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    • 专利摘要:
    The present invention provides an oral dosage form for delivering an active agent having a soft core having an active agent particle having an average size of greater than about 50 μm and a brittle shell for packaging the soft core, wherein the weight ratio of drug particle to shell is about 1.0: 0.5 to about 1.0: 15.
    公开号:KR20030009137A
    申请号:KR1020020036989
    申请日:2002-06-28
    公开日:2003-01-29
    发明作者:버닉프랭크제이；버크존제이；길모어티모시피；파팔리니미첼
    申请人:맥네일-피피씨, 인코포레이티드；
    IPC主号:
    专利说明:

    Brittle-coating, soft core dosage form
    [1] The present invention relates to an oral dosage form for administering an active agent having a soft core packaged in a brittle coating.
    [2] Active agents intended for oral administration, such as pharmaceuticals, nutritional products and the like, are often provided in solid dosage forms such as tablets, capsules, pills, lozenges or granules. Oral dosage forms are swallowed whole, chewed in the mouth, or sublingually dissolved. Chewable dosage forms are often used to administer an impractical active agent to provide a tablet for swallowing the whole, making the active agent topically available in the mouth or neck for both local effects or systemic absorption, and for pediatric and elderly patients. It is desirable to improve drug administration. For chewable dosage forms, chewing action can disperse the dosage form particles and increase the absorption of the active agent present.
    [3] Particles in chewable dosage forms have been observed to leave an unpleasant gritty feeling, an unpleasant mouthfeel, in the mouth. The term reflex refers to the form of feeling or feel that occurs in the mouth when the dosage form is ingested and is not related to olfactory nerves or taste stimuli. However, for successful dosage forms, the overall effect in the mouth is important. In general, a gritty feel is undesirable. Soft hand is preferred. See Pharmaceutical Dosage Forms, Edited by Leiberman, H.A. and Lachman, L. Marcel Dekker, Inc. New York, Volume 1, pp. 291].
    [4] In an attempt to address some of the above problems, different compositions have been investigated. Micro- or macrogranular compositions are described in US Pat. No. 5,618,527. To suppress the gritty feel, US Pat. No. 5,618,527 describes a composition in the form of a liquid or tablet consisting of spherical particles having a diameter of 125 μm or less. In addition, the particles need to have smooth edges. These conditions greatly limit drug delivery adaptability.
    [5] Another method is described in US Pat. No. 6,077,557. This patent document describes the incorporation of a calcium component into the gel. In particular, the grittyness of the calcium component is avoided by using a calcium source having a small particle size, and 90% of the calcium particles are described as being obtained when the average particle size is less than 50 μm, with the best result being described.
    [6] Other attempts to reduce gritty feeling using blends of gritty drug products and seedy fruits, such as strawberries, are described in US Pat. No. 5,102,664. In this formulation, the gritty fibrous fruit feel masks the grittyness of the active agent.
    [7] It is known to apply an outer coating to chewable tablets to protect the soft core. Often, such outer coatings contain, as main components, cellulose derivatives having a relatively high melting point, i.e., greater than 135 ° C. For example, PCT application WO 93/13758 describes the application of a thin layer of coating such as disaccharides, polysaccharides or cellulose derivatives onto compressed tablets. U.S. Pat. No. 4,828,845 discloses xylitol, film formers such as methyl cellulose, binders, optionally fillers and optionally plasticizers such as polyethylene glycol and solutions with 100% coating solution comprising water. It relates to an edible coating. The plasticizer only consists of about 3 to 7 weight percent of the coating solution described in US Pat. No. 4,828,845. U. S. Patent No. 4,327, 076 describes compressed soft chewable tablets containing antacids or other active agents which may be coated with a sealant or a spray coating of chocolate.
    [8] U. S. Patent No. 6,017, 567 describes sugar-free hard coatings of edible, chewable or pharmaceutical compositions. In particular, the hard coat is described as being formed by treating the core with sorbitol syrup and one or more other polyols in crystalline form. In particular, the described hard coatings are considered useful for coating chewing gum, sweets (such as candy), chocolate and nuts.
    [9] Alternatively, as described in US Pat. No. 4,684,534, anhydrous soft tablets have been prepared by compressing a combination of active agent, carbohydrate and binder such that the open pore structure of the formulation can be destroyed only on the stagnation surface. Because of their relatively brittle appearance, these tablets are hygroscopic, but these tablets quickly liquefy and dissolve upon chewing due to their open pore internal structure.
    [10] Another method of making soft cores in food products is described in US Pat. No. 5,362,508, wherein a core composition comprising a mixture of sucrose, invertase and a fat component is coated with a second fat component. In culture, short-chain fatty acid residues migrate from the second fat component to the core fat component to produce a soft fat mixture in the core with a lower fat solids content.
    [11] With the present invention, dosage forms have been found that mask the gritty of the active agents contained herein. This dosage form not only effectively masks the taste and feel of the active agent, but can also be conveniently eaten anywhere without water. Dosage formulations include a soft core packaged with a brittle coating. Surprisingly, the brittle coatings of the present invention not only stabilize the soft cores, but also provide masking agents against the gritty feel of the actives in chewing.
    [12] The present invention provides an oral dosage form for delivering an active agent having a soft core having an active agent particle having an average size of greater than about 50 μm and a brittle shell for packaging the soft core, wherein the weight ratio of drug particle to shell is about 1.0: 0.5 to about 1.0: 15.
    [13] The term "active agent" is used herein in a broad sense and includes materials that may accompany or be trapped within the system. For example, the active agent may be a medicament, a nutritional product, a vitamin, a supplemental diet, a nutrient, and the like and mixtures thereof.
    [14] Active agents useful herein may be selected from the class from those in the following therapeutic categories: tablet-inhibitors, alkaloids, antacids, analgesics, assimilation agents, antianginal drugs, antiallergic agents, antiarrhythmic agents, antiasthmatic agents, Antibiotics, anti-cholesterolemia, anticonvulsants, anticoagulants, antidepressants, anti-diarrheal agents, anti-emetic drugs, antihistamines, antihypertensive drugs, anti-infective agents, anti-inflammatory drugs, anti-lipid drugs, anti-emetic agents, anti-migraine drugs, anti-emetic agents, antipsychotics, Anti-seizure, anti-thyroid drug, assimilation drug, anti-obesity, antiparasitic, antipsychotic, antipyretic, antispasmodic, antithrombotic, anti-tumor, antitussive, anti-ulcer, anti-uritic, anti-anxiety, appetite stimulant Inhibitors, beta-blockers, bronchodilators, cardiovascular agents, brain dilators, chelators, cholecystekinin antagonists, chemotherapeutic agents, cognitive active agents, pregnancy regulators, coronary dilators, cough suppressants, decongestants, deodorants, Subsidiary agents, diabetic preparations, diuretics, emollients, enzymes, erythropoietic agents, expectorants, fertilizers, fungicides, gastrointestinal preparations, growth regulators, hormone replacement agents, hyperglycemic agents, hypoglycemic agents, ion exchange resins, laxatives, migraine medications, minerals Supplements, mucolytic agents, anesthetics, neuroleptics, neuromuscular drugs, NSAIDs, nutritional additives, peripheral vasodilators, polypeptides, prostaglandins, antipsychotics, rennin inhibitors, respiratory stimulants, sedatives, steroids, stimulants, sympathetic blockers , Thyroid preparations, thermostatics, uterine relaxants, vaginal preparations, vasoconstrictors, vasodilators, dizziness, vitamins, wound healing agents and the like.
    [15] Active agents that can be used in the present invention include acetaminophen; Acetic acid; Acetylsalicylic acid, including buffered forms thereof; Acrivastin; Albuterol and sulfates thereof; Alcohol; Alkaline phosphates; Allantoin; Aloe; Aluminum acetate, carbonate, chlorohydrate and hydroxide; Alprozolam; amino acid; Aminobenzoic acid; Amoxicillin; Ampicillin; Amsacrine; Assassination log; Anethol; Ascorbic acid; Aspartame; Astimazole; Atenolol; Azatidine and maleate thereof; Bacitracin; Balsam Peru; BCNU (carmustine); Beclomethasone dipropionate; Benzocaine; Benzoic acid; Benzophenones; Benzoyl peroxide; Benzquinamide and its hydrochlorides; Betaine call; Biotin; Bisacryl; Bismuth subsalicylate; Bornyl acetate; Bromopheniramine and maleates thereof; Buspyrone; Caffeine; Calamine; Calcium carbonate, carboxylate and hydroxide; Camphor; Captopril; Cascara sagrada; Castor oil; Sephachlor; Cepadroxyl; Cephalexin; Centrizin and its hydrochlorides; Cetirizine; Cetyl alcohol; Cetylpyridinium chloride; Chelated minerals; Chloramphenicol; Chlorcycline hydrochloride; Chlorhexidine gluconate; Chloroxylenol; Chloropentostatin; Chlorfeniramin and maleates and tanates thereof; Chlorpromazine; Cholestyramine resins; Choline bitartrate; Cartilage stimulating protein; Cimetidine; Cinnamedrin hydrochloride; Citalopram; Citric acid; Clarithromycin; Clemastine and fumarate thereof; Clonidine; Chlorfibrate; Cocoa butter; Cod liver oil; Codeine and fumarate and phosphate thereof; Cortisone acetate; Ciprofloxacin HCI; Cyanocobalamin; Cycline hydrochloride; Cyproheptadine; Dantron; Dexbromofeniramin maleate; Dextrometophan and its hydrohalides; Diazepam; Dibucaine; Dichloralpenazone; Diclofen and its alkali metal salts; Diclofenac sodium; Digosine; Dihydroergotamine and its hydrogenate / mesylate; Diltiazem; Dimethicone; Deoxybenzone; Diphenhydramine and its citrate; Diphenylhydramine and its hydrochlorides; Devalproex and its alkali metal salts; Docusate calcium, potassium and sodium; Doxycycline hydrate; Doxylamine succinate; Dronabinol; Eparoxane; Enalapril; Enoxacin; Ergotamine and its tartrate; Erythromycin; Estrophytate; Ethynyl estradiol; Ephedrine; Epinephrine bitartrate; Erythropoietin; Eucalyptol; Pamotidine; Phenopropene and metal salts thereof; Ferrous fumarate, gluconate and sulfate; Fexofenadine; Fluoxetine; Folic acid; Phosphphenytoin; 5-fluorouracil (5-FU); Fluoxetine; Flurbiprofen; Furosemide; Ganapentane; Gentamicin; Gemfibrozil; Glipizide; glycerin; Glyceryl stearate; Granistron; Griseofulvin; Growth hormone; Guapenesine; Hexyl resorcinol; Hydrochlorothiazide; Hydrocodone and tartrate thereof; Hydrocortisone and acetates thereof; 8-hydroxyquinoline sulfate; Hydroxyzin and pamoate and hydrochloride salts thereof; Ibuprofen; Indomethacin; Inositol; insulin; iodine; Tonics; iron; Isosorbide and its mono- and dinitrates; Isoxiccam; Ketamine; kaoline; Ketoprofen; Lactic acid; lanolin; lecithin; Chlororollide acetate; Lidocaine and its hydrochloride salt; Lipinopril; Lyotrix; Loperamide; Loratadine; Lovastatin; Luteinizing hormone; LHRH (luteinizing hormone replacing hormone); Magnesium carbonate, hydroxide, salicylate and trisilicate; Meclizin; Mefenamic acid; Meclofenamic acid; Meclofenamate sodium; Methoxyprogesterone acetate; Metheneamine mandelate; menthol; Meperidine hydrochloride; Metaproterenol sulfate; Metscopolamine and nitrates thereof; Metserzide and maleate thereof; Methyl nicotinate; Methyl salicylate; Methyl cellulose; Metoximide; Metoclopramide and halides / hydrates thereof; Metronidazole; Metoprotol tartrate; Myconazole nitrate; Mineral oil; Minoxidil; morphine; Naproxen and its alkali metal sodium salts; Nifedipine; Neomycin sulfate; Niacin; Niacinamide; nicotine; Nicotinamide; Nimesulide; Nitroglycerin; Nonoxynol-9; Noretin drone and acetates thereof; Nystatin; Octoxynol; Octoxynol-9; Octyl dimethyl PABA; Octyl methoxycinnamate; Omega-3 polyunsaturated fatty acids; Omeprazole; Ondansetron and its hydrochloride; Oxolinic acid; Oxybenzone; Oxtriphylline; Para-aminobenzoic acid (PABA); Padimate-O; Paramethadione; Pentastatin; peppermint oil; Pentaerythritol tetranitrate; Pentobarbital sodium; Perphenazine; Phenelazine sulfate; Penindamin and tartrate thereof; Peniramine maleate; Phenobarbital; phenol; Phenolphthalein; Phenylephrine and its tannates and hydrochlorides; Phenylpropanolamine; Phenytoin; Pyrmenol; Pyroxycam and salts thereof; Polymycin B sulfate; Potassium chloride and potassium nitrate; Prazepam; Flocaineamide hydrochloride; Procaterol; Promethazine and its hydrochlorides; Propoxyphene and its hydrochloride and naphsylates; Pramiracetin; Pramoxin and its hydrochloride salts; Prochlorfenazine and maleates thereof; Propanolol and its hydrochlorides; Promethazine and its hydrochlorides; Propanolol; Pseudoephedrine and its sulfates and hydrochlorides; Pyridoxine; Pyrrolamin and its hydrochloride and tannate; Quinapril; Quinidine gluconate and sulfate; Quinestrol; Ralitololin; Ranitadine; Resorcinol; Riboflavin; Salicylic acid; Scopolamine; Sesame oil; Shark liver oil; Simethicone; Sodium bicarbonate, citrate and fluoride; Sodium monofluorophosphate; Sucralate; Sulfane ethoxazole; Sulfasalazine; sulfur; Sumatriptan and succinate thereof; Tacrine and its hydrochlorides; Theophylline; Terpenadine; Thiethylperazine and maleate thereof; Timolol and maleate thereof; Thioperidone; Tramadol; Trimetrexate; Triazolam; Tretinoin; Tetracycline hydrochloride; Tolmetin; Tolnaftate; Triclosan; Trimethobenzamide and its hydrochlorides; Tripelinamine and its hydrochlorides; Tripolydine hydrochloride; Undecylenic acid; Vancomycin; Verapamil HCl; Vidarivin phosphate; Vitamins A, B, C, D, B 1 , B 2 , B 6 , B 12 , E and K; Witch Hazel; Xylometazoline hydrochloride; zinc; Zinc sulfate; Zinc undecylenate includes, but is not limited to. Activators also include food acids; Insoluble metals and inorganic hydroxides, carbonates, oxides, polycarbophiles and salts thereof; Adsorbates of active drugs against magnesium trisilicate base and magnesium aluminum silicate base and mixtures thereof, but is not limited thereto. Mixtures and pharmaceutically acceptable salts thereof and other active agents can be used.
    [16] The active agent may be in the form of fine powder, granules or large crystals, with an average particle size of about 20 to about 1000 μm and also about 150 to about 500 μm. Typically, the average size of the active agents used in the present invention exceeds 50 μm.
    [17] If the active agent exhibits an unpleasant taste, it can be coated with a taste masking coating as is known in the art. Examples of suitable taste shielding coatings are described in US Pat. No. 4,851,226, US Pat. No. 5,075,114, and US Pat. No. 5,489,436. Commercially available taste masking actives can also be used. For example, acetaminophenone particles encapsulated with ethylcellulose or other polymers by coacervation processes can be used in the present invention. Coacervation encapsulated acetaminophenone can be purchased from Eurand America, Inc., Vandalia, Ohio or Circa Inc., Dayton, Ohio.
    [18] As used herein, all ranges provided are intended to explicitly include all numbers that fall between at least the endpoints of the range.
    [19] The present invention relates to oral dosage forms for the administration of the active agent having a soft core packaged with a brittle coating. In one method for preparing the oral dosage form of the invention, the soft core is prepared first. After forming the soft core, the brittle coating can be added using conventional hard and soft panning techniques known in the art.
    [20] The soft core of the present invention can be formed by direct compression. Using this technique, the soft core is prepared by directly compressing the blend of the active agent and other suitable inert ingredients, i.e. excipients (e.g. flavors, binders, lubricants, etc.). The soft cores of the present invention can be prepared using conventional compression methods to form chewable dosage forms. Such methods include, but are not limited to, compression with dry granulation and drying with wet granulation. Compression methods include rotary compression, compression roller techniques, such as chilsonator or drip rollers, or molding, casting or extrusion techniques. These methods are well known in the art and are described in detail, for example, in Lachman, et al., The Theory and Practice of Industrial Pharmacy, Chapter 11, (3 rd Ed. 1986).
    [21] Common excipients useful in the present invention for direct compression include fillers such as water soluble compressible carbohydrates such as sucrose, mannitol, sorbitol, maltitol, xylitol, lactose and mixtures thereof; Binders such as cellulose, cellulosic derivatives, polyvinyl pyrrolidone, starch, modified starch and mixtures thereof; Disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, microcrystalline cellulose, starch and the like; Lubricants such as magnesium stearate, stearic acid, talc and waxes; Glidants such as sweeteners including colloidal silicon dioxide, aspartame, acesulfame potassium, sucrose and saccharin; Flavoring agents; Acidifying agent; Antioxidants; antiseptic; Surfactants; Wetting agents and coloring agents are included.
    [22] The soft cores of the present invention may be shaped, ie formed by various methods known in the art. One such method employs positioning a volume of particles or components in a die cavity of a rotary tablet molding machine that rotates as part of a die table from a filling position to a compression position. In the compression position, the particles are compressed between the upper punch and the lower punch. The die table then rotates in the discharge position, and the resulting tablet is pushed out of the die cavity by the lower punch and led to the discharge chute by a fixed take-up bar.
    [23] One form of soft core of the present invention may be a tablet. Tableting is typically performed so that the tablets are relatively soft. The hardness of the tablet is about 15 kp / cm 2 or less, for example about 1 to 8 kp / cm 2 or about 2 to 6 kp / cm 2 . As used herein, the term hardness is used to describe the diameter wave strength measured by a conventional pharmaceutical hardness test device, such as the Schleuniger Hardness Tester. To compare the tablet diameter values of different particles, the wave strength is normalized to the wave area (which can be approximately multiplied by the thickness of the tablet diameter). This standardized value, expressed in kp / cm 2 , is commonly referred to in the art as tablet tensile strength. General discussion of tablet hardness testing is described in reference:.. Leiberman et al, Pharmaceutical Dosage Forms- Tablets, Volume 2, 2 nd ed, Marcel Dekker Inc., 1990, pp. 213-217, 327-329.
    [24] Optionally, the dosage forms of the present invention may or may not be molded, deposited or extruded under methods conventionally known in the art, with or without active agents.
    [25] For example, the dosage form of the present invention may be formed by deposition techniques known to those skilled in the art. This method involves filling a mold (usually by gravity) with a fluid (eg liquid, suspension, melt, etc.). In general, the mold is opened at the top so that the finished form can have one flat or unformed surface. The mold is usually a starch mold formed by filling the tray with starch, flattening the surface of the starch, and then stamping the surface of the starch having the cavity from the mold plate. The cavities can have various shapes and sizes, but the vertical side is undesirable. Mold starch is generally anhydrous (typically less than 6% moisture). Sugar can be used instead of starch in this process, or brittle molds made of plastic, metal or other materials sprayed first without release agent can be used (Sugar Confectionery Manufacture, Van Nostrand Reinhold, 1990, pp. 205-206). )].
    [26] Any extrusion technique involves feeding the malleable semisolid starting material to the extruder. The extruder applies a pressure that forces the mass through the orifice that forms the dosage form in two dimensions, typically with a rope that is cut to form a piece. The starting material may be hot or cold.
    [27] Optionally, the three-dimensional shaped shape can be formed from a semisolid starting material using a unilast mold, chain mold or calender roll. The three-dimensional shaped shape can be formed by injection molding from a liquid or molten starting material.
    [28] Conventional excipients useful in the present invention for molded, deposited or extruded formulations include fillers such as water soluble single and complex carbohydrates such as sucrose, glucose, fructose, maltose, lactose, maltodextrin, low and High DE Corn Syrup and High Fructose Corn Syrup; Polyhedral alcohols and hydrogenated starch hydrolysates such as mannitol, sorbitol, maltitol, erythritol and xylitol; Hydrocolloids such as natural and modified rubbers, celluloses, modified celluloses, pectins, viscous materials, starches and modified starches, non-cellulosic polysaccharides, algal polysaccharides and mixtures thereof. More specifically, hydrocolloids include starch, gelatin, soy protein and soy protein isolates, egg albumin, agar-agar, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC). Xanthan gum, carrageenan gum, locust bean gum, alginate, acacia, carboxymethylcellulose (CMC), karaya gum, gum arabic, sodium alginate, sodium CMC, guar gum, tragaganth, hydrocolloids, etc. This includes. Other suitable water soluble polymers include inulin, fucoidan, polymerized maltotriose, and the like. Artificial sweeteners such as saccharin, aspartame, sucralose and acesulfame potassium as well as flavoring agents, edible glazes and waxes, acidifying agents, antioxidants, preservatives, surfactants, wetting agents and coloring agents are known in the art.
    [29] The brittle coating may be applied to the soft core in a manner such as spraying, roller coating, dipping, panning or enrobing. Brittle coatings may include ingredients such as natural or artificial sweeteners, colorants, flavors, plasticizers. The brittle shells of the present invention are present in a weight ratio of active agent particles to cell of about 1.0: 0.5 to about 1.0: 15, for example about 1: 0.2 to about 1.0: 12 or about 1.0: 4 to about 1.0: 9.
    [30] Generally, panning involves applying a liquid coating to the pellets, which is generally subsequently solidified by drying the coating. The brittle shell coating layer is formed by successive coating and drying steps.
    [31] The brittle shells of the present invention are carbohydrates such as mannitol, sorbitol, maltitol, xylitol, dextrose, dextrose monohydrate, maltodextrin, fructose, sucrose, lactose, maltose, xylose, sucralose and Mixtures thereof.
    [32] Conventional panning methods are generally covered with sucrose, but recently the use of other carbohydrate materials used in place of sucrose has been developed for panning. Some of these include, but are not limited to, dextrose, maltose, xylitol, isomalt, hydrogenated isomaltulose and other novel polyols or combinations thereof. These materials are cellulosic materials such as gum arabic, maltodextrin, corn syrup, gelatin, carboxymethyl cellulose or hydroxymethyl cellulose, starch and modified starch, alginate, locust bean gum, guar gum and tragaganth rubber It may be blended with, but not limited to, a panning modifier including vegetable gums, insoluble carbonates such as calcium carbonate or magnesium carbonate, and talc. Antitack agents can also be used as panning modifiers, which allow various carbohydrates and sugar alcohols to be used in the development of new panned or coated rubber products.
    [33] The bulk sweeteners used for panning are very stable and very water soluble and can be easily added to sugar solutions prepared for sugar panning. Polydextrose can be applied in sucrose coating or other sugar or alditol coating in liquid form. Polydextrose can also be added as a powder blended with other powders commonly used in some forms of conventional panning methods. Polydextrose can be added to the liquid syrup and used as panning modifier with other sugars and sugar alcohol syrups such as dextrose, sucrose, xylitol and pallatinite. Polydextrose can act as a binder for a sugar or sugar alcohol coating, or as a film former for it.
    [34] It is known to improve the coating process using sugar or altitol to add a powder coating after liquid coating. Powder coatings include polydextrose, maltodextrin, gelatin, cellulose derivatives, starch, modified starch, vegetable gums, fillers such as talc and calcium carbonate dextrose, sucrose, xylitol. This is considered to reduce the tack and allow the coating to form quickly.
    [35] The thickness of the coating is typically about 500 to about 3000 μm. The weight percent of the outer coating may range from about 10 to about 60%, such as from about 20 to about 50%, and from about 30 to about 45%, based on the total weight of the delivery system, active agent, and outer coating.
    [36] Particular aspects of the invention are illustrated by the following examples. The invention is not limited to the specific limits set forth in these examples, but is limited by the appended claims. Unless stated otherwise, the percentages and ratios set forth below are by weight.
    [37] Example
    [38] Example 1 Preparation of Compression Cores
    [39] Color blends are prepared by combining in a polyethylene bag 56 g of crospovidone NF, 28.17 g of aspartame NF, 42.26 g of citric anhydride powder and 7.04 g of FD & C Yellow # 6 Al lake. After sealing the bag, the blend is mixed back 20 times. The resulting color blend is screened through a 40 mesh hand screen and stored in a plastic bag.
    [40] Separately, 352.2 g of hydrogenated vegetable oil (Wecobee S) is heated to 56 ° C. in an oven.
    [41] In a 5 gallon Hobart mixer, 4095.0 g of coated acetaminophenone granules (containing 86% by weight of active agent) and 28.17 g of aspartame NF are combined and mixed at a setting speed of 1 for 2 minutes. The resulting blend is heated to 54 ° C. in an oven.
    [42] 176.1 g of heated hydrogenated vegetable oil is added to the heated components in the Hobart bowl with stirring for 2 minutes at a speed setting. Then continue mixing for an additional 2 minutes. The components in the bowl are then cooled to 29 ° C. for about 46 minutes.
    [43] 640.97 g of color blend, 1655.2 g of sorbitol NF (sorbidex P 16616), 1655.2 g of dextrose monohydrate USP (Cerellose), and 42.26 g of N & A orange flavor were added to the cooled mixture in Hobart balls, speed setting 1 to 3 Mix for minutes.
    [44] After mixing, 49.30 g of magnesium stearate NF and 457.8 g of xylitol NF (xylsorb 90) are added and the resulting composition is mixed at rate setting 1 for 2 minutes. The resulting granules are discharged into a plastic bag. The final granule weight was 8774 g.
    [45] The granules are then compressed onto the following physical specification targets using a 19/32 "round and deep concave tool on a Manesty Betapress:
    [46] Weight: 1249.4 mg
    [47] Shredability: 1.5kp
    [48] Thickness: 0.350 "
    [49] Fragility (5 tablets): not broken before 10 drops.
    [50] Example 2: Fan Cladding of Compressed Cores
    [51] ingredientUnit weight (mg)Batch weight (g) Part 1 Purification Cores from Example 1 (1550)624.71935.7 Hydrogenated Vegetable Oil (Wecobi M)55.0341.0 **Core Tablets (Post HVO) from Part 2 Example 1 (1550)1304.42021.8 Arabian rubber (coated gum L) (also used for part 5)15.093.0 **Purified Water USP * (also used for Part 5)45.0279.0 **Sucrose NF [Bakers Special]150.0465.0 **Citric Acid Anhydrous USP Powder2.03.10 Fermenich N & A Orange 57.842 / AP 05.511.01.55 Part 3 Tylenol Melt-Tap Core (Post Soft Pan) (1550 Pieces)1472.42250.3 Sucrose NF (Special Fine Granules) (also used for Part 6)200.01240.0 **Purified Water USP * (also used for Part 6)100.0620.0 **Opalux Orange AS-2343 (also used for Part 6)0.63.72 **Tablet Cores (Post Brittle Pan) from Part 4 Example 1 (1550)1673.02525.0 Carnuba Wax NF0.91.40 gun1673.9* Removed during processing; ** Contains more than 100% of theoretical amount; *** Calculation reference in batch records Label claim: 50 mg acetaminophen / tablet
    [52] 1550 tablet cores from Example 1 are transferred into a plastic bag and frozen at 16 ° C. 341.0 g of hydrogenated vegetable oil (Wecoby M) is heated and maintained at a temperature of about 48 to about 52 ° C. in a pan on top of the stove. The frozen tablet cores are transferred to a 16 "conventional sheathing pan (Keith Machinery Corp., Lindenhurst, NY) equipped with four # 14 tubing baffles. The cold end of the helical tube The tablet core is tumbled at a pan speed setting of 20 to 35. A portion of the heated hydrogenated vegetable oil (Weccobee M) is spun until a weight of 50 to 60 mg obtained per tablet is achieved. Load onto cores The cores are cooled using helical tubes and stored at 10-20 ° C. in the refrigerator.
    [53] Soft panning of the core is carried out using a 25% by weight Arabian rubber solution prepared by adding 93.0 g of Arabian rubber (coated gum L) to 279.0 g of purified water in a stainless steel container while mixing and continuing mixing for 1 hour. The solution is then degassed for about 6 hours under vacuum.
    [54] 1550 frozen tablet cores are transferred to a 16 "conventional sheath pan without barrier. The tablet cores are then tumbled at a pan speed of 20 to 40. The rotating cores are wetted with 20.2 g of 25% Arabian rubber solution. Add 141.3 g of cross NF (Bakers Special) and continue to tumble for 30 minutes at a 30 fan speed setting until the core appears to dry.
    [55] The rotating core is wetted with 40.0 g of additional 25% Arabian rubber solution. Subsequently, 135.4 g sucrose NF (Bakers Special), 3.10 g citric acid anhydrous USP powder and 1.55 g Permenich N & A orange 57.842 / AP 05.51 were added and 30 minutes at 25 pan speed settings until the core appeared to dry out. Continue to tumble while
    [56] An additional 12.0 g of 25% Arabian rubber solution is added to wet the rotating core. Add 35.6 g of sucrose NF (Bakers Special) and continue to tumble for 25 minutes at 25 fan speed settings until the core appears to dry. The resulting tablet is removed from the pan, sprayed on a tray and stored for 16 hours at ambient conditions (about 72 ° F./50% RH). Arabia rubber content: 72.2 g. Sucrose Consumption: 312.3 g. Obtained weight of tablet after coating: 203 mg / tablet.
    [57] A 67% sucrose solution is prepared by adding 620.0 g of purified water into a stainless steel vessel containing a magnetic stir bar. 1240.0 g of sucrose NF (special fine granules) are added while mixing to create a spiral. The vessel is then covered with aluminum foil and heated to 60-65 ° C. with continued mixing. The temperature is maintained at 60-65 ° C. while mixing for 20 minutes. The solution is then cooled to 37-43 ° C. and then the temperature is maintained in this range.
    [58] 594.0 g of 67% sucrose solution is added to a stainless steel vessel containing a magnetic stir bar. While mixing to create a spiral, add 3.72 g of Orange Lake Dye (Opallux AS-2243; Colorcon, West Point, PA), and then add the resulting Orange Lake Dye / Sucrose solution with aluminum foil. Cover, heat to 40 ° C. and mix for an additional 5 minutes.
    [59] Brittle panning of the dosage form is performed using 1550 tray dried soft panning cores. The cores are placed in a 16 "conventional sheathed fan with no barrier material and equipped with a room temperature air blower at the opening of the fan. The fan speed is set to about 20 to maintain proper tumbling. 14 of the 67% sucrose solution already prepared The coating liquid is applied onto the rotating core by manual loading The eight coating liquids of the Orange Lake dye sucrose solution are applied on the rotating core by manual loading The tablets are removed from the pan, sprayed on a tray, and ambient conditions Store for 22.5 hours at (72 ° F./50% RH) Use of 67% sucrose solution: 288.9 g Use of Lake Orange sucrose solution: 130.2 g Tablet weight obtained after coating: 177.2 mg / tablet.
    [60] Polishing of 1550 tray dried tablet cores is performed by moving the tablet cores to a 16 "conventional sheathing pan equipped with four # 14 tubing inhibitors. Tumble the tablets at a fan speed setting of 20 to 40 to maintain proper tumbling. 1.40 g of carnuba wax is added to the rotating core, continuing to tumble for 30 minutes The polished finished product is stored in a plastic bag at room temperature The resulting weight of the tablet after polishing is 1627.4 mg / tablet.
    [61] Example 3: Pectin Core
    [62] ingredientUnit weight (mg)Batch weight (g) Citric Acid Solution 50% (w / w) Purified Water USPN / A500.0 *Citric Acid USP, Anhydrous PowderN / A250.0 *gun 750.0 Raw material solution prepared in excess; ** weight before heating step *** weight after heating step; The theoretical batch weight of the purified water USP after the heating step is 75.85 g. Label claim: 80 mg acetaminophen per 1
    [63] ingredientUnit weight (mg)Batch weight (g) BOB Syrup Purified Water USP †135.8 *** 148.00 ***Sodium Citrate, Anhydrous Powder3.62.00 Citric Acid USP, Anhydrous Powder3.31.85 Pectin [Grinsted XSS 100]13.47.50 Sucrose NF (Special Fine Granules) [Pectin Degradation]44.825.00 Sucrose NF (Special Fine Granules)415.6232.10 Corn Syrup 42/43268.6150.00 Coated Acetaminophen Granules (76.5% APAP)104.658.41 N & A Touti Fruity Flavor3.62.00 Citric acid solution 50% w / v6.63.70 gun999.9 *** 558.41 ***Raw material solution prepared in excess; ** weight before heating step *** weight after heating step; The theoretical batch weight of the purified water USP after the heating step is 75.85 g. Label claim: 80 mg acetaminophen per 1
    [64] Citric acid solution (50% w / v) is prepared by placing 250 g of citric acid USP anhydrous powder into a 500 ml volumetric flask. Purified water is added to a 500 ml volumetric flask until about 3/4 is filled. The flask is placed in an acoustic bath and sonicated for 2 hours. The flask is then removed from the acoustic bath and cooled to 20 ° C. (19-21 ° C.). When the solution temperature reaches 20 ° C., purified water is added to the 500 ml level. The solution is mixed by inverting the stoppered flask several times.
    [65] Separately, 600 ml organic beakers containing 148.00 g of purified water are heated to 70 ° C. (69-72 ° C.) on a heated stir plate. The water is then mixed using a mixer equipped with three winged propellers with a diameter of 1.5 inches. Add sodium citrate anhydrous powder and citric acid USP anhydrous powder to hot purified water while mixing. Continue mixing until solution is clear (about 3 minutes).
    [66] 7.50 g of pectin (Grinsted XSS 100) and 25.00 g of sucrose NF (special fine granules) [ectin digestion] are added to a small plastic bag and the bag is inverted several times and blended. Then, the pectin / suecrose blend is added to the hot buffer formed above and continued mixing to make a pectin buffer dispersion.
    [67] Rice syrup is prepared by placing 150.0 g of corn syrup in a packing pan. 232.1 g of sucrose NF (special fine granules) are added to the pan. While mixing with a spatula, the components are heated to a temperature of 102 ° C (100-105 ° C). The prepared factant buffer dispersion is added to the pan while heating the components. The heating is continued and the water is evaporated until the weight of the component is from about 492 g to about 496 g, with 494.3 g being the target.
    [68] The following ingredients are added to rice syrup in the order listed, mixing with spatula: 2.00 g N & A Touti Fruity Flavor; 59.26 g of coated acetacetophene particles (C-873-1) and 3.70 g of 50% (w / v) citric acid solution.
    [69] The batch is then transferred to a 32 oz heated pressure pot equilibrated to 80 ° C (75 to 85 ° C). The top is placed on a heating pressure port and sufficient air pressure is applied to allow product to flow from the attachment nozzle to the 5 cc syringe. Approximately 1 g (0.7-1.1 g) of sample was taken from the dent & NU MOULD brand; Manufacturer: Melrose brand corn (National Starch and Chemical Co., Bridgewater, NJ) and jelly bean form, food grade starch from National Starch and Chemical Co., Bridgwater, NJ It is deposited in a 50/50 mixture of mineral oil imprinted with 5cc plastic syringe.
    [70] The starch mold is placed in a forced air oven at 49 ° C. (47-51 ° C.) for about 22 hours. Pectin cores are removed from mold starch and stored in plastic bags at room temperature. The average weight of the 50 cores was about 765 mg / core.
    [71] Example 4 Coating of Pectin-Based Cores
    [72] The core from Example 3 is placed on a 10 mesh screen. Excess mold starch is removed by passing compressed air over the core while gently shaking the screen. Average weight of 50 cores: 728.4 mg / core.
    [73] A 25% Arabian rubber solution is prepared by adding 38.4 g of Arabian rubber to 115.1 g of purified water in a stainless steel container and mixing for 1 hour. The solution is degassed by standing for about 16 hours at ambient conditions.
    [74] The 1400 cores are transferred to a 16 "conventional sheathing pan equipped with four # 14 tubing inhibitors. The cores are tumbling at a fan speed setting of 60 while adding 6.72 g of the 25% Arabian rubber solution to wet the rotating cores. Add 91.0 g of sucrose NF (Bakers Special) and continue to tumble for 25 minutes until the core appears to dry.The rotating core is loaded and loaded with 11.21 g of additional 25% Arabic rubber solution and wet again. (Bakers Special) Add 84.1 g Continue tumble for an additional 15 minutes until the core appears to dry The rotating core is loaded and 10.17 g of additional 25% Arabian rubber solution and wetted again. Add 74.0 grams of cross NF (Bakers Special), continue to tumble for 10 minutes until the core appears to dry out 9.90 grams of 25% Arabian rubber solution Load and wet again Add 55.0 g of sucrose NF (Bakers Special) and continue to tumble for 18 minutes until the core appears to dry.The core is then removed from the pan, sprayed on a tray and ambient Store for about 22.5 hours at conditions (about 72 ° F./50% RH) The core weight obtained after soft panning was about 195.8 mg / core.
    [75] Sucrose / Lake Red dye (Opalax Red AS-1662-D manufactured by Colorcon, Weat Point, PA) solution is prepared by mixing 966.3 g of sucrose NF with 414.7 g of purified water in a stainless steel container using a magnetic stir bar. do. The vessel is covered with aluminum foil and heated to about 60 to about 65 ° C. with continued mixing. The solution is mixed for an additional 20 minutes at about 60 to about 65 ° C. during which time the solution is visually clear. 9.2 g of Lake Red dye is added to the sucrose NF solution, replacing the foil, and mixing is continued for 10 minutes while maintaining a temperature of about 60 to about 65 ° C.
    [76] 1400 cores are transferred to a 16 "conventional sheathing pan equipped with a room temperature air blower mounted in the opening of the fan and equipped with four # 14 tubing inhibitors. Tumble at a pan speed setting of 40 while applying 20 coating liquids of sucrose / lake red dye in 18 g increments.
    [77] The pan speed is reduced to 25 settings and 10 coating liquids of additional sucrose / lake red dye solution are applied in 8-13 g increments with a drying time of 6-12 minutes in the coating liquid. The core is removed from the pan, sprayed on a tray and stored for 21 hours at ambient conditions. The weight obtained from brittle panning was about 217.2 mg / core.
    [78] Transfer 1400 cores from step F to a 16 "conventional sheathing pan equipped with four # 14 tubing inhibitors. Tumble the cores at a fan speed setting of 35. Approximately 1.17 g of carnuba wax is added to the rotating core and Continue to tumble for 10 minutes The weight obtained after polishing is about 7.6 mg / piece.
    [79] The present invention provides an oral dosage form packaged with a brittle shell capable of stabilizing the soft core that not only effectively masks the taste and feel of the active agent but also can be conveniently eaten anywhere without water.
    权利要求:
    Claims (16)
    [1" claim-type="Currently amended] (a) a soft core comprising activator particles having an average size of greater than about 50 μm and
    (b) an oral dosage form comprising a brittle shell for wrapping the soft core, wherein the weight ratio of drug particles to shell is from about 1.0: 0.5 to about 1.0: 15.
    [2" claim-type="Currently amended] The oral dosage form of claim 1, wherein the weight ratio of drug particle to shell is about 1.0: 2 to about 1.0: 12.
    [3" claim-type="Currently amended] The oral dosage form of claim 2, wherein the weight ratio of drug particle to shell is about 1.0: 4 to about 1.0: 9.
    [4" claim-type="Currently amended] The oral dosage form of claim 1, wherein the soft core is pectin-based.
    [5" claim-type="Currently amended] The oral dosage form of claim 1, wherein the soft core is gelatin-based.
    [6" claim-type="Currently amended] The oral dosage form of claim 1 wherein the friability is from about 1 to about 8 kp / cm 2 .
    [7" claim-type="Currently amended] The active agent of claim 1, wherein the active agent is acetaminophen, ibuprofen, pseudoephedrine, dextromethorphan, diphenhydramine, chlorpeniramin, calcium carbonate, magnesium hydroxide, magnesium carbonate, magnesium oxide, aluminum hydroxide, mixtures thereof and pharmaceuticals Oral dosage forms selected from the group consisting of their acceptable salts.
    [8" claim-type="Currently amended] 8. The oral dosage form of claim 7, wherein the active agent is acetaminophen or ibuprofen.
    [9" claim-type="Currently amended] The oral dosage form of claim 8, wherein the active agent is acetaminophen.
    [10" claim-type="Currently amended] The oral dosage form of claim 8, wherein the active agent is ibuprofen.
    [11" claim-type="Currently amended] 4. The active agent according to claim 3, wherein the active agent is acetaminophen, ibuprofen, pseudoephedrine, dextromethorphan, diphenhydramine, chlorpeniramin, calcium carbonate, magnesium hydroxide, magnesium carbonate, magnesium oxide, aluminum hydroxide, mixtures thereof and pharmaceuticals Oral dosage forms selected from the group consisting of their acceptable salts.
    [12" claim-type="Currently amended] The oral dosage form of claim 11, wherein the active agent is acetaminophen or ibuprofen.
    [13" claim-type="Currently amended] 13. The oral dosage form of claim 12 wherein the active agent is acetaminophen.
    [14" claim-type="Currently amended] 13. The oral dosage form of claim 12 wherein the active agent is ibuprofen.
    [15" claim-type="Currently amended] (a) a soft core comprising acetaminophen having an average size of greater than about 50 μm and
    (b) an oral dosage form comprising a brittle shell for wrapping the soft core, wherein the weight ratio of drug particles to shell is from about 1.0: 4 to about 1.0: 9.
    [16" claim-type="Currently amended] (a) a soft core comprising ibuprofen having an average size of greater than about 50 μm and
    (b) an oral dosage form comprising a brittle shell for wrapping the soft core, wherein the weight ratio of drug particles to shell is from about 1.0: 4 to about 1.0: 9.
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    同族专利:
    公开号 | 公开日
    US7914811B2|2011-03-29|
    BR0202491A|2003-04-29|
    CN1394598A|2003-02-05|
    EP1273291A1|2003-01-08|
    CA2391439C|2011-07-19|
    MXPA02006603A|2004-08-19|
    JP2003095927A|2003-04-03|
    AR034712A1|2004-03-17|
    US20030017202A1|2003-01-23|
    CA2391439A1|2002-12-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-06-29|Priority to US09/896,052
    2001-06-29|Priority to US09/896,052
    2002-06-28|Application filed by 맥네일-피피씨, 인코포레이티드
    2003-01-29|Publication of KR20030009137A
    优先权:
    申请号 | 申请日 | 专利标题
    US09/896,052|2001-06-29|
    US09/896,052|US7914811B2|2001-06-29|2001-06-29|Brittle-coating, soft core dosage form|
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