HK1211491B - Ph-dependent controlled release pharmaceutical composition for non-opioids with resistance against the influence of ethanol - Google Patents

Description

Pharmaceutical compositions for pH-dependent controlled release of ethanol-resistant non-opioid drugs

Technical Field

The present invention relates to pH-dependent controlled-release pharmaceutical compositions of non-opioid drugs having reduced sensitivity to the effects of ethanol on the release of the active compound.

Background Art

US 2003/0118641 A1 describes a process for reducing the abuse potential of oral pharmaceutical forms containing extractable opioids. In this process, resistance to extraction of the active compound by commonly used household solvents such as isopropyl alcohol, vodka, white wine vinegar, hot water or peroxide, 0.01 HCl in dilute alcohol is specifically provided. It is suggested that a micronized form of the active compound be formulated using a matrix-forming polymer and an ion exchange material, such as styrene-divinylbenzene polymer. The ion exchange material is crucial for increasing resistance to extraction of the active compound. The matrix-forming polymer clearly serves as a structure-imparting agent for the drug core. A long list of possible materials for the matrix-forming polymer is specified, including, in particular, polymethacrylates. A preferred matrix-forming agent is C ₁ -C ₆ -hydroxyalkyl-cellulose.

US 2004/0052731 A1 describes pharmaceutical forms particularly suitable for opioid active compounds which will help reduce the potential for abuse due to improper administration. It is proposed to combine lipophilic active compound variants with water-insoluble additives such as, for example, fatty acids or cross-linked, water-soluble polysaccharides.

US 2005/0163856 A1 describes a therapeutic process for treating pain patients using a pharmaceutical form containing oxycodone that has a reduced potential for abuse due to dissolution in solvents and subsequent improper administration. For this purpose, the active compound is formulated with a matrix-forming polymer selected from hydroxypropylcellulose, hydroxypropylmethylcellulose or hydroxyethylcellulose.

WO 2006/002884 A1 describes abuse-resistant oral administration forms containing polymers, in particular polyalkylene oxides, having a resistance to breaking of at least 500 N.

WO 2006/094083 A1 describes a pharmaceutical form with a controlled release profile for venlafaxine. To reduce the potential for abuse due to the addition of ethanol, the active compound is incorporated into a matrix of a gelling cross-linked polymer, such as xanthan gum. Additional hydrophobic polymers, in particular polymethacrylates, may be added as additives.

WO 2006/125483 describes the use of polymer mixtures for preparing coated pharmaceutical formulations and pharmaceutical formulations with mixed polymer coatings. These polymer mixtures are intended to provide modified release profiles tailored to the specific therapeutic requirements of different drug ingredients, which cannot be achieved using standard polymers. There is no indication of ethanol-tolerant pharmaceutical forms. The examples describe pharmaceutical forms coated with a mixture of NE and FS at a ratio of 5 to 50% by weight of FS. However, the use of large amounts of talc, as used in the present invention, is not used in the examples or recommended in the specification. A suitable coating thickness is 2-20% by weight of the core weight, which is much lower than the coating thickness required for the present invention.

WO 1994/0022431 A1 describes an oral pharmaceutical formulation containing a therapeutically effective amount of morphine for administration. It contains at least 50 individual particles having a particle size of 0.7 to 1.4 mm. Each particle has a core containing a morphine salt coated with a barrier layer. The barrier layer comprises at least one water-insoluble component selected from ethylcellulose, a copolymer synthesized from an acrylate or methacrylate, and a natural wax, and a plasticizer, and is configured to provide drug release through the barrier layer that is substantially independent of a pH in the range of 1.0 to 7.0. A serum concentration of morphine achieved over a period of at least 12 hours following administration of a single dose of the formulation is at least 50% of the maximum serum concentration.

US 2007/053698 discloses a method for sustained release administration of opioids (including but not limited to hydromorphone and oxycodone) that exhibits improved properties with respect to co-ingestion with aqueous alcohol.

definition

pH-dependent controlled-release pharmaceutical compositions

The pH-dependent controlled-release pharmaceutical composition refers to a pharmaceutical composition comprising a drug ingredient formulated with a pharmaceutically acceptable film-forming polymer and optionally other pharmaceutically acceptable excipients, wherein the pharmaceutical composition exhibits pH-dependent controlled-release of the drug ingredient.

Active pharmaceutical ingredients other than opioids

The pH-dependent controlled-release pharmaceutical composition comprises a core comprising at least one pharmaceutically active ingredient other than an opioid. Pharmaceutical compositions comprising one or more opioids (opioid agonists) are expressly excluded from the present invention.

Preferred are pharmaceutically active ingredients that are typically formulated as controlled-release or sustained-release dosage forms.

A suitable pharmaceutical active ingredient is, for example, metoprolol.

Medicinal substances for use can be found in reference books such as, for example, the Rote Liste or the Merck Index.

The active ingredients or medicinal substances for the purposes of the present invention are intended for use in the human or animal body for the following purposes:

1. To treat, alleviate, prevent or diagnose an illness, disease, physical injury or pathology;

2. Revealing the condition, state, or function of the body, or the state of mind;

3. Replace active substances or body fluids produced by the human or animal body;

4. To avoid, eliminate, or render harmless pathogens, parasites, or foreign substances; or

5. Affecting the condition, state or function of the body, or the mental state.

These pharmaceutical active substances may belong to one or more classes of active ingredients, such as ACE inhibitors, adrenergic drugs, adrenocortical steroids, acne treatment agents, aldose reductase inhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha 1 antagonists, drugs for alcohol abuse, amino acids, amoebicides, anabolic steroids, analgesics, anesthetic additives, anesthetics (non-inhaled), anesthetics (topical), analgesics (other than opioids), androgens, angina treatment agents, antagonists, antiallergics, antiallergics such as PDE inhibitors, antiallergics for asthma treatment, other antiallergics (e.g., leukotriene antagonists, antianemics, antiandrogens, anxiolytics, antiarthritis, anticardioprotectants, arrhythmic agents, antiatherosclerotic agents, antibiotics, anticholinergics, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antidiuretics, antidotes, antiemetics, antiepileptics, antifibrinolytics, anticonvulsants, anthelmintics, antihistamines, antihypertensives, antihypertensives, antihypertensives, anticoagulants, antifungals, antiestrogens, antiestrogens (non-steroidal), antiparkinsonian agents, anti-inflammatory agents, antiproliferative active ingredients, antiprotozoal active ingredients, antirheumatic agents, antischistosomal agents, antispasmodics, antithrombotics, cough suppressants, appetite suppressants, atherosclerotic drugs, antibacterials, beta-blockers, beta-blockers, Bronchodilators, carbonic anhydrase inhibitors, chemotherapeutic agents, choleretics, cholinergics, cholinergic agonists, cholinesterase inhibitors, agents for the treatment of ulcerative colitis, cyclooxygenase inhibitors, diuretics, ectoparasiticides, emetics, enzymes, enzyme inhibitors, enzyme inhibitors, antiemetic active ingredients, fibrinolytics, antifungals, gout medications, glaucoma treatments, glucocorticoids, glucocorticoid steroids, hemostatics, cardiac glycosides, histamine H2 antagonists, hormones and their inhibitors, immunotherapeutic agents, cardiotonic drugs, coccidiostats, laxatives, lipid-lowering drugs, gastrointestinal treatments, malaria treatments, migraine medications, microbicides, Crohn's disease, cancer metastasis inhibitors, migraine medications, mineral preparations, activities that increase motility Ingredients, muscle relaxants, neuroleptics, active ingredients for estrogen therapy, osteoporosis, otological drugs, antiparkinsonian drugs, herbal medicines, proton pump inhibitors, prostaglandins, active ingredients for the treatment of benign prostatic hyperplasia, active ingredients for the treatment of pruritus, active ingredients for psoriasis, psychoactive drugs, free radical scavengers, renin antagonists, thyroid therapeutic agents, active ingredients for the treatment of seborrhea, active ingredients for the treatment of seasickness, antispasmodics, alpha- and beta-sympathomimetics, platelet aggregation inhibitors, sedatives, ulcer therapeutics, other ulcer therapeutics, agents for the treatment of urolithiasis, antivirals, vitamins, cytokines, active ingredients for combination therapy with cytostatics.

Examples of suitable active ingredients other than opioids are, for example, acarbose, aspirin, abacavir, aceclofenac, aclarubicin, acyclovir, actinomycin, adalimumab, adefovir, adefovir dipivoxil, adenosylmethionine, adrenaline and adrenaline derivatives, α-galactosidase, β-agacitase, alemtuzumab, almotriptan, alphacept, allopurinol, almotriptan, alosetron, alprostadil, amantadine, ambroxol, amisulpride, amlodipine, amoxicillin, 5-aminosalicylic acid, amimetics, succinate, dapoxetine ... Triptyline, amlodipine, amoxicillin, amprenavir, anakinra, anastrozole, androgens and androgen derivatives, apomorphine, aripiprazole, arsenic trioxide, artemether, atenolol, atorvastatin, atosiban, azathioprine, azelaic acid, barbituric acid derivatives, balsalazide, basiliximab, beclapermin, beclomethasone, bemiparin, benzodiazepines, betahistine, bexarotene, bezafibrate, bicalutamide, bimatoprost, bosentan, botulinus toxim, brimonidine, brinzolamide, budesonide, budipine, bufetanide, bumetanide, bupropion, butizine, calcitonin, calcium channel blockers, calcium salts, candesartan, capecitabine, captopril, carbamazepine, carifenacin, carvedilol, caspofungin, cefaclor, cefadroxil, cefalosporins, cefditoren, cefprozil, celecoxib, cepecitabine, cerivastatim, cetirizine, cetrorelix, cetuximab, chenodeoxycholic acid, chorionic gonadotropin, cyclosporine, cidofovir, cimetidine, ciprofloxacin, cisplatin, cladribine, clarithromycin, clavulanic acid , clindamycin, clobutinol, clonidine, clopidogrel, caffeine, cholestyramine, cromolyn, cotrimoxazole, coumarins and coumarin derivatives, darbepoetin, cysteamine, cysteine, cytarabine, cyclophosphamide, cyproterone acetate, cytarabine, daclizumab, dalfopristin, danaparin, dapoxetine, darbepoetin, defepripone, desipramine, desirudin, desloaratadine, desmopressin, desogestrel, desonide, dexibuprofen, dexketoprofen, disoproxil, diazepam and diazepam derivatives, dihydralazine, diltiazem, dimenhydrinate, dimethyl sulfoxide, dimeticon, pivaloyloxymethyl, dipyridar noi, dolasetron, domperidone and domperidane derivatives, donepzil, dopamine, doxazosin, doxorubizin, doxylamine, diclofenac, divalproex, dronabinol, drospirenone, drotrexone alfa, dutasteride, ebastine, econazole, efavirenz, eletripan, emidastine, emtricitabine, enalapril, encepur, entacapone, enfurvirtide, ephedrine, epinephrine, eplerenone, epoetin and epoetin derivatives, eprosartan, eptifibatide, ertapenem, esomeprazole, estrogens and estrogen derivatives, etanercept , ethynestradiol, etofenamate, etofibrate, ethynethline, etonogestrel, etoposide, exemestane, exetimib, famciclovir, famotidine, faropenandaloxate, felodipine, fenofibrate, fenticonazole, fexofenadine, finasteride, fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, flupirtine, flutamide, fluvastatin, follitropin, fomivirsen, fondaparinux, formoterol, fosfomicin, frovatriptan, furosemide, fusidic acid, gadobenate, galantamine, gallopamil, ganciclovir, ganirelix, gatifloxacin , gefitinib, gemfibrozil, gentamicin, gepirone, progestogens and progestogen derivatives, ginkgo biloba, glatiramer, glyburide, glipizide, glucagon, sorbitol and sorbitol derivatives, glucosamine and glucosamine derivatives, glycoside antibiotics, glutathione, glycerol and glycerol derivatives, hypothalamic hormones, goserelin, grepafloxacin, gyrase inhibitors, guanethidine, gyrase inhibitors, hemin chloride, halofantrine, haloperidol, urea derivatives as oral antidiabetic agents, heparin and heparin derivatives, cardiac glycosides, hyaluronic acid, hydralazine, hydrochlorothiazide and hydrochlorothiazide derivatives, hydroxyomeprazole, hydroxyzine, ibritumomab, Ibuprofen, idarubicin, ifliximab, ifosfamide, iloprost, imatinib, imidapril, imiglucerase, imipramine, imiquimod, imidapril, indomethacin, indolaamine, infliximab, insulin, insulin glargine preparations, interferons, irbesartan, irinotecan, isoconazole, isoproterenol, itraconazole, ivabradine, iodine and iodine derivatives, St. John's wort, potassium salts, ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole, laronidase, latanoprost, leflunomide, lepirudin, lercanidipine, letrozole, levomethadol acetate, levetiracetam, levocetirizine, levodopa, ricofilone, linezolid, lipin avir, lipoic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramine, lodoxamide, lomefloxacin, lomustine, loperamide, lopinavir, loratadine, lornoxicam, losartan, lumefantrine, luteinizing hormone, magnesium salts, macrolide antibiotics, mangafodipir, maprotiline, mebendazole, mebeverine, meclizine, mefenamic acid, mefloquine, meloxicam, memantine, mepindolol, meprobamate, meropenem, mesalamine, methsuximide, metamizole, metformin, methotrexate, methyl 5-amino-4-oxopentanoate, methylnaloxone, methylnaltrexone, methylphenidate, methylprednisolone, methixene (metformin), methotrexate, methyl 5-amino-4-oxopentanoate, methylnaloxone, methylnaltrexone, methylphenidate, methylprednisolone, methixene (met ixen), metoclopramide, metoprolol, metronidazole, mianserin, mibefradil, miconazole, mifepristone, miglitol, miglustad, minocycline, minoxidil, misoprostol, mitomycin, mizolastine, modafinil, moexipril, montelukast, moroctocog, moxifloxacin, ergot alkaloids, naloxone, naproxen, naratriptan, noscapine, natamycin, nateglinide, nebivolol, nefazodone, nelfinavir, neostigmine, neramexan, nevirapine, nicergoline, nikethamide, nifedipine, niflumic acid, nimodipine, nimozole, nimustine, nesiritide, nisoldipine, norfloxacin, novamine sulphone, narcotine, nystatin, ofloxacin, oktotride, olanzapine, olmesartan, olsalazine, oseltamivir, omeprazole, omoconazole, ondansetron, orlistat, oseltamivir, oxacepromazine, oxaliplatin, oxaprozin, oxcarbacepin, oxiconazole, oxymetazoline, palivizumab, palanosetron, pantoprazole, acetaminophen, parecoxib, paroxetine, pegaspargase, pegylated interferon, pegfilgrastrim, penciclovir Wei, oral penicillins, pentifylline, pentoxifylline, peptide antibiotics, perindopril, perphenazine, meperidine, plant extracts, antipyrine, pheniramine, phenylbutyric acid, phenytoin, phenothiazines, fenserin, phenylbutazone, phenytoin, pimecrolimus, pimozide, pindolol, pioglitazone, piperazine, piracetam, pirenzepine, piribedil, pirlindol, piroxicam, pramipexol, pramlintide, pravastatin, prazosin, procaine, promazine, propiverine, propranolol, propionic acid derivatives, Isopropylantipyrine, prostaglandins, prothionamide, prophylline, quetiapine, quinapril, quinprilat, quinupristine, ramipril, ranitidine, rabeprazole, raloxifen, ranolazine, rasburicase, reboxetin, repaclinides, reproterol, reserpine, revofloxacin, ribavirin, rifampin, riluzole, rimexolone, risedronate, risperidone, ritonavir, rituximab, rivast imen, risatriptan, rofecoxib, ropinirol, ropivacaine, rosiglitazone, roxatidine, roxithromycin, spirocogenin, rosuvastatin, rutin and rutin derivatives, saba grass, salbutamol, salicylates, salmeterol, saperconazole, thyroid hormones, scopolamine, selegiline, sertaconazole, sertindole, sertraline, sevelamer, sibutramine, sildenafil, silicates, simvastatin, sirolimus, sitosterol, sotalol, sirolimus , sparfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralfate, sulbactam, sulfonamide, sulfasalazine, sulpiride, sultamicillin, sultiam, sumatriptan, succinylcholine chloride, tacrine, tacrolimus, tadalafil, taliolol, tasalidin, tamoxifen, tasonamine, tazarotene, tegafur, tegaserod, telithromycin, telmisartan, temoporfin, temozolomide, tenatoprazole, tenecteplase, teniposide, tenofovir, tenoxicam, teriparatide, terazosin, temoxifen, temozolomide ... Binafine, terbutaline, terfenadine, teriparatide, terlipressin, tertalol, testosterone and testosterone derivatives, tetracyclines, tetrahydrozoline, tizosentan, theobromine, theophylline, theophylline derivatives, methimazole, thiotepa, thr. growth factors, tiagabine, sulpiride, tibolone, ticlopidine, timolol, tinidazole, tioconazole, thioguanine, tiotropium, thioxolone, tirazetam, tiroclad, tirofiban, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone, tolterodine, topiramate , topotecan, torasemide, trandolapril, tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, trepostinil, triamcinolone and triamcinolone derivatives, triamterene, trifluoperidol, trifluridine, trimetazidine, trimethoprim, trimipramine, tripelennamine, triprolidine, trifosfamide, tromantanamide, tromethamine, tropalpine, trovafloxacin, troxerutin, tulobuterol, trypsins, tyramine, gramicidin, urapidil, ursodeoxycholic acid, theophylline ursodeoxycholic acid, valacyclovir Vir, valdecoxib, valganciclovir, valproic acid, valsartan, vancomycin, vardenafil, vecuronium, venlafaxine, verapamil, verteporfin, adenosine, vigabatrin, viloxazine, vinblastine, vincristine, vindesine, vinorelbine, vinpocetine, vequadil, vitamin D and vitamin D derivatives, voriconazole, warfarin, nicantrin, ximelagatran, xipamide, zafirlukast, zalcitabine, zaleplon, zanamivir, zidovudine, ziprasidone, zoledronic acid, zolmid, zolpidem, zoplicone, and zotepine.

If desired, the active ingredients may also be used in the form of their pharmaceutically acceptable salts or derivatives, and in the case of chiral active ingredients, it is possible to use racemates or mixtures of optical isomers and diastereomers. If desired, the compositions of the present invention may also comprise two or more active pharmaceutical ingredients.

pH-dependent controlled release

pH-dependent controlled release of a drug ingredient means that when a drug composition is exposed to buffered USP media having different pH values in an in vitro dissolution test, wherein the pH value is within the range of about pH 1 to about pH 7 and is changed at about 1 pH interval, the amount of the drug ingredient released or dissolved in the media at a certain time interval is significantly different in the media with different pH values.

Buffered USP media with different pH values are known to those skilled in the art. USP media with different pH values can have, for example, pH 1.2, pH 2.0, pH 5.8, pH 6.8, and pH 7.4. In vitro dissolution testing can be performed in a USP dissolution apparatus, such as apparatus II (paddle method), at 37° C. with a dissolution stirring rate of 100 rpm, and certain time intervals can be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours or even longer.

When tested in media with different pH values, pH 1.2, 2.0, 4.5, 6.8 and 7.4, the dissolution rates in media with different pH values were significantly different.

For example, the behavior of a typical pH-independent controlled release is described, for example, in WO 1994/022431 A1 (see in particular page 13, Table 5), in contrast to the behavior of the pH-dependent controlled release of the present invention.

In particular, the pH release behavior of the pharmaceutical composition of the present invention is pH-dependent due to its gastric acid resistance, meaning that in a USP medium at pH 1.2, only 10% of the drug ingredient is released within 2 hours, while in a USP medium at a higher pH value, such as a USP medium at pH 7.4, significantly more than 10% of the drug ingredient is released within 2 hours. In contrast, the pH-independent controlled-release form of WO 1994/022431 A1 (see, page 13, Table 5) shows the same 15% release rate after 2 hours in a buffered medium at pH 1.2 or pH 7.4.

polymer mixture

The term polymer mixture in the sense of the present invention is understood to mean a mixture of:

i) 40-95% by weight, based on the dry weight of the polymer mixture, of at least one water-insoluble, substantially neutral olefinic polymer or copolymer, and

ii) 5-60 wt. %, based on the dry weight of the polymer mixture, of at least one anionic polymer or copolymer which is insoluble in a buffered medium at a pH below 4.0 and soluble at least in the range of pH 7.0 to pH 8.0.

The neutral cellulose compound also present in the coating layer is not calculated as part of this polymer mixture, but is calculated separately relative to the dry weight of this polymer mixture. The emulsifier present in the coating layer is also calculated based on the dry weight of the polymer mixture of compounds i) and ii) without the neutral cellulose polymer.

Inert non-porous lubricant

The coating layer may additionally contain 110-250% by weight, preferably 140-220% by weight, of a non-porous, inert lubricant, based on the dry weight of the polymer mixture.

Lubricants (sometimes also called glidants) are pharmaceutically acceptable substances that help prevent polymers from agglomerating during the coating process.

Porous lubricants such as silicon dioxide powder are not suitable for the purpose of the present invention.The porous structure may cause a capillary effect which promotes enhanced penetration of the coating by a medium containing aqueous alcohol (ethanol), in particular a medium containing aqueous ethanol.

Inert means that the lubricant generally does not react chemically with other substances and is insoluble or only slightly soluble in water and/or ethanol.

Insoluble or only slightly soluble means requiring more than 10 parts by weight of solvent per 1 part by weight of solute. In addition, the inert non-porous lubricant does not substantially affect the glass transition temperature of the coating polymer mixture.

Lubricants such as glycerol monostearate (GMS), which cannot be applied to the coating in sufficient amounts to impart resistance to aqueous media containing ethanol, are themselves unsuitable in the sense of the present invention. Glycerol monostearate (GMS) is therefore not inert in the sense of the present invention.

The non-porous inert lubricant may be a layered silica component, a pigment, or a stearate compound.

The inert lubricant may be calcium stearate or magnesium stearate. The inert lubricant may be TiO ₂ .

The inert non-porous lubricant is most preferably talc.

Ethanol tolerance drug preparations

Alcohol-tolerant drug formulations are formulations with release kinetics that are not significantly affected by the presence of ethanol. Alcohol tolerance may be an important registration requirement in the near future. Conventional drug coatings, particularly coatings on pellets, do not have adequate alcohol tolerance. Surprisingly, it has been discovered that coatings that combine an insoluble film-forming agent with a soluble film-forming agent provide greater alcohol tolerance.

An ethanol-resistant (or sometimes referred to as stable) formulation is defined by comparing in vitro release data obtained from tests performed in a medium without alcohol and in a corresponding medium containing 40% ethanol at a pH of 6.8 (see Appendix for details) and maintaining the difference in release profile below 15% if the release in the medium without alcohol is less than 20% of the total dose and maintaining the difference in release profile below 30% if the release is between 20% and 80% of the total dose.

Purpose and Outcomes

The present invention is based on controlled-release pharmaceutical forms for oral administration. These types of pharmaceutical forms are intended to release the active compound more or more prolonged, typically during intestinal transit. The goal is to achieve, by means of suitable formulation of the pharmaceutical form, that after an initial increase in the blood level of the active compound, the blood level remains within the therapeutically optimal range for as long as possible. In particular, excessively high blood levels of the active compound should be avoided, as they may have toxic effects.

In the case of delayed-release formulations for oral pharmaceutical forms, the influence of gastric and intestinal fluids, in particular the ionic strength and the environmental pH, is essentially taken into account in a manner known per se in the art. The problem is that the ideal rate of release of the active compound assumed here can be altered by the patient's general lifestyle, carelessness, or addiction to ethanol or ethanol-containing beverages. In these cases, pharmaceutical forms, which are actually designed for use in a completely aqueous medium, are additionally exposed to a medium containing a greater or lesser strength of ethanol.

Due to the dissolution of oral delayed-release pharmaceutical forms in alcoholic beverages, or the simultaneous or overlapping ingestion of oral delayed-release pharmaceutical forms and alcoholic beverages, undesirable or even serious acceleration or slowing down of the release of the active compound may occur. In most cases, the presence of ethanol causes the release of the composition to be accelerated. This acceleration is a major problem, while slowing down is usually less critical. It must be taken into account that an absolute value of an acceleration or increase in the release of the pharmaceutical active ingredient exceeding 30% relative to the % release under the condition of not having 40% ethanol is serious.

Because not all patients are aware of the risks of concomitantly ingesting controlled-release drug forms and beverages containing ethanol, or do not or are unable to comply with appropriate warnings, prompts, or recommendations, the goal is to design oral delayed-release drug forms such that their mode of action is affected as little as possible by the presence of ethanol.

The object of the present invention is expressly not to stimulate, promote or enable the ingestion of alcohol-containing beverages with delayed-release pharmaceutical forms, but rather to reduce or avoid the potentially fatal consequences of intentional or unintentional misuse or abuse.

Purpose of the present invention

Because of the unpredictability of in vivo effects, the present invention is based on in vitro conditions as a basis for objectively understood measurements. As harsh test conditions, in vitro conditions according to USP Method 1 (basket method), 100 rpm, at pH 6.8 buffered (European Pharmacopoeia (EP)), with and without the addition of 40% (v/v) ethanol can be selected.

One object of the present invention is achieved when the controlled-release pharmaceutical composition meets the following conditions:

When the pharmaceutical active ingredient is released to an extent of less than 20% without the addition of 40% (v/v) ethanol at 100 rpm and buffered at pH 1.2 for the first 2 hours and pH 6.8 for the remainder of the time according to USP Method 1 (basket method), the release rate with the addition of 40% (v/v) ethanol should not differ by more than ±15% from the corresponding release value without the addition of 40% (v/v) ethanol. For example, when the pharmaceutical active ingredient is released to an extent of 18% without the addition of 40% (v/v) ethanol, the release rate with the addition of 40% (v/v) ethanol should not differ by more than ±15% from the release value without the addition of 40% (v/v) ethanol, which means that the extent of release with the addition of 40% (v/v) ethanol may be in the range of 3 to 33%.

When the pharmaceutical active ingredient is released to an extent of 20-80% without the addition of 40% (v/v) ethanol at 100 rpm and buffered at pH 1.2 for the first 2 hours and pH 6.8 for the remainder of the time according to USP Method 1 (basket method), the release rate with the addition of 40% (v/v) ethanol should not differ by more than ±30% from the corresponding release value without the addition of 40% (v/v) ethanol. For example, when the pharmaceutical active ingredient is released to an extent of 50% without the addition of 40% (v/v) ethanol, the release rate with the addition of 40% (v/v) ethanol should not differ by more than ±30% from the release value without the addition of 40% (v/v) ethanol, which means that the extent of release with the addition of 40% (v/v) ethanol can be in the range of 20 to 80%.

Controlled-release pharmaceutical compositions that meet this condition are considered to be resistant to severely accelerated release of the active compound due to careless or addictive behavior of patients associated with the use of ethanol or beverages containing ethanol.

This scenario essentially involves the ingestion of an alcoholic beverage simultaneously with or subsequent to the ingestion of a controlled-release form, thereby exposing the drug form to a strong ethanol-containing medium in the stomach or intestine.

An object of the present invention is to provide a pharmaceutical composition for non-opioid drugs that is resistant to the effects of ethanol.

Another object of the present invention is to provide a controlled release pharmaceutical composition that is resistant to ethanol and also resistant to the effects of intragastric use without the need for adding special enteric coatings such as coating with enteric film-forming polymers having a large number of anionic groups such as S or L or L100-55.

This is achieved by the controlled release pharmaceutical composition of the present invention, characterized in that the extent of release of the active ingredient in simulated gastric fluid pH 1.2 is 10% or less within 2 hours with or without the addition of 40% ethanol (v/v).

Another objective was the storage stability of the pharmaceutical composition, which should be further improved to within the range of 60-100 expressed as f ₂ -value (storage stability=good).

Measurement method

The percentage release of the active compound can be measured, for example, by online UV spectroscopy at a wavelength suitable for the respective active compound. HPLC determinations may also be employed. Such methodologies are well known to those skilled in the art.

The release of the active compound can be determined according to USP, specifically USP 28-NF23, General Chapter <711>, Dissolution, Apparatus 2 (Paddles), Method <724> "Delayed-Release (Enteric-Coated) Products - General Drug Release Criteria." Correct citation is required! Method B (100 rpm, 37°C), Type I Basket, with the following modifications: The drug form is tested in a 0.1 N HCl buffered at pH 1.2 for the first 2 hours and in a phosphate buffered saline buffered at pH 6.8 (European Pharmacopoeia (EP), which corresponds to an artificial intestinal medium) for the remainder of the test. Measurements in aqueous media containing ethanol are performed using an appropriate amount of 30% or preferably 40% (v/v) ethanol in the medium.

Storage stability

In general, drug substances should be evaluated under storage conditions (allowing appropriate tolerances) to test thermal stability and, if applicable, sensitivity to moisture (ICH Guideline Q1A(R2), 6 February 2003).

Accelerated conditions for drug substances: 40°C ± 2°C, 75% RH (relative humidity) ± 5% RH, sealed container, for 6 months. Storage stability can be expressed using the so-called similarity factor _f² , or _f² value. The similarity factor _f² is inversely proportional to the average squared distance between the two release profiles before and after storage. Over the past decade, the _f² calculation has become a recommended method in several FDA industry manuals. The calculation method is known to those skilled in the art. _{An f²} value of 100 means no deviation in the average squared distance between the two release profiles before and after storage.

Storage stability is considered acceptable when the deviation of the _release characteristics before and after storage is expressed as a similarity of 50 or more but less than 60, as represented by the _f2 value. Storage stability is considered good when the deviation of the release characteristics before and after storage is expressed as an f2 value of 60 to 100. Storability tests are well known to those skilled in the art.

Detailed description of the invention

The present invention relates to:

A pH-dependent controlled-release pharmaceutical composition comprising:

a core comprising at least one pharmaceutically active ingredient that is not an opioid, wherein the core is coated with at least one coating layer that controls the release of the pharmaceutical composition,

The coating layer comprises a polymer mixture of:

i) 40-95 wt. %, preferably 60-95 wt. %, most preferably 70-90 wt. %, based on the dry weight of the polymer mixture, of at least one water-insoluble, substantially neutral olefinic polymer or copolymer, and

ii) 5 to 60 wt. %, preferably 5 to 40 wt. %, most preferably 10 to 30 wt. %, based on the dry weight of the polymer mixture, of at least one anionic polymer or copolymer which is insoluble in a buffer medium below pH 4.0 and soluble at least in the range of pH 7.0 to pH 8.0,

The characteristics are,

The coating layer further comprises, essentially contains or contains 110-250 wt %, preferably 140-220 wt % of a non-porous inert lubricant, 1-35 wt %, preferably 2-30 wt %, most preferably 5-25 wt % of at least one neutral cellulose compound, and 1-25 wt %, preferably 5-20 wt %, most preferably 5-15 wt % of at least one emulsifier, all based on the dry weight of the polymer mixture.

core

In a manner known per se in the art, a core or pellet core containing the active ingredient forms the basis of the coating of the vinyl (co)polymer. Granulation can be carried out on balls (blank pellet cores) or pellets without a core that do not contain the active ingredient, and a pellet core can be prepared. First, a circular matrix containing the active ingredient with or without a core is prepared. By means of a fluidized bed process, the liquid can be applied to a placebo pellet or other suitable carrier material, and the solvent or suspending agent can be evaporated. Depending on the preparation method, a drying step can be added. The spraying step and subsequent drying can be repeated several times until the predetermined amount of the active pharmaceutical ingredient has been fully applied.

Conventionally, the active ingredient is added to an organic solvent or water and mixed. To ensure satisfactory sprayability, it is usually necessary to formulate the mixture with a relatively low viscosity. The addition of a detergent, such as Tween, at a concentration of 0.1 to 20% by weight, preferably 0.5 to 10% by weight, helps reduce surface tension.

Besides the active ingredients, they may contain further pharmaceutical excipients: binders such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), humectants, disintegration aids, disintegrants, (meth)acrylates, starch and its derivatives, sugar solubilizers or other substances.

Suitable administration methods are known, see, for example, Bauer, Lehmann, Osterwald, Rothgang "Arzneiformen" [Coated Pharmaceutical Forms] Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, Chapter 7, pages 165-196.

The details can be further known to those skilled in the art from textbooks. For example, see:

- Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie [Textbook of Pharmaceutical Technology]; Verlag Chemie Weinheim-Beerfield Beach/Florida-Basle.

- Sucker, H., Fuchs, P., Speiser, P.: Pharmazeutische Technologie [Pharmaceutical Technology], George Thieme Verlag Stuttgart (1991), in particular Chapters 15 and 16, pp. 626-642.

- Gennaro, A., R. (Editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pennsylvania (1985), Chapter 88, pp. 1567-1573.

- List, P.H. (1982): Arzneiformenlehre [Pharmaceutical Form Theory], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart.

The pellet cores can be rounded by processes such as rotor agglomeration, precipitation, or spraying, in particular by ultrasonic vortex spraying, to obtain cores or pellet cores of a given size, for example, 50 to 2500 microns, which are still uncoated. This has the advantage that the entire core volume is available for active ingredient loading. Thus, the active ingredient loading is increased compared to embodiments with an inert core.

The cores of the minitablets can be prepared using a direct compaction method.

Besides the pharmaceutically active ingredient, the core may contain further pharmaceutical excipients: binders, such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), wetting agents, disintegration aids, disintegrants, starch and its derivatives, sugar solubilizers or other substances.

Controlled release coating of pharmaceutical compositions

The core is coated with at least one, preferably one or more, and preferably only one coating layer that controls the release of the pharmaceutical composition. The coating layer imparts resistance to aqueous media containing ethanol to the release profile. The coating layer that controls the release of the pharmaceutical composition can also be referred to as an outer coating layer because it surrounds the core.

The (external) coating layer controls the release of the pharmaceutical composition and imparts resistance to aqueous media containing ethanol to the release profile.

In case the core ingredients are incompatible with the coating ingredients, a barrier subcoat may be applied between the core and the (outer) coating layer.

The coating layer controlling the release of the pharmaceutical composition may additionally be covered by a non-functional, preferably water-soluble, top coating which has substantially no influence on the release characteristics.

After the core or pellet core containing the active ingredient is prepared, they are supplied to the spraying process of the coating layer to obtain the coated core or coated pellet respectively. The coating is prepared by spraying from an organic solution or preferably from an aqueous dispersion. For the purpose of implementation, it is important to obtain a uniform, non-porous coating. Conventionally, after the spraying process and before the start of the conditioning process, the coated pellet is dried in sequence for a few minutes. Conventionally, the polymer coating contains pharmaceutically customary excipients, such as, for example, a release agent or a plasticizer.

Based on the weight of the core, the coating layer that controls the release of the pharmaceutical composition is present in an amount of at least 10 weight %.Based on the weight of the core, the coating is preferably present in an amount of 20-200 weight %, preferably 30-100 weight %, more preferably 40-80 weight %.

The amount of coating may correspond to an average coating thickness in the range of about 20-200 microns, preferably 50-150 microns.

Coated pellets

The controlled release pharmaceutical composition may preferably be in the form of coated pellets, mini-tablets or tablets having an overall mean diameter of 100 to 5000 microns, preferably 100 to 2000 microns, most preferably 300-1000 microns.

The controlled release pharmaceutical composition of the present invention may be in the form of coated pellets having an overall average diameter of 100 to 700 microns, preferably more than 200 microns or more than 500 microns, or 250-400 microns.

The controlled release pharmaceutical composition of the present invention may be in the form of coated pellets, mini-tablets or tablets having an overall average diameter of 1400 to 5000 microns, preferably 1500 to 4000 microns, most preferably 1800 to 3500 microns.

When the overall mean diameter of the coated pellets is from 100 to 700 microns, preferably greater than 200 microns or greater than 500 microns, or from 250 to 400 microns, the coating should be present in an amount of at least 100% by weight based on the weight of the core.

When the overall mean diameter of the coated pellets is from 1400 to 5000 microns, preferably greater than 2000 microns or greater than 2500 microns, or from 2500 to 3500 microns, the coating should be present in an amount of at least 30% by weight based on the weight of the core.

microtablets

The controlled release pharmaceutical composition may preferably be in the form of coated mini-tablets, wherein the mini-tablets have an average diameter of 1 to 5 mm.

tablet

With the completion of the present invention, it is possible to provide coated tablets with gastric acid resistance and ethanol resistance, for example in sizes from 1 mm to a maximum of 50 mm. This is advantageous for active ingredients that are harmful to the gastric mucosa or unstable in gastric juice when provided in tablet form.

Water-insoluble, substantially neutral vinyl polymers or copolymers

Water-insoluble, substantially neutral olefinic polymers or copolymers are understood to mean those polymers or copolymers which are insoluble in water throughout the pH range of 1 to 14 and are only swellable in water.

Vinyl polymers are derived from the polymerization of monomers having vinyl groups, such as (meth)acrylic monomers.

"Substantially neutral" in a sense means that the polymer may contain only a small amount of ionic groups, if any. Even if a small amount of ionic groups are present, the physico-chemical properties of such a polymer are almost the same as those of a polymer without any ionic groups. "Substantially neutral" in a sense means, in particular, that the polymer contains less than 5, less than 4, less than 3, less than 2 or less than 1% by weight of monomer residues having anionic or cationic side groups. Preferably, the water-insoluble neutral olefinic polymer or copolymer does not contain any cationic groups. Most preferably, the water-insoluble, substantially neutral olefinic polymer or copolymer does not contain any ionic groups at all and is therefore a neutral water-insoluble olefinic polymer (100% neutral).

In particular, water-insoluble (meth)acrylic polymers containing 5 or 10% by weight of monomer residues containing cationic quaternary ammonium groups, such as types RS or RL, are not suitable for the purposes of the present invention because the resulting pharmaceutical compositions are not sufficiently resistant to the effects of 40% ethanol.

Typically, only one or one type of water-insoluble, substantially neutral vinyl polymer or copolymer is present in the pharmaceutical composition. However, if appropriate, it is also possible for two or more water-insoluble polymers or copolymers or two or more types of these polymers or copolymers to be present simultaneously with each other or in a mixture.

Water-insoluble polymers of the polyvinyl acetate type

Suitable water-insoluble polymers are polymers of the polyvinyl acetate type or copolymers derived therefrom.

Examples of water-insoluble polymers or copolymers of the polyvinyl acetate type are polyvinyl acetate (PVAc, Kollicoat), vinyl acetate-vinylpyrrolidone copolymer (VA64).

Water-insoluble (meth)acrylic acid copolymer

Among the water-insoluble (meth)acrylic copolymers, neutral or substantially neutral methacrylate copolymers are suitable for the purposes of the present invention.

Neutral (meth)acrylate copolymer (NE type)

Neutral or substantially neutral methacrylate copolymers contain (meth)acrylate monomers having neutral groups, especially C 1 -C 4 -alkyl groups, to an extent of at least more than 95% by weight, in particular to an extent of at least 98% by weight, preferably to an extent of at least 99% by weight, in particular to an extent of at least ₉₉ % by weight, more preferably to an extent of ₁₀₀ % by weight.

Suitable (meth)acrylate monomers having a neutral group are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate, preferably methyl methacrylate, ethyl acrylate and methyl acrylate.

Methacrylate monomers having anionic groups such as acrylic acid and/or methacrylic acid may be present in small amounts of less than 5 wt%, preferably not more than 2 wt%, more preferably not more than 1 wt% or 0.05 to 1 wt%.

Suitable examples are neutral or substantially neutral (meth)acrylate copolymers (NE) composed of 20 to 40% by weight of ethyl acrylate, 60 to 80% by weight of methyl methacrylate and 0 to less than 5% by weight, preferably 0 to 2% by weight or 0.05 to 1% by weight, of acrylic acid or methacrylic acid.

NE and NM are copolymers composed of free-radically polymerized units of 30 wt. % ethyl acrylate and 70 wt. % methyl methacrylate.

Suitable water-insoluble polymers are copolymers composed of more than 95 to up to 100% by weight of C ₁ -C ₄ -alkyl acrylic acid or methacrylic acid esters and less than 5% by weight of free-radically polymerized units of acrylic acid or methacrylic acid.

Water-soluble anionic polymer

Water-soluble anionic polymers in the sense of the present invention are polymers which are insoluble below pH 5.0 in a suitable buffered medium, preferably in a buffered medium according to the US Pharmacopoeia or the European Pharmacopoeia, and are soluble in the range of pH 7.0 to pH 8.0, preferably in the range of pH 6.0 to 8.0, most preferably in the range of pH 5.5 to 8.0. In a suitable buffered aqueous medium, the majority of the polymers which are soluble in the range of pH 7.0 to pH 8.0 are insoluble in pure or demineralized water.

Water-soluble anionic cellulose derivatives

Anionic cellulose derivatives are based on natural cellulose chains and are chemically modified with anionic compounds. The polymers can be partially or completely neutralized, preferably with alkali ions. Examples of anionic cellulose derivatives are cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethylcellulose (CMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) or cellulose acetate succinate (CAS).

Water-soluble anionic (meth)acrylate copolymer

Suitable water-soluble anionic (meth)acrylate copolymers are composed of 25 to 95% by weight, preferably 40 to 95% by weight, in particular 60 to 40% by weight, of free-radically polymerized C ₁ -C ₄ -alkyl acrylic acid or methacrylic acid esters and 75 to 5% by weight, preferably 60 to 5% by weight, in particular 40 to 60% by weight, of free-radically polymerized units of (meth)acrylate monomers having anionic groups.

The proportions generally add up to 100% by weight. However, small amounts of up to 10% by weight, or from 0 to 10% by weight, for example from 1 to 5% by weight, of additional monomers capable of olefinic copolymerization, such as, for example, hydroxyethyl methacrylate or hydroxyethyl acrylate, may also be present without impairing or altering the fundamental properties of the invention. However, it is preferred that no additional monomers capable of olefinic copolymerization are present. It is generally preferred that, apart from those monomers explicitly mentioned, no additional monomers are present in the water-soluble anionic (meth)acrylate copolymer.

C ₁ -C ₄ -Alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

The (meth)acrylate monomer having an anionic group is, for example, acrylic acid, preferably methacrylic acid.

Suitable anionic (meth)acrylate copolymers are those composed of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate (L type or L 100-55 type).

L is a copolymer of 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. The pH at which the specific active ingredient begins to be released in intestinal fluid or artificial intestinal fluid may be pH 6.0.

L 100-55 is a copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylic acid. L 30D-55 is a dispersion containing 30% by weight of L 100-55. The pH at which the specific active ingredient begins to be released in intestinal fluid or simulated intestinal fluid may be pH 5.5.

Likewise suitable are anionic (meth)acrylate copolymers composed of 20 to 40% by weight of methacrylic acid and 80 to 60% by weight of methyl methacrylate (S type). The pH at which the release of the specific active ingredient begins in intestinal fluid or simulated intestinal fluid may be pH 7.0.

Suitable (meth)acrylate copolymers are those composed of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid (FS type). The pH at which the release of the specific active ingredient begins in intestinal fluid or simulated intestinal fluid may be pH 7.0.

FS is a copolymer composed of 25 wt% methyl methacrylate, 65 wt% methyl acrylate and 10 wt% methacrylic acid. FS30D is a dispersion containing 30 wt% FS.

Copolymers having the following composition are also suitable:

20 to 34% by weight of methacrylic acid and/or acrylic acid,

20 to 69 weight percent of methyl acrylate, and

0 to 40% by weight of ethyl acrylate, and/or, if appropriate,

0 to 10% by weight of additional monomers capable of olefin copolymerization,

The proviso is that the glass transition temperature of the copolymer according to ISO 11357-2, subsection 3.3.3, does not exceed 60° C. The (meth)acrylate copolymers are particularly suitable because they have good elongation at break properties for compressing pellets into tablets.

Copolymers having the following composition are also suitable:

20 to 33% by weight of methacrylic acid and/or acrylic acid,

5 to 30% by weight of methyl acrylate, and

20 to 40 weight percent ethyl acrylate, and

from 10 to 30% by weight of butyl methacrylate, and, if appropriate,

0 to 10% by weight of additional monomers capable of olefin copolymerization,

The proportion of the monomers in total is 100% by weight.

Provided that the glass transition temperature of the copolymer according to ISO 11357-2, subsection 3.3.3 (midpoint temperature T _mg ) is 55-70° C. Copolymers of this type are particularly suitable because they have good mechanical properties for compressing pellets into tablets.

The above-mentioned copolymers consist in particular of the following free-radically polymerized units:

20 to 33% by weight, preferably 25 to 32% by weight, particularly preferably 28 to 31% by weight, of methacrylic acid or acrylic acid, preferably methacrylic acid,

5 to 30% by weight, preferably 10 to 28% by weight, particularly preferably 15 to 25% by weight, of methyl acrylate,

20 to 40% by weight, preferably 25 to 35% by weight, particularly preferably 18 to 22% by weight, of ethyl acrylate, and

more than 10 to 30% by weight, preferably 15 to 25% by weight, particularly preferably 18 to 22% by weight, of butyl methacrylate,

The monomer composition is selected so that the glass transition temperature of the copolymer is 55-70°C, preferably 59-66°C, and particularly preferably 60-65°C.

In this context, the glass transition temperature refers to the midpoint temperature _Tmg according to ISO 11357-2, subsection 3.3.3. The measurement is carried out without added plasticizer, with a residual monomer content (REMO) below 100 ppm, at a heating rate of 10°C/min and under a nitrogen atmosphere.

The copolymer preferably comprises substantially to completely 90, 95, or 99 to 100 weight percent of methacrylic acid, methyl acrylate, ethyl acrylate, and butyl methacrylate monomers within the aforementioned amount ranges.

However, it is possible for small amounts in the range of 0 to 10% by weight, for example 1 to 5% by weight, of further monomers capable of olefinic copolymerization, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinyl pyrrolidone, vinyl malonic acid, styrene, vinyl alcohol, vinyl acetate and/or derivatives thereof, to be additionally present without necessarily impairing the essential properties.

Preparation of anionic (meth)acrylate copolymers

Anionic (meth)acrylate copolymers can be prepared in a manner known per se in the art by free-radical polymerization of monomers (see, for example, EP 0 704 207 A2 and EP 0 704 208 A2). The copolymers of the invention can be prepared in a manner known per se in the art by free-radical emulsion polymerization in aqueous phase, preferably in the presence of anionic emulsifiers, for example, by the process described in DE-C 2 135 073.

The copolymers can be prepared by conventional methods of free-radical polymerization, either continuously or discontinuously (batch process), in the presence of a free-radical initiator and, if appropriate, a regulator for adjusting the undiluted molecular weight, in solution polymerization, by bead polymerization, or by emulsion polymerization. The average molecular weight Mw (weight average, determined, for example, by measuring the solution viscosity) can be in the range of, for example, 80,000 to 1,000,000 (g/mol). Preference is given to emulsion polymerization carried out in aqueous phase in the presence of a water-soluble initiator and a (preferably anionic) emulsifier.

In the case of bulk polymerization, the polymer can be obtained in solid form by rolling, extrusion, pelletizing or thermal cutting.

(Meth)acrylate copolymers are obtained by free radical bulk polymerization, solution polymerization, bead polymerization, or emulsion polymerization in a manner known per se. They must be processed to the particle size range according to the invention by suitable grinding, drying, or spraying processes. This can be done by simple rolling of the extruded and cooled pellets or by thermal cutting.

The use of powders can be advantageous, particularly with regard to mixtures with other powders or liquids. Suitable apparatus for producing powders are well known to those skilled in the art, such as air jet mills, pinned disc mills, and multi-chamber mills. If appropriate, a suitable screening step may also be included. A suitable mill for industrial large-scale production is, for example, an opposed jet mill (Multi No. 4200) operating at a gauge pressure of approximately 6 bar.

Partial neutralization

The anionic polymers can be partially or completely neutralized with bases. Suitable bases are those clearly mentioned in EP 0 088 951 A2 or WO 2004/096185, or those derived therefrom. In particular, they are: sodium hydroxide solution, potassium hydroxide solution (KOH), ammonium hydroxide, or organic bases such as, for example, triethanolamine, sodium carbonate, potassium carbonate, sodium bicarbonate, trisodium phosphate, trisodium citrate or ammonia, or physiologically tolerated amines such as triethanolamine or tris(hydroxymethyl)aminomethane. Other suitable cationic organic bases are the basic amino acids histidine, arginine and/or lysine.

Multiparticulate drug form

The controlled release pharmaceutical composition of the present invention may have the form of pellets contained in a multiparticulate pharmaceutical form such as a compressed tablet, capsule, sachet, effervescent tablet or reconstitutable powder.

Top coating and subcoating

The controlled-release pharmaceutical composition of the present invention may be further coated with a subcoat and/or a topcoat.

The bottom coating can be located between the core and the coating layer (controlling layer) that controls the release of the pharmaceutically active substance. The bottom coating can have the effect of separating the material of the core that may be incompatible with each other from the material of the control layer. The bottom coating has virtually no effect on the release characteristics. The bottom coating is preferably substantially water-soluble, for example, it can include a material such as hydroxypropyl methylcellulose (HPMC) as a film-forming agent. The average thickness of the bottom coating is very thin, for example, no more than 15 microns, preferably no more than 10 microns.

The top coating is also preferably substantially water-soluble. The top coating may have the effect of imparting color to the pharmaceutical form or protecting the pharmaceutical form from environmental influences, such as moisture during storage. The top coating may comprise a binder, for example, a water-soluble polymer such as a polysaccharide or HPMC or a sugar compound such as sucrose. The top coating may additionally contain a small amount of a pharmaceutical excipient such as a pigment or lubricant. The top coating has substantially no effect on the release characteristics.

The terms subcoating and topcoating are well known to the person skilled in the art.

Process for preparing the pharmaceutical form of the invention

The controlled-release pharmaceutical compositions of the present invention can be prepared in a manner known per se in the art by methods customary in pharmacy such as direct compression, compression of dry, wet or agglomerated granules and subsequent spheronization, wet or dry granulation or direct pelletization or bonding (powder layering) of powders to beads or neutral cores (blank cores) which do not contain the active ingredient or to granules containing the active ingredient and applying a polymer coating by a spraying process or by fluidized-bed granulation.

Excipients/customary additives

The core furthermore contains excipients or customary additives, respectively, in addition to the pharmaceutically active ingredient in a manner known to the person skilled in the art. The further excipients are not critical to the invention.

The coating layer can also contain excipient or customary additive in a manner well known to those skilled in the art in addition to polymer mixture, non-porous inert lubricant, neutral cellulose compound and emulsifier as basic components. If excipient is included in the coating layer, however, it is always different from necessary ingredients, and necessary ingredients are polymer mixture, non-porous inert lubricant, neutral cellulose compound and emulsifier. Compared with necessary ingredients (i.e. polymer mixture, non-porous inert lubricant, neutral cellulose compound and emulsifier), other excipient is not key for the present invention. Other excipient does not contribute to favourable invention effect. Preferably, in the dry weight of total coating layer, the amount of other excipient in the coating layer is lower than 5 weight %, more preferably lower than 2 weight %. Most preferably, there is no other excipient in the coating layer.

Pharmaceutically customary excipients, occasionally also referred to as customary additives, are added to the formulations of the invention, preferably during the production of the granules or powders. All excipients or customary additives used must of course always be toxicologically acceptable and can be used in pharmaceuticals, in particular without risk to the patient.

The amount and application of the excipients used in pharmacy are well known to those skilled in the art for drug coating or coating. Examples of possible excipients used in pharmacy or additives are releasing agents, pigments, stabilizers, antioxidants, pore formers, penetration aids, glossing agents, aromatic substances and flavorings. They are used as processing aids and are intended to ensure reliable and reproducible production processes and good long-term storage stability, or they realize other favorable properties in pharmaceutical forms. They are added to the polymer formulation before processing and can affect the permeability of the coating, when appropriate, might utilize this as another control parameter.

pigment:

As previously mentioned, pigments can be used in the coating layer to act as non-porous inert lubricants to promote tolerance to the effects of ethanol. If pigments are added as excipients that do not contribute to the present invention, they can be added to the topcoat above the coating layer to provide a certain color. Pigments that act as non-porous inert lubricants or as excipients that do not contribute to the present invention in the coating layer are generally non-toxic and suitable for pharmaceutical purposes. In this regard, see, for example: Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmittel, Harald, Boldt Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4, page 156 (1978); Arzneimittelfarbstoffverordnung Am Farb V of 25.08.1980.

Examples of pigments are orange yellow, carmine lake, colored pigments based on aluminum oxide or azo dyes, sulfonic acid dyes, Orange S (E110, C.I. 15985, FD&C Yellow 6), Indigo Carmine (E132, C.I. 73015, FD&C Blue 2), Tartrazine (E 102, C.I. 19140, FD&C Yellow 5), Ponceau 4R (E 125, C.I. 16255, FD&C Cochineal Red A), Quinoline Yellow (E 104, C.I. 47005, FD&C Yellow 10), Erythrosine (E 127, C.I. 45430, FD&C Red 3), Azorubine (E 122, C.I. 14720, FD&C Carmoisine), Amaranth (E 103, C.I. 19140, FD&C Yellow 5), 123, C.I.16185, FD&C Red 2), Acid Brilliant Green (E 142, C.I.44090, FD&C Green S).

The E number designates a pigment in relation to an EU number. See also: "Deutsche Forschungsgemeinschaft, Farbstoffe für Lebensmittel, Harald Boldt Verlag KG, Boppard (1978); Deutsche Lebensmittelrundschau 74, No. 4, p. 156 (1978); Arzneimittelfarbstoffverordnung Am Farb V of 25.08.1980. FD&C numbers refer to the approval numbers for use in foods, drugs, and cosmetics approved by the U.S. Food and Drug Administration (FDA) as described in the following: U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors: Code of Federal Regulations—Title 21 Color Additive Regulations Part 82, Listing of Certified Provisionally Listed Colors and Specifications (CFR 21 Part 82).

plasticizers

Another additive may also be a plasticizer. A plasticizer may advantageously be added to the coating layer. A typical amount is 0 to 50 wt %, preferably 5 to 20 wt %, based on the weight of the (meth)acrylate copolymer of the coating layer. Preferably, no plasticizer is added to the coating layer.

Plasticizers influence the functionality of the polymer layer and vary depending on their type (lipophilic or hydrophilic) and the amount added. Plasticizers lower the glass transition temperature and promote film formation by physically interacting with the polymer, depending on the amount added. Suitable substances typically have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups, such as hydroxyl, ester, or amino groups, within the molecule.

Examples of suitable plasticizers are alkyl citrates, glycerides, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to 12 000. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS). In addition, mention will be made of esters that are generally liquid at room temperature, such as citrates, phthalates, sebacates or castor oil. Esters of citric acid and sebacic acid are preferably used.

The addition of the plasticizer to the formulation can be carried out in a known manner, ie directly into the aqueous solution or after thermal pretreatment of the mixture. It is also possible to use mixtures of plasticizers.

Adding neutral cellulose compounds to the coating

The coating layer further comprises 1 to 35% by weight, preferably 2-30% by weight, and most preferably 5-25% by weight, of at least one neutral cellulose compound, based on the dry weight of the polymer mixture (compounds i) and ii). The neutral cellulose compound is a neutral cellulose derivative and can preferably be an ethyl ether or methyl ether of cellulose. Most preferably, the neutral cellulose compound is hydroxyethylcellulose or hydroxypropylmethylcellulose (HPMC).

Adding emulsifiers to the coating

The present inventors have discovered that the addition of one or more emulsifiers to the coating appears to indirectly improve the tolerability of the pharmaceutical composition. It is speculated that the presence of a detergent in the spray suspension promotes a more complete film-forming process. A more complete film appears to be more resistant to the effects of ethanol than a film formed without a certain amount of emulsifier in the coating. Films formed without a certain amount of emulsifier in the coating are thought to be slightly more porous than films formed in the presence of an emulsifier. Thus, the role of the emulsifier in the film-forming process, while not yet fully understood, may be similar to, but different from, the role of the coated pellets in the curing process. Even more surprisingly, the presence or absence of ethanol in the medium appears to have no negative impact or change on the release characteristics themselves.

Therefore, the controlled release pharmaceutical composition according to the invention may additionally comprise 2 to 20 wt. %, preferably 5-15 wt. %, based on the dry weight of the polymer mixture (compounds i) and ii)) of at least one emulsifier, preferably a nonionic emulsifier.

Preferred emulsifiers are polyoxyethylene derivatives of sorbitan esters.

Most preferably, the detergent is polyoxyethylene sorbitan monooleate (polyethylene glycol sorbitan monooleate, CAS Reg. No. 9005-65-6, eg 80).

Improved storage stability

Surprisingly, when either the cellulose compound or the emulsifier is used alone in a pharmaceutical composition, there is no effect on storage stability. In this case, the storage stability is still acceptable, which means there is still room for improvement. However, when the cellulose compound and the emulsifier are used together, the storage stability becomes much better and can be called excellent.

application

The pH-dependent controlled-release pharmaceutical composition of the present invention can be used to reduce the risk of enhanced release of the contained pharmaceutically active ingredient due to simultaneous or subsequent ingestion of ethanol-containing beverages (misuse) after oral administration.

Example

method

Model drugs

Metoprolol was used as a model drug for the studies.

Dissolution studies

The test was performed according to USP 28-NF23, General Chapter <711>, Dissolution, in simulated gastric fluid at pH 1.2 for the first 2 hours and then in buffered medium at pH 6.8.

Dissolution parameters:

Apparatus: USP Type I (basket method)

RPM: 100/min

Temperature: 37.5±0.5℃

Dissolution volume: 500ml.

Remove volume: Use a pipette to manually remove 5 ml without adding medium

Detection method: HPLC

Dissolution medium 1:

Simulated gastric fluid pH 1.2 (European Pharmacopoeia = EP)

Dissolution medium 2:

Simulated gastric fluid pH 1.2 (European Pharmacopoeia = EP), containing 40% (v/v) ethanol

Dissolution medium 3:

Phosphate buffered saline pH 6.8 (European Pharmacopoeia = EP)

Dissolution medium 4:

Phosphate buffered saline pH 6.8 containing 40% v/v alcohol, EP - 0.9 _g of _KH2PO4 , 1.8 g of _K2HPO4 , 7.65 g of NaCl, 540 ml _of demineralized water and 360 ml of alcohol were used.

Copolymer

NE is a copolymer composed of free-radically polymerized units of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.

FS is a copolymer composed of free-radically polymerized units of 25% by weight of methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid.

Preparation details

In a fluidized bed processing apparatus using bottom spraying, cores (sugar spheres, blank pellets) of 1700-2000 microns were loaded with metoprolol. Polyvinylpyrrolidone (K25) was used as a binder. 900 g of blank pellet cores were coated with 270 g of metoprolol bound in 80 g of binder (K25).

Preparation of coating suspension:

The dispersions are mixed in a suitable container applying gentle agitation. Lubricants and different polymers are dissolved or dispersed in water applying high shear forces.

Pour the lubricant suspension into the dispersion applying gentle stirring. Stirring is continued throughout the coating process.

Coating process:

The drug-coated pellets were coated with different coating suspensions in a fluidized bed apparatus under appropriate conditions: a spray rate of approximately 10-20 g of coating suspension/minute/kg of cores and a bed temperature of approximately 25-28°C. After coating, the pellets were fluidized in the fluidized bed apparatus at 50°C for one hour. Micronized talc was used as an excipient. The coated pellets had an average diameter of approximately 3,000 microns.

Storage stability

Storage stability is considered acceptable when the deviation of the release characteristics before and after storage is similarity expressed as an _f2 value of 50 or more but less than 60. Storage stability is considered good when the deviation of the release characteristics before and after storage is expressed as an _f2 value of 60 to 100.

Claims (16)

1. A pH-dependent controlled-release pharmaceutical composition comprising: A core comprising at least one non-opioid pharmaceutically active ingredient, wherein the core is coated with at least one coating layer that controls the release of the pharmaceutical composition. The coating layer comprises a polymer mixture of the following substances: i) 70-90% by weight, based on the dry weight of the polymer mixture, of at least one water-insoluble, substantially neutral olefin polymer or copolymer, which is a neutral or substantially neutral (meth)acrylate copolymer composed of 20-40% by weight of ethyl acrylate, 60-80% by weight of methyl methacrylate, and 0-less than 5% by weight of acrylic acid or methacrylic acid, and ii) Based on the dry weight of the polymer mixture, 10-30% by weight of at least one anionic polymer or copolymer, insoluble in buffer media below pH 4.0 and soluble in at least the pH range of 7.0 to 8.0, comprising 10-30% by weight methyl methacrylate, 50-70% by weight methyl acrylate and 5-15% by weight methacrylic acid (meth)acrylate copolymer. The coating layer is characterized by further containing 140-220% by weight of a non-porous inert lubricant, 1-35% by weight of at least one neutral cellulose compound, and 1-25% by weight of at least one emulsifier, all based on the dry weight of the polymer mixture, wherein the neutral cellulose compound is hydroxypropyl methylcellulose or hydroxyethyl cellulose, the non-porous inert lubricant is talc or stearate compound, and the emulsifier is a polyoxyethylene derivative of sorbitan ester. 2. The pH-dependent controlled-release pharmaceutical composition of claim 1, characterized in that the inert lubricant is calcium stearate or magnesium stearate. 3. The pH-dependent controlled-release pharmaceutical composition of claim 1 or 2, characterized in that the emulsifier is polyethoxylated sorbitan monooleate. 4. The pH-dependent controlled-release pharmaceutical composition of claim 1 or 2, characterized in that, under in vitro conditions according to the USP paddle method, at 100 rpm, at a buffered pH of 6.8, in a medium with and without the addition of 40% (v/v) ethanol, the pharmaceutical composition has the following properties: • When the release of the active pharmaceutical ingredient is less than 20% without the addition of 40% (v/v) ethanol, the difference in release rate with the addition of 40% (v/v) ethanol shall not exceed ±15% of the corresponding release value without the addition of 40% (v/v) ethanol. • When the release of the active pharmaceutical ingredient reaches 20-80% without the addition of 40% (v/v) ethanol, the difference in release rate under the condition of adding 40% (v/v) ethanol shall not exceed ±30% of the corresponding release value under the condition of not adding 40% (v/v) ethanol. 5. The pH-dependent controlled-release pharmaceutical composition of claim 1 or 2, characterized in that the active pharmaceutical ingredient is metoprolol or a pharmaceutically acceptable salt of metoprolol. 6. The pH-dependent controlled release pharmaceutical composition of claim 1 or 2, characterized in that the pharmaceutical composition is in the form of a pellet contained in a multi-particle pharmaceutical form. 7. The pH-dependent controlled-release pharmaceutical composition of claim 6, characterized in that the multi-particulate pharmaceutical form is a compressed tablet, capsule, sachet, or reconfigurable powder. 8. The pH-dependent controlled-release pharmaceutical composition of claim 6, characterized in that the multi-particulate pharmaceutical form is an effervescent tablet. 9. The pH-dependent controlled-release pharmaceutical composition of claim 1 or 2, characterized in that the pharmaceutical composition has a bottom coating and/or a top coating. 10. The pH-dependent controlled-release pharmaceutical composition of claim 1 or 2, characterized in that the pharmaceutical composition is in the form of coated pellets with a total average diameter of 100 to 5000 micrometers. 11. The pH-dependent controlled-release pharmaceutical composition of claim 10, characterized in that the total average diameter of the coated pellets is 100 to 700 micrometers. 12. The pH-dependent controlled-release pharmaceutical composition of claim 10, characterized in that the total average diameter of the coated pellets is 1400-5000 micrometers. 13. The pH-dependent controlled-release pharmaceutical composition of claim 12, characterized in that the coating layer is present in an amount of at least 30% by weight of the core. 14. The pH-dependent controlled release pharmaceutical composition of claim 1 or 2, characterized in that the release of the active ingredient is 10% or less in simulated gastric fluid pH 1.2 within 2 hours with or without the addition of 40% ethanol (v/v). 15. The pH-dependent controlled release pharmaceutical composition of claim 1 or 2, characterized in that it reduces the risk of enhanced or reduced release of the contained active pharmaceutical ingredient due to simultaneous or subsequent ingestion of a beverage containing ethanol after oral intake. 16. A method for preparing a pH-dependent controlled-release pharmaceutical composition according to any one of claims 1 to 15, wherein the method is carried out in a known manner by direct pressing, pressing of dry, wet or agglomerated particles and subsequent spheroidization, wet granulation or dry granulation or direct pelleting, or by layering powder onto beads or neutral cores or particles containing active ingredients and by applying polymer coating through a spraying process or by fluidized bed granulation.