body fluid that originate in human body or animal body;

4. avoid, eliminate or in and pathogen, parasite or allogenic material; Or

5. affect disease, condition or function or the mental status.

Be applicable to according to preparaton of the present invention, in principle, preferably can as many bead dosage form, the tablet comprising pill, micro-tablet, capsule, wafer, effervescent tablet or for any active pharmaceutical substance of the composition of the dry powder doses of oral suspension or bioactive substance for using.

Treatment classification

These pharmaceutically active substances can belong to the classification of one or more active substances, as weight reduction agent (appetite suppressant, anoretic), antacid (anti-acidosisagents), analeptic (antihypoxic), analgesic (antirheumatic), vermifuge, antiallergic agent, anti-anemic drug, anti-arrhythmic agents, antibiotics (anti-infective), anti-dementia drug (nootropics), antidiabetic drug, antidote, Bendectin (vertigo reagent), antuepileptic, antihemorrhagic reagent (antifibrinolytics and other hemorrhage), antihypertensive, hypoglycemia medicament, hypotension medicament, anticoagulation, antifungal agent, antiparasitic agents, anti-inflammatory agent, antitussive (expectorant), arteriosclerosis agent, balneation agent and thermotherapeutic agent, receptor blocking agent, calcium channel blocker and renin angiotensin-aldosterone system inhibitor, bronchus medicine (antiasthmatics), choleretic and biliary tract therapeutic agent, cholinergic drug, adrenocortical hormones, dermatologic medicine, disinfectant (antimicrobial drug), diet agent (nutrient), the medicament of diagnostic agent and preparation diagnosis, diuretic, the medicament of blood circulation promoting, withdrawal agent (being used for the treatment of the medicament of addiction), enzyme inhibitor, for the preparation of enzyme defect, transport protein, cellosolve, senile disease medicine, gout preparation, flu and influenza medicine and C&S's medicine, gynecological drug, piles medicine (rectum medicine), liver medicine, hypnotic (tranquilizer), hypophysis hormones, hypothalamic hormone class and other modulability peptide and inhibitor thereof, immunomodulator, infusion and standard liquid injection, organ perfusion liquid, heart medicine, caries preventive agent, periodontosis medicine and other dental formulations, arteria coronaria preparation, laxative, lipid lowerers, local anesthetic (Neurotherapeutic agent), gastrointestinal drug, migraine remedy, mineral preparations, oral and throat medicine, muscle relaxant, anesthetics, neuropathy preparation and other neurotropic drug, medicament for the eyes, osteoporosis agent (calcium-and bone metabolism regulator), otology medicament, anti-Parkinson medicament and other medicine for extrapyramidal tract obstacle, antipsychotic drugs, nose section medicine (hole medicament), antasthenic (tonic), thyradin, serum, immunoglobulin and vaccine, sex hormones and inhibitor thereof, spasmolytic (anticholinergic), anticoagulant, tuberculosis medicine, mood change medicament, urinary system medicine, for the medicament of disorder of vein, vitamins, wound and treating acne agent, cytostatic agent and other anti-tumor agents and protective agent, biomaterial, medicine synthetics.

Active substance

The example of suitable activity material comprises 5-aminosalicylic acid (salicylicacid), Abacavir (abacavir), abarelix (abarelix), Orencia (abatacept), Acamprosate (acamprosate), acarbose (acarbose), Aceclofenac (aceclofenac), acetylsalicylic acid, Acitretin (acitretin), Aclarubicin (aclarubicin), D actinomycin D (actinomycin), ACV (acyclovir), adalimumab (adalimumab), adefovirdipivoxil (adefovir), adefovir dipivoxil (adefovirdipivoxil), adenosine, adenosylmethionine (adenosylmethionine), adrenaline, adriamycin (adriacin), alpha-galactosidase, β-A Jiaxi enzyme, Aldesleukin (aldesleukin), Amevive (alefacept), A Lun pearl monoclonal antibody (alemtuzumab), Alendronate (alendronate), Alfacalcidol (alfacalcidol), Alfuzosin (alfuzosin), Ah's glucosidase α (alglucosidasealfa), aliskiren (aliskiren), alitretinoin (alitretinoin), Allopurinol (allopurinol), almotriptan (almotriptan), Alosetron (alosetron), Amevive (alefacept), alprazolam (alprazolam), Alprostadil (alprostadil), amantadine (amantadine), ambrisentan (ambrisentan), ambroxol (ambroxol), Amifostine (amifostin), amiodarone (amiodarone), Amisulpride (amisulpride), amitriptyline (amitriptyline), Amlodipine (amlodipine), Amoxicillin (amoxicillin), amphotericin B (amphotericinB), APV (amprenavir), anagrelide (anagrelide), anakinra (anakinra), Anastrozole (anastrozole), male sex hormone, thiamines (thiamin, aneurin), anidulafungin (anidulafungin), apomorphine (apomorphine), aprepitant (aprepitant), Aprotinin (aprotinin), argatroban (argatroban), Aripiprazole (aripiprazole), arsenic trioxide, Artemether (artemether), ascorbic acid,Atazanavir (atazanavir), atenolol (atenolol), atomoxetine (atomoxetine), Atorvastatin (atorvastatin), Atosiban (atosiban), axerophthol, imuran (azathioprine), azelaic acid, azithromycin (azithromycin), AZT (aztreonam), Balsalazide (balsalazide), barbituric acid derivatives, basiliximab (basiliximab), beclapermin, beclomethasone (beclometasone), bemiparin, benazepil (benazepril), Benidipine (benidipine), Benzodiazepine, Betahistine (betahistin), betamethasone (betamethasone), Avastin (bevacizumab), bexarotene (bexarotene), Bezafibrate (bezafibrate), Bicalutamide (bicalutamide), bimatoprost (bimatoprost), biotin, bisoprolol (bisoprolol), bivalirudin (bivalirudin), bortezomib (bortezomib), Bosentan (bosentan), botulinum toxin (botulinumtoxin), Brimonidine (brimonidine), brinzolamide (brinzolamide), Bucillamine (bucillamine), budesonide (budesonide), budipine (budipine), bufexamac (bufexamac), bumetanide (bumetanide), buprenorphine (buprenorphine), Bupropion (bupropion), butizine, calcitonin (calcitonin), calcium, calcium antagonist, Candesartan (candesartan), capecitabine (capecitabine), captopril (captopril), carbamazepine (carbamazepine), carbetocin (carbetocin), carbidopa (carbidopa), carboplatin (carboplatin), card glutamic acid (carglumicacid), Carvedilol (carvedilol), Caspofungin (caspofungin), Cefaclor (cefaclor), cefadroxil (cefadroxil), cefalexin (cefalexin), cynnematin (cephalosporin), Cefdinir (cefdinir), Cefditoren (cefditoren), Cefepime (cefepime), Cefixime (cefixime),Cefotiam (cefotiam), Cefozopran (cefozopran), Cefprozil (cefprozil), ceftriaxone (ceftriaxon), cefuroxime (cefuroxime), celecoxib (celecoxib), cepecitabine, cerivastatin (cerivastatin), cetirizine (cetirizine), Cetrorelix (cetrorelix), Cetuximab (cetuximab), cevimeline (cevimeline), chenodeoxycholic acid (chenodeoxycholicacid), chorionic gonadotrophin (choriogonadotropin), ciclesonide (ciclesonide), ring born of the same parents' elements (cyclosporine), cidofovir (cidofovir), cilastatin (cilastatin), Cilostazol (cilostazol), Cimetidine (cimetidine), CNC (cinacalcet), Ciprofloxacin (ciprofloxacin), cis-platinum (cisplatin), Citalopram (citalopram), Cladribine (cladribine), CLA (clarithromycin), clavulanic acid (clavulanicacid), clindamycin (clindamycin), clobetasol (clobetasol), clobutinol (clobutinol), clofarabine (clofarabine), clonidine (clonidine), clopidogrel (clopidogrel), cobalamin, codeine (codeine), caffeine (caffeine), colesevelam (colesevelam), Cholestyramine (cholestyramine), SMZco (cotrimoxazole), Cromoglycic acid (cromoglicicacid), Cromoglycic acid (cromolyn), cumarin (coumarin), endoxan (cyclophosphamide), ring born of the same parents' elements (cyclosporine), cyproterone (cyproterone), cysteamine (cysteamine), cysteine (cysteine), cytarabine (cytarabine), dabigatran etcxilate (dabigatranetexilate), daclizumab (daclizumab), Dalfopristin (dalfopristine), danaparoid (danaparoid), Dapiprazole (dapiprazole), Daptomycin (daptomycin), darbepoetin (darbepoetin), darifenacin (darifenacin), Prezista (darunavir),Dasatinib (dasatinib), Deferiprone (deferiprone), DEFERASIROX (deferasirox), desipramine (desipramine), Desirudin (desirudin), desloratadine (desloratadine), minirin (desmopressine), Desogestrel (desogestrel), desonide (desonide), Dexibuprofen (dexibuprofen), Dexketoprofen (dexketoprofen), dexrazoxane (dexrazoxane), diazepam (diazepam), vigorous Temin α of generation (diboterminalfa), Diclofenac (diclofenac), Didanosine (didanosine), Dihydralazine (dihydralazine), ground that sulphur (diltiazem), dramamine (dimenhydrinate), methyl-sulfoxide (dimethyl sulfoxide), dimeticone (dimethicone), pivaloyloxymethyl (dipivoxil), Dipyridamole (dipyridamole), disoproxil, disopyramide (disopyramide), divalproex, docetaxel (docetaxel), docosane-1-alcohol, Dolasetron (dolasetron), domperidone (domperidone), donepezil (donepezil), dopamine (dopamine), Dornase Alfa (dornasealfa), Dorzolamide (dorzolamide), Doxazosin (doxazosine), doxercalciferol (doxercalciferol), doxifluridine (doxifluridine), Doxorubicin (doxorubicine), doxylamine (doxylamine), Dronabinol (dronabinol), droperidol (droperidol), Drospirenone (drospirenone), flexing gram solidifying α (drotrecoginalpha), Duloxetine (duloxetine), dutasteride (dutasteride), Ebastine (ebastine), Ecabet (ecabet), econazole (econazole), according to storehouse pearl monoclonal antibody (eculizumab),Efalizumab (efalizumab), efavirenz (efavirenz), Eflornithine (eflornithine), eletriptan (eletriptan), Emedastine (emedastine), emtricitabine (emtricitabine), enalapril (enalapril), encepur, enfurvirtide, Enoxaparin (enoxaparin), Entacapone (entacapone), Entecavir (entecavir), Epalrestat (epalrestat), ephedrine (ephedrine), epinastine (epinastine), adrenaline (epinephrine), epirubicin (epirubicine), eplerenone (eplerenone), Epoetin (epoetin), according to general Losartan (eprosartan), eptacog alfa (eptacogalfa), eptifibatide (eptifibatide), rely on Temin α (eptoterminalfa), Tarceva (erlotinib), ertapenem (ertapenem), escitalopram (escitalopram), esomeprazole (esomeprazole), estradiol, female hormone, Etanercept (etanercept), Ethenzamide (ethenzamide), ethinyloestradiol, etofenamate (etofenamate), Etofibrate (etofibrate), Etofylline (etofylline), Etonogestrel (etonogestrel), Etoposide (etoposide), etoricoxib (etoricoxib), everolimus (everolimus), Exemestane (exemestane), Exenatide (exenatide), ezetimibe (ezetimibe), FCV (famciclovir), famotidine (famotidine), Epi-ADM (farmorubicin), faropenem daloxate (faropenemdaloxate), felbinac (felbinac), felodipine (felodipine), fenofibrate (fenofibrate), fentanyl (fentanyl), Fenticonazole (fenticonazole), fexofenadine (fexofenadine), Filgrastim (filgastrim), Finasteride (finasteride), Fluconazole (fluconazole), fludarabine (fludarabine), flunarizine (flunarizine), fluorometholone (fluorometholone), fluorouracil (fluorouracil),Prozac (fluoxetine), Flupirtine (flupirtine), Flurbiprofen (flurbiprofen), Flutamide (flutamide), fluticasone (fluticasone), Fluvastatin (fluvastatin), Fluvoxamine (fluvoxamine), follitropic hormone (follitropin), folic acid, Fomepizole (fomepizole), Fomivirsen (fomivirsen), fondaparinux, Formoterol (formoterol), that Wei of furan mountain (fosamprenavir), the general amine of Fosaprepitant (fosaprepitantdimeglumine), fosfomicin, fosinopril (fosinopril), SB 209509 (frovatriptan), fulvestrant (fulvestrant), frusemide (furosemide), Fusidic Acid (fusidicacid), Gabapentin (gabapentin), gadobenate (gadobenate), gadolinium shellfish acid (gadobenicacid), Gadobutrol (gadobutrol), Gadodiamide (gadodiamide), gadolinium spray acid (gadopenteticacid), galanthamine (galantamine), gallopamil (gallopamil), dagger-axe thioesterase (galsulfase), GCV (ganciclovir), Ganirelix (ganirelix), gatifloxacin (gatifloxacin), Gefitinib (gefitinib), gemcitabine (gemcitabine), Gemfibrozil (gemfibrozil), gentamicin (gentamicin), Gepirone (gepirone), gestagen, gestodene, ginkgo, glatiramer (glatiramer), glibenclamide (glibenclamide), gliclazide (gliclazide), Glimepiride (glimepiride), Glipizide (glipizide), glucagons (glucagon), glucitol, Glucosamine (glucosamine), glutathione (glutathione), glibenclamide (glyburide), glycerine, glyceryl trinitrate, glucosides antibiotics, Goserelin (goserelin), Granisetron (granisetron), Grepafloxacin (grepafloxacin), guanethidine (guanethidine), gyrase (gyrase) inhibitor, halofantrine (halofantrine), haloperole (haloperidol), X-factor (haemin), as the urea derivative of oral antidiabetic,Heparin (heparin), cardiac glycoside (cardiacglycosides), hyaluronic acid, hydrolazine (hydralazine), Hydrochioro (hydrochlorothiazide), 5-Hydroxyomeprazole (hydroxyomeprazole), hydroxyzine (hydroxyzine), hypothalamic hormone class, ibandronic acid (ibandronicacid), ibritumomab, brufen (ibuprofen), idarubicin (idarubicin), elaprase (idursulfase), ifliximab, ifosfamide (ifosfamide), iloprost (iloprost), Imatinib (imatinib), Imidapril (imidapril), Imiglucerase (imiglucerase), Imipenem (imipenem), imipramine (imipramine), imiquimod (imiquimod), indinavir (indinavir), Indomethacin (indometacin), indoramin (indoramin), infliximab (infliximab), insulin glargine preparation (insulinglargin), insulin (insulin), interferon (interferon), interleukins, Iohexol (iohexol), Iopamidol (iopamidol), Iopromide (iopromide), iosarcol (iosarcol), Ipratropium Bromide (ipratropiumbromide), Irbesartan (irbesartan), Irinotecan (irinotecan), Isoconazole (isoconazole), isoprel (isoprenaline), isobide (isosorbide), Itraconazole (itraconazole), Ivabradine (ivabradine), iodine, St.-John's-wort, sylvite, ketoconazole (ketoconazole), Ketoprofen (ketoprofen), Ketotifen (ketotifen), lacidipine (lacidipine), Lamivudine (lamivudine), Lamotrigine (lamotrigine), blue auspicious phthalein (lanreotide), Lansoprazole (lansoprazole), lanthanum carbonate (ester), La Luoni enzyme (laronidase), Latanoprost (latanoprost), leflunomide (leflunomide), lenalidomide (lenalidomide), lepirudin (lepirudin), Lercanidipine (lercanidipine), leteprinim (leteprinim), Letrozole (letrozole),Leuproside (leuprolide), levacetylmethadol (levacetylmethadol), lavo-ofloxacin (levafloxacin), Levetiracetam (levetiracetam), chirocaine (levobupivacaine), levocabastine (levocabastin), levocetirizine (levocetirizine), levodopa (levodopa), Levodropropizine (levodropropizine), lavo-ofloxacin (levofloxazine), levomethadone (levomethadone), Levonorgestrel (levonorgestrel), Levothyroxine (levothyroxine), Li Kaofeilong (licofelone), lidocaine (lidocaine), limaprost (limaprost), Linezolid (linezolid), liothyronine (liothyronine), liponic acid, lisinopril (lisinopril), lisuride (lisuride), Lodoxamide (lodoxamide), lofepramine (lofepramine), Lomefloxacin (lomefloxacin), lomustine (lomustine), Loperamide (loperamide), Lopinavir (lopinavir), Loratadine (loratadine), Lornoxicam (lornoxicam), Losartan (losartan), lotoprendol etabonate (loteprednoletabonate), Lovastatin (lovastatin), loxoprofen (loxoprofen), lumefantrine (lumefantrine), Lu meter Kao former times (lumiracoxib), luteotropin (lutropin), magnesium, macrolide (macrolide) antibiotics, mangafodipir (mangafodipir), Manidipine (manidipine), maprotiline (maprotiline), MVC (maraviroc), Maxacalcitol (maxacalcitol), mebendazol (mebendazole), mebeverine (mebeverine), Mecasermin (mecasermin), meclozine (meclozine), mefenamic acid (mefenamicacid), Mefloquine (mefloquine), melatonin (melatonin), Meloxicam (meloxicam), melphalan (melphalan), Memantine (memantine), menadione (menaquinone), menadione (menadione), mepindolol (mepindolol),Meprobamate (meprobamate), Meropenem (meropenem), 5-aminosalicylic acid (mesalamine), Mesalazine (mesalazine), first amber amine (mesuximide), analgin (metamizole), metaxalone (metaxalone), melbine (metformin), methadone (methadone), methopterin (methotrexate), methoxypolyethylene glycol-Epoetin Beta (epoetinbeta), methyl-(5-amino-LA ester), methyl-(5-amino-LA ester) methylnaloxone (naloxone), methyl naltrexone (methylnaltrexone), methylphenidate (methylphenidate), methylprednisolone (methylprednisolone), methixene (metixen), Metoclopramide (metoclopramide), metoprolol, metronidazole (metronidazole), Mianserin (mianserin), mibefradil (mibefradil), MFG (micafungin), Miconazole (miconazole), mifepristone (mifepristone), Miglitol (miglitol), Mai Gesita (miglustat), minocycline (minocycline), minoxidil (minoxidil), Mirtazapine (mirtazapine), Misoprostol (misoprostol), mitomycin (mitomycin), mitoxantrone (mitoxantrone), Mizolastine (mizolastine), modafinil (modafinil), Moexipril (moexipril), Mometasone (mometasone) furoate (ester), montelukast (montelukast), moroctocog alfa (moroctocogalfa), morphine, Mosapride (mosapride), MOXIFLOXACIN (moxifloxacin), ergot (ergot) alkaloid, Mycophenolate Mofetil (mycophenolatemofetil), Nadifloxacin (nadifloxacin), Nadroparin Calcium (nadroparinecalcium), naftidrofuryl (naftidrofuryl), Nalbuphine (nalbuphine), naloxone (naloxone), naproxen (naproxen), naratriptan (naratriptan), coscopin (narcotine), natalizumab (natalizumab), Natamycin (natamycin), Nateglinide (nateglinide), phenylbutyrate sodium,Nebivolol (nebivolol), Nefazodone (nefazodone), nelarabine (nelarabine), viracept see nelfinaivr (nelfinavir), neostigmine (neostigmine), neramexane (neramexane), Nesiritide (nesiritide), NVP (nevirapine), nicotinic acid (niacin), nicardipine (nicardipine), Nicergoline (nicergoline), nikethamidum (nikethamide), nicorandil (nicorandil), nicotinic acid, nifedipine (nifedipine), Niflumic Acid (niflumicacid), AMN107 (nilotinib), Nilvadipine (nilvadipine), Nimodipine (nimodipine), Nimorazole (nimorazole), Nimustine (nimustine), Nisoldipine (nisoldipine), nitisinone (nitisinone), norelstromin (norelgestromin), Norfloxacin (norfloxacin), narcotine (noscapin), analgin (novaminsulfon), nystatin (nystatin), Octreotide (octreotide), Ofloxacin (ofloxacin), Octreotide (octreotride), Olanzapine (olanzapine), Olmesartan (olmesartan), olopatadine (olopatadine), Olsalazine (olsalazine), omalizumab (omalizumab), Omeprazole (omeprazole), Omoconazole (omoconazole), Ondansetron (ondansetron), orlistat (orlistat), oseltamivir (oseltamivir), oxacephem (oxacephem), Oxaceprol (oxaceprol), OXA (oxacillin), oxaliplatin (oxaliplatin), olsapozine (oxaprozin), Oxcarbazepine (oxcarbazepine), Oxiconazole (oxiconazole), Oxycodone (oxycodone), oxymetazoline (oxymetazoline), taxol (paclitaxel), Pa Lifuming (palifermin), Paliperidone (paliperidone), palivizumab (palivizumab), palonosetron (palonosetron), Panipenem (Panipenem), Victibix (panitumumab), Pantoprazole (pantoprazole), pantothenic acid,Paracetamol (paracetamol), parathryoid hormone, parecoxib (parecoxib), paricalcitol (paricalcitol), Paxil (paroxetine), Pei Jiatani (pegaptanib), Pegaspargase (pegaspargase), pegfilgrastrim, glycol interferon (peginterferon), pemetrexed (pemetrexed), Penciclovir (penciclovir), penicillin (oral), pentazocine (pentazocine), Pentifylline (pentifylline), PTX (pentoxifylline), peptide antibiotics, perfluoropropane (perflutren), Perindopril (perindopril), perphenazine (perphenazine), pethidine (pethidine), plant extracts, antipyrine (phenazone), pheniramine (pheniramine), phenthazine (phenothiazines), fragrant cycolin (phenserine), phenylbutazone (phenylbutazone), phenylbutyric acid, phenytoinum naticum (phenytoin), phylloquinone, Pilsicainide (pilsicainide), Elidel (pimecrolimus), Pimozide (pimozide), pindolol (pindolol), Pioglitazone (pioglitazone), Piperacillin (piperacillin), piperazine, Piracetam (piracetam), pirenzepine (pirenzepine), piribedil (piribedil), pirlindole (pirlindole), piroxicam (piroxicam), porphines nurse (porfimer), posaconazole (posaconazole), Pramipexole (pramipexole), pramlintide (pramlintide), Pranlukast (pranlukast), Pravastatin (pravastatin), prazosin (prazosin), lyrica (pregabalin), procaine (procaine), promazine (promazine), propanoic derivatives, Propiverine (propiverine), Propofol (propofol), Propranolol (propranolol), propyphenazone (propyphenazone), prostaglandin, protionamide (protionamide), Proxypbylline (proxyphylline), pyridoxol, Quetiapine (quetiapine), quinapril (quinapril), Quinupristin (quinupristin),Rabeprazole (rabeprazole), racecadotril (racecadotril), Raloxifene (raloxifene), draw for drawing Wei (raltegravir), Ramipril (ramipril), Lucentis (ranibizumab), ranitidine (ranitidine), ranolazine (ranolazine), Rasagiline (rasagiline), rasburicase (rasburicase), Reboxetine (reboxetine), Repaglinide (repaglinide), Reproterol (reproterol), Reserpine (reserpine), Retapamulin (retapamulin), retinol, revofloxacin, Ribavirin (ribavirin), riboflavin, rifampin (rifampicin), rifaximin (rifaximin), Riluzole (riluzole), Rimexolone (rimexolone), ACOMPLIA (rimonabant), Risedronate (risedronate), Risperidone (risperidone), Ritonavir (ritonavir), Rituximab (rituximab), bright (rivastigmine) of Li Fansi, rizatriptan (rizatriptan), rofecoxib (rofecoxib), Ropinirole (ropinirole), Ropivacaine (ropivacaine), Rosiglitazone (rosiglitazone), rosuvastatin (rosuvastatin), rotigotine (rotigotine), Roxatidine (roxatidine), ROX (roxithromycin), rufinamide (rufinamide), ruscogenine (ruscogenin), rutin (rutoside), cevadilla (sabadilla), salbutamol (salbutamol), salicylic acid (salicylicacid), salmeterol (salmeterol), Saperconazole (saperconazole), Sargramostim (sargramostim), thyroid hormones, hyoscine (scopolamine), selegiline (selegiline), Sertaconazole (sertaconazole), Sertindole (sertindol), Sertraline (sertraline), sevelamer (sevelamer), sevoflurane (sevofluran), sibutramine (sibutramine), sildenafil, silicate, Simvastatin (simvastatin), sirolimus (sirolimus), Xi Gelieting (sitagliptine),Sitaxentan (sitaxentan), sitosterol (sitosterol), sivelestat (sivelestat), YM-905 (solifenacin), growth hormone (somatropin), Sorafenib (sorafenib), Sotalol (sotalol), Spaglumic Acid (spagluminicacid), Sparfloxacin (sparfloxacin), spectinomycin (spectinomycin), spiramvcin (spiramycin), Spirapril (spirapril), spirolactone (spironolactone), stavudine (stavudine), Stiripentol (stiripentol), streptomysin (streptomycin), Strontium Ranelate (strontiumranelate), ulcerlmin (sucralfate), sufentanil (sufentanil), Sulbactam (sulbactam), SASP (sulfasalazine), sulfonamide, Sulpiride (sulpiride), Sultamicillin (sultamicillin), Sultiame (sultiame), sumatriptan (sumatriptan), Sutent (sunitinib), Suxamethonium Chloride (suxamethoniumchloride), Tacrine (tacrine), tacrolimus (tacrolimus), Tadalafei (tadalafil), tafluprost (tafluprost), taliolol, Talsaclidine (talsaclidine), TAM (tamoxifen), Tamsulosin (tamsulosin), Tandospirone (tandospirone), tasonermin (tasonermin), tazarotene (tazarotene), Tazobactam (tazobactam), Tegafur (tegafur), tegaserod (tegaserod), Sebivo (telbivudine), Ketek (telithromycin), Telmisartan (telmisartan), Temocapril (temocapril), Temoporfin (temoporfin), Temozolomide (temozolomide), CCI-779 (temsirolimus), tenatoprazole (tenatoprazole), TNK (tenecteplase), Teniposide (teniposide), tenofovir (tenofovir), tenoxicam (tenoxicam), Terazosin (terazosin), Terbinafine (terbinafine), Terbutaline (terbutaline), RMI 9918 (terfenadine),Teriparatide (teriparatide), terlipressin (terlipressin), tertatolol (tertatolol), testosterone (testosterone), tetrabenazine (tetrabenazine), tetracycline (tetracycline), Tetryzoline (tetryzoline), tezosentan (tezosentan), theobromine (theobromine), theophylline (theophylline), methimazole (thiamazole), thiamines, phosphinothioylidynetrisaziridine (thiotepa), fibrin ferment (thrombin), thyrotropin alfa (thyrotropinalfa), thyroxine (thyroxine), Tiagabine (tiagabine), Tiapride (tiapride), Tibolone (tibolone), ticlopidine (ticlopidine), tigecycline (tigecycline), Tilidine (tilidine), timolol (timolol), Tinidazole (tinidazole), tioconazole (tioconazole), thioguanine (tioguanine), tiotropium, tioxolone (thioxolone), tipranavir (tipranavir), tirofiban (tirofiban), tiropramide (tiropramide), Tizanidine (tizanidine), TOB (tobramycin), tocopherol α/β/gamma/delta, tolazoline (tolazoline), orinase (tolbutamide), Tolcapone (tolcapone), Tolnaftate (tolnaftate), Tolperisone (tolperisone), Tolterodine (tolterodine), Topiramate (topiramate), Hycamtin (topotecan), Torasemide (torasemide), ET-743 (trabectedin), tramadol (tramadol), Tramazoline (tramazoline), Trandolapril (trandolapril), parnitene (tranylcypromine), trapidil (trapidil), Herceptin (trastuzumab), travoprost (travoprost), Trazodone (trazodone), trepostinil, fluoxyprednisolone (triamcinolone), dyrenium (triamterene), Trifluperidol (trifluperidol), Trifluridine (trifluridine), Trofosfamide (trofosfamide), Trimetazidine (trimetazidine),TMP (trimethoprim), trimipramine (trimipramine), Tripelennamine (tripelennamine), triprolidine (triprolidine), tirofiban (tirofiban), tromantadine (tromantadine), tromethamine (trometamol), tropane (tropalpin), trovafloxacin (trovafloxacin), Troxerutin (troxerutin), trypsase (trypsin), tulobuterol (tulobuterol), tyrasamine, tyrothricin (tyrothricin), Urapidil (urapidil), urso (ursodeoxycholicacid), urso (ursodiol), Valaciclovir (valaciclovir), valdecoxib (valdecoxib), valganciclovir (valganciclovir), valproic acid (valproicacid), Valsartan (valsartan), vancomycin (vancomycin), Vardenafil (vardenafil), varenicline (vareniclin), dimension storehouse oronain (vecuroniumchloride), Venlafaxine (venlafaxine), Verapamil (verapamil), Verteporfin (verteporfin), arabinosy ladenosine (vidarabine), sabril (vigabatrin), vildagliptin (vildagliptin), Viloxazine (viloxazine), vincaleukoblastinum (vinblastine), pervone (vincamin), vincristine (vincristine), eldisine (vindesine), vinorelbine (vinorelbine), Vinpocetine (vinpocetine), viquidil (viquidil), voglibose (voglibose), voriconazole (voriconazole), warfarin (warfarin), Buddhist nun's gram Landrina (xantinolnicotinate), ximelagatran (ximelagatran), Xipamide (xipamide), zafirlukast (zafirlukast), zalcitabine (zalcitabine), Zaleplon (zaleplon), zanamivir (zanamivir), ziconotide (ziconotide), Zidovudine (zidovudine), Ziprasidone (ziprasidon), zoledronic acid (zoledronicacid), assistant meter Qu (zolmitriptan), zolpidem (zolpidem), Zonisamide (zonisamide),Zopiclone (zopiclone), Zotepine (zotepine) etc.

If wished, active substance can also they drug use salt or have comparable (if necessary, the action spectrum slightly changed) chemical derivative form use, and when chiral acti ve material, optical isomer and racemic mixture or diastereoisomeric mixture are all operable.If wished, compound of the present invention can also comprise two or more active pharmaceutical substances.

Give resistance to alcohol repellency coatings

The resistance to alcohol repellency coatings of term imparting represents the coating on core, comprise active constituents of medicine, the polymer moieties that wherein said coating comprises at least 70, at least 80, at least 90, at least 95, at least 99 or 100 % by weight a) and excipient part b) mixture, wherein

Described polymer moieties a) by water-insoluble, basic neutral polyvinyl or ethylenic copolymer forms and

Excipient part b) be made up of following excipient:

B1) the non-cellular inert lubricant of 100 to 250,110 to 240,150 to 220 % by weight,

B2) cellulosic cpd of 1 to 35,2 to 30,5 to 28 or 15 to 25 % by weight,

B3) emulsifying agent of 0.1 to 25,0.8 to 20,1 to 15 or 5 to 12 % by weight and additional or alternative in b3),

B4) plasticizer of 0.1 to 30,1 to 25,2 to 22 or 5 to 15 % by weight

Wherein excipient part b) excipient calculate based on polymer moieties dry weight a) respectively.Described polymer moieties a) and excipient part b) be mixed uniformly each other.

For the patience of influence of ethanol

Resistance to alcohol repellency pharmaceutical formulation has not by the preparaton that there is the release dynamics of appreciable impact of ethanol.In the near future resistance to alcohol repellency may be important registration requirement.Coating or the standard pharmaceutical composition without coating normally not resistance to for alcohol.Be surprisingly found out that these coatings provide acceptable alcohol resistance if comprise according to of the present invention the core that the coating giving resistance to alcohol repellency coatings is applied to the pharmaceutical composition of the pharmaceutical composition, the pharmaceutical composition of sustained release, enteric coating pharmaceutical composition or the pulse release that at once discharge.Resistance to alcohol repellency preparaton is sometimes also referred to as rugged preparaton.

Patience (resistance to alcohol repellency pharmaceutical formulation) for influence of ethanol be defined as be added with 40% (v/v) ethanol according in the buffer medium of USP in pH1.2 and/or the release characteristic that measures under the conditions in vitro of pH6.8, with compared with release characteristics determined in the same media of ethanol, accelerate to be no more than 20% under the impact of the medium containing 40% ethanol, preferably more than 10%, and delay to be no more than 20%, preferably more than 10%.Generally speaking, the speed-up ratio of release characteristic delays more dangerous.Therefore, the upper limit that release characteristic accelerates, preferably more than 10%, more preferably no more than 5%, does not even more preferably have the acceleration of release characteristic at all.

Depend on specific pharmaceutical composition, can changing by application conditions of USP test, if such as have to have to 50,100 or 150rpm with paddle or basket method or stirring.For resistance to alcohol repellency mensuration, as long as the dependence test for certain drug compositions and the test condition with or without ethanol are identical, by which kind of USP Test Application in certain drug compositions be inessential.

In meaning of the present invention, the patience for influence of ethanol should measure in the relevant time period expecting significant result of active component release.Period of described significant selection from or between 10 to 80% the accumulated dose discharged without the medium of ethanol.In this period, the patience for influence of ethanol should be at least n=3 with the number of n, but preferably more than 3, such as n=4,5,6,7,8,9,10,11 or 12 equally distributed test points measure.The number of significant selected test point depend on from or total period of release characteristic of accumulated dose release between 10 to 80%.Period, the longer equally distributed test point that can meaningfully select was more.First test point should be first complete hour or halfhour time point when the point of release of 10% or afterwards.Last test point should be when 80% point of release or before last complete hour or halfhour time point.Other test point should be 10 and 80% release mutually or within centre (n=3) or whole hour or the halfhour time point of equally distributed (n>3).The percentage ratio accelerated or delay is discharged to obtain arithmetic mean of instantaneous value by the arithmetic mean of instantaneous value (arithmetic average) of n value.

Term "and/or" in " in pH1.2 and/or under the conditions in vitro of pH6.8 " represents and has different significant conditions for different pharmaceutical compositions.Patience for influence of ethanol should only measure in the relevant time period of active component release.

The pharmaceutical composition such as at once discharged by usual within the short time interval being less than 2 hours release of active ingredients.In this case, the conditions in vitro in pH1.2 of simulated gastric fluid is enough to be used in test.Usually without the need to testing in pH6.8.

On the other hand, the pharmaceutical composition of sustained release has the active component release of such as 6 to 12 hours or even more hours, usually in the first two hour release more than 10%.In this case in pH1.2 and the test under the conditions in vitro of pH6.8 be significant.

Enteric coating pharmaceutical composition is defined as almost not to be had the release of active component or is less than the release of 10% in pH1.2 the first two hour.In this case significant test request extraly have with without the medium of 40% ethanol in resistance to alcohol repellency in the test of pH1.2 phase end after 2 hours.If be no more than the accumulated dose of 10% in the release of pH1.2 in the medium with 40% ethanol after 2 hours, this test can proceed in 10% to 80% release mutually as described above in pH6.8.If should discharge after 2 hours in the medium with 40% ethanol in pH1.2 and exceed 10%, this intestinal pharmaceutical composition is considered to the impact of not resistance to ethanol and does not need to test in pH6.8 again.

The pharmaceutical composition of pulse release is defined as showing the lag time of the defined a few hours (can be 4,5 or 6 hours) almost not having active component to discharge or to be less than 10% release before pH6.8 discharges within the period (can be 1 or 2 hour) that active component is relatively short in pulsion phase.Significant test request is resistance to alcohol repellency in the test of hysteretic state end in the medium with 40% ethanol extraly in this case.If be no more than the accumulated dose of 10% in the medium with 40% ethanol in the release of hysteretic state end in pH6.8, this test can proceed in 10% to 80% release mutually as described above in pH6.8.If should release in hysteretic state end in the medium with 40% ethanol in pH6.8 and exceed 10% of accumulated dose, this pulse pharmaceutical composition is considered to the impact of not resistance to ethanol and does not need to test in pH6.8 again.

The subtraction of the arithmetic average that the percentage ratio accelerated under 40% impact containing the medium of ethanol or delay is calculated by corresponding single release value and they calculates.The n release value taking from the medium with ethanol is subtracted each other and the arithmetic average of calculated difference to the corresponding n release value taken from without the medium of ethanol.Positive result represents the acceleration of release; Negative test represent delay release.

The controlled release pharmaceutical compositions meeting these conditions can be considered to ethanol be not intended to containing the patient that the use of the beverage of ethanol is relevant or addiction behavior time hinder the accelerated release in vitro of danger or delay reactive compound.This situation substantially with take in No alcoholic beverages together with controlled release drug form simultaneously or mutually continuously so that medicament forms is exposed to the high medium containing ethanol in stomach or intestinal.

But of the present invention is not stimulate, promote or make and delay-discharge the beverage consumed containing ethanol together with medicament forms and become possibility motivatedly, but relaxes or avoid deliberate or misuse or the possible fatal consequences abused unintentionally.

calculate embodiment 1:

If by there is the medium of ethanol and being 8% (=positive 8%) without the arithmetic average that the active component release in the medium of ethanol calculates, then caused the acceleration of 8% by the impact of ethanol.Controlled release pharmaceutical compositions is considered to resistance to influence of ethanol in this case, because in the limit being no more than 20% acceleration.

calculate embodiment 2:

If by there is the medium of ethanol and discharge the arithmetic average calculated without the active component in the medium of ethanol be negative 23%, then causing 23% delay by the impact of ethanol.Controlled release pharmaceutical compositions is not considered to resistance to influence of ethanol in this case, because delay off limits being no more than 20%.

Measuring method

The measurement of the percentage of the active component of release can be carried out in the wavelength being suitable for each reactive compound by online UV spectrum.It is also possible that HPLC measures.Described method is familiar for those skilled in the art.

The release of active component can measure according to USP, particularly USP32-NF27, GeneralChapter<711>, Dissolution, Apparatus2 (basket method), Method<724> " DelayedRelease (EntericCoated) Articles-General, GeneralDrugReleaseStandard ", method B (100rpm, 37 DEG C), I type basket, there is following variation: said medicine form is tested first 2 hours in pH1.2 0.1NHCl medium or in the phosphate buffer (European Pharmacopoeia (EP)) of pH6.8 corresponding to artificial intestinal medium.40% ethanol (v/v) in medium is used to carry out the test in the water-bearing media containing ethanol.If suitable or for required for specific controlled release pharmaceutical compositions; depend on the type and size (tablet that little or large pill is little or large) of included active component and releasing pattern, paddle method different from basket method can adopt 50,100 or 150rpm.

Core

Controlled release pharmaceutical compositions according to the present invention comprises core containing active constituents of medicine and it can be pill without coating or coated pill.Term pill should comprise the granule and sheet that can be understood to large scale pill at this point.

Without the pill of coating as core

Described core can comprise the neutral carrier pill without coating, such as neutral celphere (non-pareilles), and on it, active component is bonded in binding agent, as lactose or polyvinylpyrrolidone.Described core can alternatively, comprise with the pill without coating of the form of the polymeric matrix of the wherein binding activities composition without coating.Described core can comprise the pill without coating be made up of the active component of crystallization.

When core is the pill without coating, described in there is the coating giving resistance to alcohol repellency coatings have first for pharmaceutical composition provides the function of desired releasing properties and next impact for ethanol to provide the function of patience.

Coating pill is as core

Described core can comprise the coating pill containing active constituents of medicine.Described coating pill can be the pharmaceutical composition being easy to prepare or be obtained commercially, and it should be endowed the impact that the resistance to ethanol of release characteristics of the active constituents of medicine comprised consequently given by resistance to alcohol repellency coatings coating.Described coating pill can be the pharmaceutical formulation at once discharged.Described coating pill can be the pharmaceutical formulation of sustained release.Described coating pill can be enteric coating pharmaceutical formulation.

When core is coating pill, described in there is the coating giving resistance to alcohol repellency coatings there is the impact providing and offset ethanol so that the function keeping original release characteristic in fact not change in acceptable acceleration or the defined limit that delays.

Coating or without the sheet of coating as core

Described core can be coating or the sheet without coating, preferably has 1 ~ 50 or the size of 10 ~ 25mm or length in one direction.Described can such as have ball, spheroid, dish or torpedo.Preferred enteric coating (resistance to stomach) sheet can be used as core.

Art for coating

Present invention is disclosed by spray art preferred bed spray coating give resistance to alcohol repellency coatings coating contain active component without coating or the coated core method for the preparation of controlled release pharmaceutical compositions.

Without core pelletized of the pill of coating

Core without the pill of coating can manufacture in pelletized technique.Full circle, the pill comprising active component or do not have with neutral carrier is out manufactured.Full circle, the substrate comprising active component or do not have with neutral carrier is out manufactured.When fluid bed processor method, liquid can be applied over placebo pill or other suitable carrier material, and solvent or antisettling agent are evaporated.According to preparation technology, drying steps can be added.Spray step and drying subsequently can repeat for several times until applied the amount of the active constituents of medicine be intended to completely.Alternatively, wet-method extrusion, melt extrude, spraying dry, melt pelletization or wet granulation can be used for manufacturing without the pill of coating.

Described active component is brought into organic solvent or water in principle and mixes.In order to ensure the satisfaction of the spray applicability of mixture, be usually necessary that preparation has relatively low viscous mixture.Add cleaning agent, such as Tween, with the concentration of 0.1 to 20, preferably 0.5 to 10 % by weight, capillary reduction can be conducive to.

Outside active component, described spray suspension liquid can comprise other medicines excipient: binding agent as lactose, polyvinylpyrrolidone (PVP), wetting agent, disintegrate auxiliary agent, disintegrating agent, starch and derivant thereof, sugared solubilizing agent or other.

The suitable technique that applies such as is known in Bauer, Lehmann, Osterwald, Rothgang " arzneiformen " [coated medicament forms] WissenschaftlicheVerlagsgesellschaftmbHStuttgart, Chap.7, pp.165-196.

The known more details of those skilled in the art from textbook.See, such as:

-Voigt, R. (1984): LehrbuchderpharmazeutischenTechnologie [pharmacopedics technique textbook]; VerlagChemieWeinheim-BeerfieldBeach/Florida-Basle.

-Sucker, H., Fuchs, P., Speiser, P.:PharmazeutischeTechnologie [pharmacopedics technique], GeorgeThiemeVerlagStuttgart (1991), particularly 15 and 16 chapters, pp.626-642.

-Gennaro,A.,R.(Editor),Remington'sPharmaceuticalSciences,MackPublishingCo.,EastonPennsylvania(1985),Chapter88,pp.1567-1573。

-List, P.H. (1982): Arzneiformenlehre [medicament forms is theoretical], WissenschaftlicheVerlagsgesellschaftmbH, Stuttgart.

Pill core is by the method full circle of the cohesion of such as rotor, precipitation or spray art.Particularly ultrasonic whirlpool spray art can be employed to obtain the definition size of the pill core that there is no coating, such as 100-5000 μm.This has the advantage that whole core volume can be used for carrying active ingredients.The load of active component can be enhanced thus once again relative to the example with inert core.The technique of direct compression can be used for manufacturing microplate core.Outside active constituents of medicine, the pill core without coating can comprise other medicines excipient: binding agent as lactose, polyvinylpyrrolidone (PVP), wetting agent, disintegrate auxiliary agent, disintegrating agent, starch and derivant thereof, sugared solubilizing agent or other.

Coated pill granule

According to controlled release pharmaceutical compositions of the present invention, it is characterized in that give resistance to alcohol repellency coatings based on core Weight computation with at least 2, at least 3, at least 4, at least 5, preferably 10 to 500 % by weight amount exist.

Described controlled release pharmaceutical compositions can preferably to have overall mean diameter 100-5000 μm, preferably 100 to 2000, most preferably coating pill (core) agent of 300 to 1000 μm, the form of micro-tablet exist.

Controlled release pharmaceutical compositions according to the present invention is to have overall average diameter in the scope of 100 to 700 μm, preferably greater than 200 μm or exist more than 500 μm or in the form of coating pill (core) agent in the scope of 250 and 400 μm.

Controlled release pharmaceutical compositions according to the present invention is to have the micro-tablet of overall mean diameter in the scope of 1400 to 5000 μm, preferably 1500 to 4000, most preferably 1800 to 3500 μm or the form existence of tablet.

When coating pill (core) has within the scope of 100 to 700 μm, preferably greater than 200 μm or more than 500 μm or at the overall mean diameter within the scope of 250 and 400 μm, give resistance to alcohol repellency coatings based on core Weight computation can at least 20, at least 30, at least 50, at least 100 % by weight amount exist.

When coating pill (core) to have within the scope of 1400 to 5000 μm, preferably greater than 2000 μm or overall mean diameter more than 2500 μm or within the scope of 2500 and 3500 μm, coatings should based on the Weight computation of core with at least 10, at least 20, at least 30 % by weight amount exist.

Micro-tablet

Can micro-tablet be provided when realizing of the present invention, such as, with the size of 1 to 5mm, having and giving resistance to alcohol repellency coatings.

Tablet

Can tablet be provided when realizing of the present invention, such as, with the size of 1 to 50mm, there is resistance to stomach and resistance to alcohol repellency coating.

Polymer moieties a)

Described polymer moieties a) is made up of one or more water-insolubles, basic neutral polyvinyl or ethylenic copolymer.Preferably described polymer moieties a) based on core Weight computation with at least 3.0, at least 3.2, at least 3.5, at least 9, at least 15, at least 25, at least 35 % by weight amount exist.

Water-insoluble, basic neutral polyvinyl or copolymer

Term water-insoluble, basic neutral polyvinyl or copolymer need not represent a kind of polymer or copolymer a1).Term water-insoluble, basic neutral polyvinyl or copolymer represent one or more polymer or copolymer a1) meaning.

Term water-insoluble, basic neutral polyvinyl or ethylenic copolymer represent includes water-insoluble within the scope of whole pH of 1 to 14 or only those polymer of swellable or copolymer in water.

Polyvinyl is derived from the polyreaction of monomer such as (methyl) acrylic monomers with vinyl groups.

Described water-insoluble, basic neutral polyvinyl a1) based on described polymer moieties dry weight a) with 60 to 99,75 to 98,80 to 95 or 85 to 95 % by weight amount be present in described polymer moieties a) in.

If basic neutrality represents the polymer that wherein fundamentally can comprise only ionic group in a small amount.Even if there is ionic group in a small amount, the physical-chemical behavior of this kind of polymer is almost identical with the physical-chemical behavior of the polymer without any ionic group.Basic neutrality represent especially wherein comprise be less than 5, be less than 4, be less than 3, be less than 2 or the monomer residue that is less than 1 % by weight there is the polymer of anionic or cationic pendant groups.Preferably water-insoluble neutral vinyl polymers or copolymer do not comprise any cationic groups.Most preferably water-insoluble, basic neutral polyvinyl or copolymer do not comprise any ionic group and are therefore neutral water-insoluble polyvinyls (100% is neutral).

Water-insoluble (methyl) acrylate copolymer be made up of the monomer residue of the cation type quaternary ammonium group of 5 or 10 % by weight, such as type rS or rL, is unsuitable for object of the present invention, because the pharmaceutical composition obtained is not enough to the impact of resistance to 40% ethanol.Therefore water-insoluble (methyl) acrylate copolymer that the monomer residue comprising at least 1 % by weight, at least 2%, at least 3%, at least 4% or at least 5 % by weight has cationic quaternary ammonium group can be excluded in scope of the present invention.

Generally speaking, an a kind of or class water-insoluble, basic neutral polyvinyl or copolymer is only had to be present in pharmaceutical composition.But, also possibly, if suitably, this kind of polymer of two or more insoluble polymers or copolymer or type or copolymer is adjacent one another are or exist in the mixture.

Polyvinyl acetate ester type insoluble polymer

Suitable water-insoluble, basic neutral polyvinyl or copolymer can be polyvinyl acetate polymer class or the copolymer derived from it.

The example of water-insoluble polyvinyl acetate esters polymer or copolymer be polyvinyl acetate (PVAc, Kollicoat), vinyl acetate-vinylpyrrolidone-copolymer ( vA64).

Water-insoluble (methyl) acrylic acid series copolymer

Suitable water-insoluble, basic neutral polyvinyl or copolymer can most preferably (methyl) acrylic acid series copolymer classes.

Neutral (methyl) acrylate copolymer ( nE type)

Neutral or basic neutral methacrylic acid esters copolymer by least more than 95 % by weight degree, particularly at least 98 % by weight degree, preferably at least 99 % by weight degree, more preferably (methyl) acrylate monomer of 100 % by weight degree there is tral residue, particularly C ₁-to C ₄-alkyl residue.

Suitable (methyl) acrylate monomer with tral residue is, such as methyl methacrylate, ethyl methacrylate, butyl methacrylate, acrylic acid methyl ester., ethyl acrylate, butyl acrylate.Preferably methyl methacrylate, ethyl acrylate and acrylic acid methyl ester..

There is the methacrylate monomer of ion residue, such as acrylic acid and/or methacrylic acid, can a small amount of to be less than 5 % by weight, preferably more than 2 % by weight, more preferably no more than 1 or 0.05 to 1 % by weight exist.

Suitable example be by the ethyl acrylate of 20 to 40 % by weight, 60 to 80 % by weight the neutrality that forms to the acrylic or methacrylic acid being less than 5 % by weight, preferably 0 to 2 or 0.05 to 1 % by weight of methyl methacrylate and 0 or in fact neutral (methyl) acrylate copolymer ( nE type).

nE and nM is the copolymer that forms of the radical polymerization unit of methyl methacrylate by the ethyl acrylate of 30 % by weight and 70 % by weight.

Suitable insoluble polymer be by more than 95 until the C of the acrylic or methacrylic acid of 100 % by weight ₁-to C ₄the copolymer that-Arrcostab is formed with the radical polymerization unit of the acrylic or methacrylic acid being less than 5 % by weight.

Excipient part b)

The resistance to alcohol repellency coatings of described imparting also comprises the excipient part b be made up of following excipient):

B1) the non-cellular inert lubricant of 100 to 250 % by weight,

B2) cellulosic cpd of 1 to 35 % by weight,

B4) plasticizer of 0.1 to 30 % by weight

Described excipient part b) can by excipient b1), b2), b3) and b4) to form.

Described excipient part b) can by excipient b1), b2) and b3) to form.

Described excipient part b) can by excipient b1), b2) and b4) to form.

Excipient quoted in all cases adds to 100%.

Inertia non-cellular lubricant b1)

Give the described excipient part b of resistance to alcohol repellency coatings) calculate based on described polymer moieties dry weight a) the non-cellular inert lubricant comprising 60 to 250,90 to 240,110 to 230 or 140 to 220 % by weight.

Lubricant (sometimes also referred to as fluidizer) is the acceptable material of pharmacy, and it contributes to preventing the core coagulation during art for coating through polymer coating.

Porous lubricant such as tripoli powder is unsuitable for object of the present invention, and loose structure may cause capillary action effect so that promote moisture permeating the enhancing of coating containing alcohol (ethanol) medium.

Inertia represents that lubricant is usually insoluble not with other material generation chemical action or is only slightly soluble in water and/or ethanol.Insoluble or only slightly soluble represent the solvent of 1 weight portion solute needs more than 10 weight portions.In addition, inertia non-cellular lubricant does not affect the glass transition temperature of the polymeric blends of coating substantially.

Can not be applied to coatings with enough amounts with lubricant such as the glyceryl monostearate (GMS) realized for the patience of the water-bearing media containing ethanol itself is be unsuitable in meaning of the present invention.Therefore glyceryl monostearate (GMS) is non-inert and therefore gets rid of in meaning of the present invention.

Described non-cellular inert lubricant can be the tripoli component of stratification, pigment or stearate compound.

Inert lubricant can be Ca-or Mg-stearate.Inert lubricant can be TiO ₂.

Most preferably inertia non-cellular lubricant Pulvis Talci.Talcous dissimilar in, have and be preferable over by the mean diameter of the determination of laser diffraction Pulvis Talci within the scope of 12 to 50, preferably 15-25 μm the Pulvis Talci having and to be less than 12 μm by the mean diameter of determination of laser diffraction.It is preferred for having by the Pulvis Talci of mean diameter within the scope of 12 to 50, preferably 15-25 μm of determination of laser diffraction, because it seems that it to strengthen relative to core give the impact (see embodiment 1-6) of resistance to alcohol repellency coatings total amount, since accelerate and delay value to be all observed (embodiment 1-3).This opens by using the thickness of coating as truing tool between the possibility of accelerating and delaying to carry out meticulous adjustment.When using the Pulvis Talci having and to be less than 12 μm by the mean diameter of determination of laser diffraction, only observe acceleration figure (embodiment 4-6), it allows the meticulous adjustment of acceleration aspect and and can not delay to carry out meticulous adjustment between acceleration.

Cellulosic cpd b2)

Give the excipient part b of resistance to alcohol repellency coatings) calculate based on described polymer moieties dry weight a) the cellulosic cpd b2 comprising 1 to 35,2 to 30,5 to 28 or 15 to 25 % by weight).Described cellulosic cpd preferred neutral fibre element compound, more preferably water-soluble cellulose derivative.Neutral fibre element compound can be cellulosic neutral derivant and can the methyl ether of preferred cellulose, ethylether or propyl ether.Most preferred neutral fibre element compound is hydroxypropyl emthylcellulose (HPMC), hydroxyethyl-cellulose (HEC), sodium-carboxymethyl cellulose (Na-CMC) or methylcellulose.Described cellulosic cpd is considered for the resistance to alcohol repellency coatings of protection imparting and avoids being invaded by ethanol.The expansion in the hole in a kind of closed coatings may be there is under the existence of ethanol.

Emulsifying agent b3)

Give the described excipient part b of resistance to alcohol repellency coatings) calculate the emulsifying agent that can comprise 0.1 to 25,0.8 to 20,1 to 15 or 5 to 12 % by weight, preferred nonionic emulsifier based on described polymer moieties dry weight a).

Inventor finds in coating, add the patience that one or more can improve pharmaceutical composition indirectly.Infer that the cleaning agent existed in spray suspension liquid promotes that film forming process becomes more perfect.More perfect film it seems the impact of the more resistance to ethanol of film that can be formed than the emulsifying agent that there is not specified quantitative in coating.Do not exist in coating the emulsifying agent of specified quantitative form film and than there is the film that emulsifying agent formed, there is slightly many holes by inference.Though therefore the effect of emulsifying agent in film forming process can not be entirely understood may similar in appearance to but inconsistent in the solidification process imposing on coating pill.Surprisingly no matter whether ethanol is present in medium and it seems do not have negative effect or change to release characteristic itself further.

Preferably emulsifying agent is the polyethylene oxide derivatives of sorbitan esters or Sorbitan alcohol ether.

Most preferably, described cleaning agent be polyoxyethylene sorbitan monoleate (Polyethylene Glycol dehydrating sorbitol monooleate CAS number of registration 9005-65-6, such as 80).

Plasticizer b4)

Give the described excipient part b of resistance to alcohol repellency coatings) calculate (one or more) plasticizer that can comprise 0.1 to 30,1 to 25,2 to 22 or 5 to 15 % by weight based on described polymer moieties dry weight a).

Plasticizer partly or entirely can substitute emulsifier component b3).Technique effect may to emulsifying agent produce similar.Plasticizer depends on type (lipophilic type or hydrophilic) and addition, and plasticizer can affect gives the functional of resistance to alcohol repellency coatings.Depend on added amount, plasticizer realizes the reduction of glass transition temperature by the mutual physical action of the polymer with described polymeric blends and promotes that film is formed.Suitable material usually has the molecular weight between 100 and 20000 and comprises one or more hydrophilic group in the molecule, such as hydroxyl, ester or amino group.

The example of suitable plasticizer is citric acid alkane ester, glyceride type, phthalic acid alkyl ester, decanedioic acid alkane ester, sucrose ester, sorbitan esters class, ethyl sebacate, dibutyl sebacate and Macrogol 200 to 12000.Preferred plasticizer is triethyl citrate (TEC), CitroflexA-2 (ATEC), ethyl sebacate and dibutyl sebacate (DBS).Also should also be mentioned that the ester being generally liquid state under room temperature, as citric acid ester type, phthalate, sebacic acid ester or Oleum Ricini.The esters of citric acid and decanedioic acid (sebacinicacid) preferably uses.

Plasticizer is added into preparaton can carry out in the known manner, directly, adds to aqueous solution or after the Grape berry of mixture.Also possibly the mixture of plasticizer is adopted.

Other medicines excipient

If give resistance to alcohol repellency coatings comprise be less than 100 % by weight (they can be 70,80,90,95 or 99 % by weight) and described polymer moieties a) and excipient part b), its can also comprise until 30 until 20 until 10 until 5 or until being different from polymer moieties polymer a) and being different from excipient part b of 1 % by weight (can be 30,20,10,5 or 1 % by weight)) the other medicines excipient of excipient.Therefore term other medicines excipient does not comprise water-insoluble, basic neutral polyvinyl or ethylenic copolymer in meaning of the present invention, non-cellular inert lubricant, cellulosic cpd, emulsifying agent or plasticizer.The resistance to alcohol repellency coatings of described imparting and other excipient add to 100%.The not substantive imparting of other excipient described or impact or with owing to polymer moieties a) and excipient part b) the resistance to alcohol repellency effect reaction of imparting of mixture.Other excipient of this kind can be such as pigment.Most preferably there is not other medicines excipient in the resistance to alcohol repellency coatings of imparting.

Other medicines excipient conventional in pharmacy also refers to conventional additives sometimes, preferably during preparing granule or powder, is added into preparaton of the present invention.Certainly, be necessary that the excipient of all employings or conventional additives are that toxicology is acceptable and available all the time, particularly for patient's devoid of risk in medicine.

The amount adopted in above-mentioned framework and be familiar for the other medicines excipient of drug coating for technical staff in pharmacy.The example of possible other medicines excipient conventional in pharmacy can be such as antioxidant, pore-forming agent, polishing material, aromatic substance or flavoring agent.They can be used as process auxiliaries and intention guarantees that reliable and reproducible preparation process and good long term storage stability or they realize other favourable character in medicament forms.Other medicines excipient can be added into and give resistance to alcohol repellency coating layer formulation before implementing coating by spray art.

Many granule medicaments form

The form comprising pill in many granule medicaments form can be had, such as, with the form of tablet agent, capsule, wafer, effervescent tablet or reconfigurable powder according to controlled release pharmaceutical compositions of the present invention.

Top coat (TopCoats) and sublevel coating (SubCoats)

Assemble or coating with sublevel coating and/or top coat further according to controlled release pharmaceutical compositions of the present invention.

Sublevel coating can be positioned between core and the coatings (key-course) controlling pharmaceutically active substance release.Sublevel coating can have the function material of core being isolated from the material that can be incompatible each other key-course.Described sublevel coating does not affect release characteristics or resistance to alcohol repellency substantially.Sublevel coating is preferably water miscible substantially, and such as it can by material as hydroxypropyl emthylcellulose (HPMC) forms as film former.The average thickness of described sublevel coatings is very thin, such as, be no more than 15 μm, preferably more than 10 μm.

Top coat can exist and be preferably water miscible substantially.Top coat can have dyeing medicament forms or avoid the impact of environment such as dampness at lay up period.Described top coat can be made up of binding agent, and such as water-soluble polymer is as polysaccharide or HPMC, or sugar compounds is as sucrose.Described top coat can comprise drug excipient as pigment or lubricant in a small amount further.Top coat described in described top coat does not affect release characteristics or resistance to alcohol repellency substantially.

Described expression sublevel coating and top coat are well-known to those skilled in the art.

pigment in top coat

Pigment as already explained may be used for coatings and serves as the effect promoted for the non-cellular inert lubricant of the patience of influence of ethanol.If pigment adds without the excipient of contribution as to the present invention, they may be added to top coat in coatings to obtain some colors.In coatings, serve as the effect of non-cellular inert lubricant or be suitable for medicament purpose as to the present invention without the pigment used of excipient effect of contribution yes usually avirulence.Related to this, also see such as: DeutscheForschungsgemeinschaft, Farbstoffef ü rLebensmittel, Harald, BoldtVerlagKG, Boppard (1978); DeutscheLebensmittelrundschau74, No.4, p.156 (1978); ArzneimittelfarbstoffverordnungAmFarbVof25.08.1980.

The example of pigment is titanium dioxide, Fructus Citri tangerinae is yellow, cochinealredlake, color based on Alumina or azo dye dyeing is plain, sulfonic acid dye, orange S (E110, C.I.15985, FD & CYellow6), indigo carmine (indigocarmine) (E132, C.I.73015, FD & CBlue2), tartrazines (E102, C.I.19140, FD & CYellow5), Ponceau4R (E125, C.I.16255, FD & CCochinealRedA), D C Yellow No. 10 (E104, C.I.47005, FD & CYellow10), erythrosine (E127, C.I.45430, FD & CRed3), azorubine (E122, C.I.14720, FD & CCarmoisine), amaranth (E123, C.I.16185, FD & CRed2), acid viride nitens (E142, C.I.44090, FD & CGreenS).

The E code referred to for pigment relates to EU numbering.Related to thisly, also see " DeutscheForschungsgemeinschaft, Farbstoffef ü rLebensmittel, HaraldBoldtVerlagKG, Boppard (1978); DeutscheLebensmittelrundschau74, No.4, p.156 (1978); ArzneimittelfarbstoffverordnungAmFarbVof25.08.1980.FD & C numbers food, medicine and the cosmetics examination & approval relating to U.S. food and medicine mechanism (FDA), it is described in: U.S.FoodandDrugAdministration, CenterforFoodSafetyandAppliedNutrition, OfficeofCosmeticsandColors:CodeofFederalRegulations-Titl e21ColorAdditiveRegulationsPart82, ListingofCertifiedProvisionallyListedColorsandSpecificat ions (CFR21Part82).

Prepare the method according to medicament forms of the present invention

Can be prepared by medicine common process in a way known according to controlled release pharmaceutical compositions of the present invention; as direct pressing; the compacting of dry, wet or sintered particles and full circle continuous mutually; wet method and melt extruding, wet method or non-slurry pelletizing or directly pelletized or by bond powders (powder bed) to the globule of active substance or neutral core (celphere) is upper or to the granule comprising active component or by applying polymer coating in spray art or pass through fluidized bed prilling.

Give the amount of resistance to alcohol repellency coatings relative to core

According to controlled release pharmaceutical compositions of the present invention, it is characterized in that described polymer moieties a) based on core Weight computation with at least 3.0, at least 3.2, at least 3.5 % by weight amount exist.

Controlled release pharmaceutical compositions according to the present invention is characterized by described core can be coating or have the pill of average diameter within the scope of 100 to 5000 μm without coating.Described core also can be coating or the tablet of size at least one direction with 1 to 50 or 10 to 25mm without coating.Described can such as have ball, spheroid, dish or torpedo.

Relative to large core, little core has large surface.Therefore to be sprayed to little core in % by weight the resistance to alcohol repellency coatings of imparting amount generally higher than the amount for strengthening core to give identical or close effect.Since be difficult to define and measure in μm coating thickness, the core with different average diameter is categorized as the optimum range of amount that three types are used for giving with % by weight definition resistance to alcohol repellency coatings by inventor.

Described core can be characterized by according to controlled release pharmaceutical compositions of the present invention there is average diameter (little core) in the scope of 100 to 700 μm and to be 15 to 200,25 to 300 or 50 to 500 % by weight giving polymer moieties polymer dry amount of substance a) in resistance to alcohol repellency coatings based on the Weight computation of core.

Described core can be characterized by according to controlled release pharmaceutical compositions of the present invention to have more than 700 and until average diameter (middle-sized core) in the scope of 1400 μm and be 10 to 150,15 to 200 or 25 to 300 % by weight giving polymer moieties polymer dry amount of substance a) in resistance to alcohol repellency coatings based on the Weight computation of core.

Described core can be characterized by according to controlled release pharmaceutical compositions of the present invention to have more than 1400 and until average diameter (large core) in the scope of 5000 μm and be 5 to 100,10 to 120 or 20 to 150 % by weight giving polymer moieties polymer dry amount of substance a) in resistance to alcohol repellency coatings based on the Weight computation of core.

Use

PH dependency controlled release pharmaceutical compositions according to the present invention can be used for reducing the active constituents of medicine comprised is strengthened release after oral absorption risk (misuse) by the alcoholic beverages consumption continued simultaneously or mutually.

Embodiment

Drug model

Metoprolol succinate and naloxone hydrochloride is used to study as drug model.

Dissolution studies

Coating pill is tested as follows:

According to USP32-NF27, GeneralChapter<711>, Dissolution, the first two hour in simulated gastric fluid pH1.2 and then at the medium of buffering in pH6.8.

Solubility parameter:

naloxone hydrochloride

Instrument: USP type-I (basket method)

RPM:100/min。

Temperature: 37.5 ± 0.5 DEG C

Meltage: 500ml.

Return taken amount: use pipet to fetch 5ml by hand, without covering medium.

Detecting pattern: HPLC

metoprolol succinate

Instrument: USP type-II (paddle method)

RPM:100/min。

Temperature: 37.5 ± 0.5 DEG C

Meltage: 900ml.

Detecting pattern: online UV-VIS

Dissolve medium 1:

The Gastric pH 1.2 (European Pharmacopoeia=EP) of simulation

Dissolve medium 2:

The Gastric pH 1.2 (European Pharmacopoeia=EP) of simulation is containing 40% (v/v) ethanol

Dissolve medium 3:

The saline pH6.8 (European Pharmacopoeia=EP) of phosphate-buffered

Dissolve medium 4:

The saline pH6.8 (European Pharmacopoeia=EP) of phosphate-buffered is containing 40% (v/v) ethanol

Polymer moieties is a): water-insoluble, basic neutral ethylenic copolymer

nEbe used as water-insoluble, basic neutral ethylenic copolymer (polymer moieties a)). nEethyl acrylate by 30 % by weight and 70 % by weight the radical polymerization unit of methyl methacrylate form.

Excipient part b)

non-cellular inert lubricant b1):

Pharmaceutical purpose Pulvis Talci: there is the Pulvis Talci that mean diameter is 19.3 μm (being determined as 10 μm through sedimentation) through determination of laser diffraction

Pharmaceutical purpose Pulvis Talci M: there is the Pulvis Talci that mean diameter is 10.5 μm (being determined as 4.7 μm through sedimentation) through determination of laser diffraction

cellulosic cpd b2): hydroxypropyl emthylcellulose

emulsifying agent b3): Polysorbat80

Preparation comprises the core of active component

The end is used to be sprayed at the sugared ball (celphere) loading 1700-2000 micron in fluid bed processor with metoprolol succinate or naloxone hydrochloride.

naloxone hydrochloride

Polyvinylpyrrolidone ( k25) binding agent is used as.Be incorporated into 80g binding agent ( the celphere of the 270g metoprolol succinate coating 900g K25).

metoprolol succinate

Polyvinylpyrrolidone ( k25) binding agent is used as.Be incorporated into 4.5g binding agent ( the celphere of 90g metoprolol succinate coating 900g K25).Further 120g Pulvis Talci and 30g silicon dioxide are used as the lubricant on core.

medicine covering

Under gentle agitation by polyvinylpyrrolidone ( k25) and active component water-soluble.Use high shearing force and lubricant is scattered in water.Described lubricant-suspension is poured under mild agitation polyvinylpyrrolidone ( k25) solution.Continue stirring and run through whole coating process.

With the resistance to alcohol repellency coatings Dragees of imparting

film coating suspension preparation:

Use high shearing force non-cellular inert lubricant, emulsifying agent and cellulosic cpd (excipient part b)) be dissolved in or be scattered in water.Under mild agitation lubricant-suspension is poured into nE dispersion liquid.Continue stirring and run through whole coating process.

coating process:

By the different film coating suspension coating of the pill of medicine covering under condition suitable in fluid unit, described felicity condition is that spray rate is about the every kg core of 10-20g/min film coating suspension and bed tempertaure is about 25-28 DEG C.The nozzle place spraying pressure being 1.2mm at diameter is 1.5 to 2.2 bar.After pill is carried out coating in fluid bed processor about 40 DEG C and about 45% relative humidity fluidisation half an hour.Coated pill has average diameter and is about 2600-3000 μm.

The coated core comprising active component obtained is that pH1.2 and/or pH6.8 has and test without in the corresponding dissolve medium of 40% (v/v) ethanol.The results are shown in table 1-2 and 2-2.The arithmetic average that the release value of boldface type is discussed with regard to " patience for influence of ethanol " before being used to calculate.

Embodiment is discussed

The impact of embodiment 1 to 3 comparative example 4 to 6 display Pulvis Talci type.

Comparative example C1 display is used alone Pulvis Talci but does not have cellulosic cpd (HPMC=hydroxypropyl emthylcellulose) and do not have emulsifying agent (Polysorbat80) not realize resistance to alcohol repellency.Comparative example C2 is cellulose-less compound (HPMC) then.Comparative example C3 is emulsifier-free (Polysorbat80) then.Do not observe resistance to alcohol repellency in both of these case.Alcohol repellencyly embodiment 1 to 9 is found according to the present invention is resistance to.Embodiment 2 and 6 is presented at the acceleration that the medium with ethanol is less than 10%.

The preferred following Examples of the application:

1. controlled release pharmaceutical compositions, it comprises

Core containing active constituents of medicine,

Wherein said core is endowed resistance to alcohol repellency coatings coating, described resistance to alcohol repellency coatings be added with 40% (v/v) ethanol according in the buffer medium of USP in pH1.2 and/or have the effect of giving active constituents of medicine release characteristic resistance to influence of ethanol under the conditions in vitro of pH6.8

Wherein the impact of resistance to ethanol represents with compared with release characteristic determined in the same media of ethanol, and the release characteristic under the impact of the medium containing 40% ethanol accelerates be no more than 20% and delay to be no more than 20%,

Wherein give polymer moieties that resistance to alcohol repellency coatings comprises at least 70 % by weight a) and excipient part b) mixture, wherein

Described polymer moieties a) by water-insoluble, basic neutral polyvinyl or copolymer forms and

Excipient part b) be made up of following excipient:

B1) the non-cellular inert lubricant of 100 to 250 % by weight,

B2) cellulosic cpd of 1 to 35 % by weight,

B4) plasticizer of 0.1 to 30 % by weight

2., according to the controlled release pharmaceutical compositions of example 1, it is characterized in that the described core containing active constituents of medicine is the pill without coating.

3., according to the controlled release pharmaceutical compositions of example 2, it is characterized in that described core comprises active component thereon and is incorporated into neutral carrier pill in binding agent.

4., according to the controlled release pharmaceutical compositions of example 2, it is characterized in that described core is included in the polymeric matrix of wherein binding activities composition.

5., according to the controlled release pharmaceutical compositions of example 2, it is characterized in that described core comprises the pill be made up of the active component of crystallization.

6., according to the controlled release pharmaceutical compositions of example 1, it is characterized in that the described core containing active constituents of medicine is coating pill.

7., according to the controlled release pharmaceutical compositions of example 6, it is characterized in that described coating pill is the pharmaceutical formulation of sustained release.

8., according to the controlled release pharmaceutical compositions of example 6, it is characterized in that described coating pill is enteric coating pharmaceutical formulation.

9., according to the controlled release pharmaceutical compositions of one or more example 1 to 8, it is characterized in that the resistance to alcohol repellency coatings of described imparting comprises until 20 % by weight be different from polymer moieties polymer a) and be different from excipient part b) the other medicines excipient of excipient.

10. according to the controlled release pharmaceutical compositions of one or more example 1 to 9, it is characterized in that described water-insoluble, basic neutral polyvinyl or copolymer be by more than 95 until the C of 100 % by weight acrylic or methacrylic acid ₁-to C ₄the copolymer that-Arrcostab is formed with the radical polymerization unit of the acrylic or methacrylic acid being less than 5 % by weight.

11., according to the controlled release pharmaceutical compositions of one or more example 1 to 9, is characterized in that the basic neutral polymer of described water-insoluble or copolymer are polyvinyl acetate type polymer or polyvinyl acetate type copolymer.

12. according to the controlled release pharmaceutical compositions of one or more example 1 to 11, it is characterized in that described non-cellular inert lubricant is the tripoli component of stratification, pigment or stearate compound.

13., according to the controlled release pharmaceutical compositions of example 12, is characterized in that described non-cellular inert lubricant is Talcum.

14., according to the controlled release pharmaceutical compositions of example 12, is characterized in that described non-cellular inert lubricant is Ca-or Mg-stearate.

15., according to the controlled release pharmaceutical compositions of one or more example 1 to 14, is characterized in that described cellulosic cpd is water-soluble cellulose derivative.

16. according to the controlled release pharmaceutical compositions of example 15, it is characterized in that described neutral fibre element compound is hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, sodium-carboxymethyl cellulose or methylcellulose.

17., according to the controlled release pharmaceutical compositions of one or more example 1 to 16, is characterized in that described emulsifying agent is nonionic emulsifier.

18., according to the controlled release pharmaceutical compositions of example 17, is characterized in that described cleaning agent is the polyethylene oxide derivatives of sorbitan esters or Sorbitan alcohol ether.

19., according to the controlled release pharmaceutical compositions of example 17 or 18, is characterized in that described cleaning agent is polyethoxy dehydrating sorbitol monooleate.

20., according to the controlled release pharmaceutical compositions of one or more example 1 to 19, is characterized in that described active constituents of medicine has and are categorized as sl. sol. dissolubility in ethanol.

21., according to the controlled release pharmaceutical compositions of example 1 or 20, is characterized in that described active constituents of medicine is OPIOIDS or OPIOIDS antagonist.

22. according to the controlled release pharmaceutical compositions of example 21, it is characterized in that described active constituents of medicine is morphine or naloxone or the acceptable salt of its pharmacy.

23., according to the controlled release pharmaceutical compositions of one or more example 1 to 19, is characterized in that described active constituents of medicine has and are categorized as slightly molten dissolubility in ethanol.

24., according to the controlled release pharmaceutical compositions of example 23, is characterized in that described active constituents of medicine is metoprolol or the acceptable salt of its pharmacy.

25., according to the controlled release pharmaceutical compositions of one or more example 1 to 24, is characterized in that it is with the form of the pill comprised in many granule medicaments form, with the form of tablet agent, capsule, wafer, effervescent tablet or reconfigurable powder.

26., according to the controlled release pharmaceutical compositions of one or more example 1 to 25, is characterized in that also being equipped with top coat in addition.

27. according to the controlled release pharmaceutical compositions of one or more example 1 to 26, it is characterized in that described polymer moieties a) based on core Weight computation with at least 3.0 % by weight amount exist.

28., according to the controlled release pharmaceutical compositions of one or more example 1 to 27, is characterized in that described core has the average diameter within the scope of 100 to 5000 μm.

29. according to the controlled release pharmaceutical compositions of example 28, it is characterized in that described core has the average diameter within the scope of 100 to 700 μm and Weight computation polymer moieties polymer dry amount of substance a) in the resistance to alcohol repellency coatings of imparting based on core is 15 to 200 % by weight.

30. according to the controlled release pharmaceutical compositions of example 28, it is characterized in that described core has more than 700 and until the average diameter in the scope of 1400 μm and Weight computation polymer moieties polymer dry amount of substance a) in the resistance to alcohol repellency coatings of imparting based on core are 10 to 150 % by weight.

31. according to the controlled release pharmaceutical compositions of example 28, it is characterized in that described core has more than 1400 and until the average diameter in the scope of 5000 μm and Weight computation polymer moieties polymer dry amount of substance a) in the resistance to alcohol repellency coatings of imparting based on core are 5 to 100 % by weight.

32. according to the controlled release pharmaceutical compositions of example 1, it is characterized in that the described core containing active constituents of medicine is without coating or coated tablet.

33. preparations are according to the method for the controlled release pharmaceutical compositions of one or more example 1 to 32, and it carries out coating by what comprise active component without the resistance to alcohol repellency coatings of coating or coated core imparting by spray method or bed spray coating.

34. according to the purposes of the controlled release pharmaceutical compositions of one or more example 1 to 32, its for reducing comprised active constituents of medicine after oral absorption by simultaneously or alcoholic beverages consumption continuous mutually strengthen or reduce the risk of release.

Claims

1. controlled release pharmaceutical compositions, it comprises

Core containing active constituents of medicine,

Described polymer moieties a) is made up of water-insoluble, basic neutral polyvinyl or copolymer, described water-insoluble, basic neutral polyvinyl or copolymer be by more than 95 until the C of 100 % by weight acrylic or methacrylic acid ₁-to C ₄the copolymer that-Arrcostab and the radical polymerization unit of acrylic or methacrylic acid being less than 5 % by weight are formed, and/or polyvinyl acetate type polymer or polyvinyl acetate type copolymer,

With

Excipient part b) be made up of following excipient:

B1) the non-cellular inert lubricant of 100 to 250 % by weight, it is selected from the tripoli component of stratification, pigment or stearate compound,

B2) cellulosic cpd of 1 to 35 % by weight, described cellulosic cpd is cellulosic methyl ether, ethylether or propyl ether,

B3) nonionic emulsifier of 0.1 to 25 % by weight, it is the polyethylene oxide derivatives of sorbitan esters or Sorbitan alcohol ether,

2. controlled release pharmaceutical compositions according to claim 1, is characterized in that the described core containing active constituents of medicine is the pill without coating.

3. controlled release pharmaceutical compositions according to claim 2, is characterized in that described core comprises active component thereon and is incorporated into neutral carrier pill in binding agent.

4. controlled release pharmaceutical compositions according to claim 2, is characterized in that described core is included in the polymeric matrix of wherein binding activities composition.

5. controlled release pharmaceutical compositions according to claim 2, is characterized in that described core comprises the pill be made up of the active component of crystallization.

6. controlled release pharmaceutical compositions according to claim 1, is characterized in that the described core containing active constituents of medicine is coating pill.

7. controlled release pharmaceutical compositions according to claim 6, is characterized in that described coating pill is the pharmaceutical formulation of sustained release.

8. controlled release pharmaceutical compositions according to claim 6, is characterized in that described coating pill is enteric coating pharmaceutical formulation.

9., according to the controlled release pharmaceutical compositions of any one of claim 1 to 8, it is characterized in that the resistance to alcohol repellency coatings of described imparting comprises until 20 % by weight be different from polymer moieties polymer a) and be different from excipient part b) the other medicines excipient of excipient.

10. controlled release pharmaceutical compositions according to claim 1, is characterized in that described non-cellular inert lubricant is Talcum.

11. controlled release pharmaceutical compositions according to claim 1, is characterized in that described non-cellular inert lubricant is Ca-or Mg-stearate.

12. controlled release pharmaceutical compositions according to claim 1, is characterized in that described neutral fibre element compound is hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, sodium-carboxymethyl cellulose or methylcellulose.

13. controlled release pharmaceutical compositions according to claim 1, is characterized in that described nonionic emulsifier is polyethoxy dehydrating sorbitol monooleate.

14., according to the controlled release pharmaceutical compositions of any one of claim 1 to 8, is characterized in that described active constituents of medicine has and are categorized as sl. sol. dissolubility in ethanol.

15. controlled release pharmaceutical compositions according to claim 1, is characterized in that described active constituents of medicine is OPIOIDS or OPIOIDS antagonist.

16. controlled release pharmaceutical compositions according to claim 15, is characterized in that described active constituents of medicine is morphine or naloxone or the acceptable salt of its pharmacy.

17. according to 1 controlled release pharmaceutical compositions, it is characterized in that described active constituents of medicine has and be categorized as slightly molten dissolubility in ethanol.

18. controlled release pharmaceutical compositions according to claim 17, is characterized in that described active constituents of medicine is metoprolol or the acceptable salt of its pharmacy.

19., according to the controlled release pharmaceutical compositions of any one of claim 1 to 8, is characterized in that it is with the form of the pill comprised in many granule medicaments form, with the form of tablet agent, capsule, wafer, effervescent tablet or reconfigurable powder.

20., according to the controlled release pharmaceutical compositions of any one of claim 1 to 8, is characterized in that also being equipped with top coat in addition.

21. according to the controlled release pharmaceutical compositions of any one of claim 1 to 8, it is characterized in that described polymer moieties a) based on core Weight computation with at least 3.0 % by weight amount exist.

22., according to the controlled release pharmaceutical compositions of any one of claim 1 to 8, is characterized in that described core has the average diameter within the scope of 100 to 5000 μm.

23. controlled release pharmaceutical compositions according to claim 22, is characterized in that described core has the average diameter within the scope of 100 to 700 μm and Weight computation polymer moieties polymer dry amount of substance a) in the resistance to alcohol repellency coatings of imparting based on core is 15 to 200 % by weight.

24. controlled release pharmaceutical compositions according to claim 22, is characterized in that described core has more than 700 and until the average diameter in the scope of 1400 μm and Weight computation polymer moieties polymer dry amount of substance a) in the resistance to alcohol repellency coatings of imparting based on core are 10 to 150 % by weight.

25. controlled release pharmaceutical compositions according to claim 22, is characterized in that described core has more than 1400 and until the average diameter in the scope of 5000 μm and Weight computation polymer moieties polymer dry amount of substance a) in the resistance to alcohol repellency coatings of imparting based on core are 5 to 100 % by weight.

26. controlled release pharmaceutical compositions according to claim 1, is characterized in that the described core containing active constituents of medicine is without coating or coated tablet.

27. preparations are according to the method for the controlled release pharmaceutical compositions of any one of claim 1 to 26, and it carries out coating by what comprise active component without the resistance to alcohol repellency coatings of coating or coated core imparting by spray method or bed spray coating.