Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

• the present invention relates to improved solid pharmaceutical dosage forms.
• the present invention is concerned with enhancing the dissolution of hydrophobic drugs.
• Hydrophobic Drugs As is well known, many pharmaceutically active compounds intended for oral administration are poorly soluble in water. Hydrophobic drugs do not generally dissolve easily and rapidly in the gastro-intestinal tract. This hydrophobic property often makes it difficult to formulate a drug so that it exhibits a satisfactory bioavailability profile in vivo. Poor bioavailability may lead to ineffective therapy, the need for higher dosing and/or undesirable side effects.
• hydrophobic drug may improve the dissolution of the dosage units within the gastro-intestinal tract. Furthermore, for some hydrophobic drugs, the addition of a surfactant during processing may improve the bioavailability of the product due to improved wetting of the hydrophobic active ingredient, leading to faster dissolution and absorption.
• U.S. Patent No. 4,344,934 discloses a mixture or solution of a poorly water-soluble drug with a pharmaceutically acceptable water-soluble polymer, wherein said mixture or solution has been treated with a minor amount of a wetting agent selected from anionic and cationic surfactants.
• Such compositions are formed as follows: First, a mixture or solution of the drug with the water-soluble polymer is formed. The mixture can be formed in a solvent or solvent mixture which is a mutual solvent for both the drug and the polymer.
• the drug-polymer mixture or solution After the drug-polymer mixture or solution has been formed in a solvent, it is dried by spray-drying, flash evaporation or air drying.
• the powdered drug-polymer mixture is then treated with an amount of a primarily aqueous wetting solution containing a wetting agent selected from anionic and cationic surfactants.
• the treated mixture is then again dried and, if necessary, it is milled, screened or ground prior to formulating into suitable dosage forms with pharmaceutically acceptable excipients.
• U.S. Patent No. 5,827,541 discloses a process for the preparation of an oral, rapidly disintegrating dosage form of a hydrophobic drug.
• the process comprises forming a suspension of the hydrophobic drug in a solvent containing a pharmaceutically acceptable surfactant together with a water-soluble or water- dispersible carrier material; forming discrete units of the suspension; and removing solvent from the discrete units under conditions whereby a network of the carrier material carrying a dosage of the hydrophobic drug is formed.
• a unique type of solid dosage form may be obtained by deposition of an active pharmaceutical ingredient on a pharmaceutically acceptable substrate.
• Various means for depositing pure active ingredients such as weighing, spraying or spreading, can be used to generate the dosage form as taught, for example, in the following patents and patent publications, the disclosures of which are incorporated by reference herein in their entireties: U.S. Patent Nos. 5,845,463, 5,240,049, 5,018,335 and 4,640,322, as well as WO 00/09249, SU 1803328 and GB 2238768.
• electrostatic deposition methodologies can be used.
• electrostatic deposition In the electrostatic deposition process, a cloud or stream of charged particles of the active ingredient is exposed to, or directed towards, a substrate, at the surface of which substrate a pattern of opposite charges has been established. In this fashion, a measured dosage of the active ingredient can be adhered to the substrate.
• Preferred electrostatically deposited dosage forms are disclosed in published international patent application number WO 99/63972, assigned to the assignee of the present invention, the disclosure of which is incorporated by reference herein in its entirety.
• the final dosage form may suffer from the same problems of poor dissolution and poor bioavailability that were discussed above with respect to conventional solid dosage forms of hydrophobic drugs.
• the prior art approach, involving the intimate admixture of the hydrophobic drug and a surfactant, would be difficult or impossible to implement in the context of electrostatic deposition.
• the drug and surfactant powders are to be blended prior to electrostatic deposition on the substrate, it may be difficult to obtain a suitably homogenous blend, or to maintain such homogeneity during the charging and delivery to the substrate.
• co-deposition of two different powders would require that both powders behave similarly during the deposition, but this is difficult to achieve since different powders often have different optimum deposition parameters.
• the surfactant may deposit only under a charge opposite that utilized for the active ingredient.
• One possible solution would be to deposit the active ingredient and the surfactant sequentially. However, there may be difficulty in forming depositions on top of pre-existing depositions, due to charge dissipation.
• improved solid pharmaceutical dosage formulations are provided, characterized by the enhanced dissolution of hydrophobic drugs.
• the formulations comprise: a base substrate comprising a first polymer; a deposit, comprising a therapeutic amount of a hydrophobic drag, deposited on the base substrate; a cover substrate comprising a second polymer, the cover substrate covering the deposit and joined to the base substrate by a bond that surrounds the deposit; and a dissolution-enhancing amount of a surfactant, disposed within a carrier that is segregated from, but in contact with, the deposit.
• FIG. 1 depicts an isometric view of a product comprising a strip package containing a plurality of unit forms in accordance with the prior art.
• FIG. 2 depicts a cover layer of a prior art strip package partially separated from a substrate.
• FIG. 3 depicts a side view of an illustrative unit form in accordance with the prior art.
• FIG. 4 depicts a top view of the illustrative unit form of FIG. 3.
• FIG. 5 depicts components of various embodiments of unit forms of the present invention.
• FIG. 6 is a graph of dissolution profiles for the drag CCN00401.
• FIG. 7 is a graph of dissolution profiles for the drag hydrocortisone.
• FIG. 8 is a graph of dissolution profiles for the drag glipizide.
• FIGS. 1 through 4 depict the general structure of prior art dosage forms which are to be improved in accordance with the present invention.
• product 1 comprises a package 2 that is realized as a strip 4 having an array of unit dosage forms 6.
• Strip 4 comprises a substrate 8 and a cover layer 9.
• Substrate 8 and cover layer 9 each comprise a substantially planar, flexible film or sheet.
• one of either substrate 8 or cover layer 9 includes an array of semi-spherical bubbles, concavities, blisters or depressions (hereinafter “bubbles”) 12 that are advantageously arranged in columns and rows.
• bubbles semi-spherical bubbles, concavities, blisters or depressions
• cover layer 9 comprises a three-by-five array of such bubbles 12, although more or fewer bubbles may suitably be provided.
• Substrate 8 and cover layer 9 are advantageously formed to have a thickness of about 0.001 inches (0.0254 mm) and typically comprise a thermoplastic material.
• Materials suitable for use as substrate 8 and/or cover layer 9 include, without limitation, polymers and copolymers of polyvinyl alcohol, polyvinyl pyrrolidinone, polysaccharide polymers, acrylate polymers, methacrylate polymers, phthalate polymers, polyvinyl acetate, methyl cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, polyethylene oxide, polypropylene, polyester and polyamide films, Eudragits (that is, polymers and copolymers containing methacrylic acid), starch- based polymers, gelatin and the like.
• Polyvinyl alcohol films suitable for use as the substrate and/or cover layer are commercially available from Polymer Films, Inc. of West Haven, CT; Chris Craft of Gary, IN; Aquafilm of Winston-Salem, NC; Idroplast S.p.A. of Montecatini Terme (PT), Italy; Aicello Chemical Co., Ltd. of Toyohashi; Japan; and Soltec of Paris, France.
• a deposit of a dry active ingredient 14, in the form of powder(s)/grains hereinafter, "powder" is disposed between substrate 8 and cover layer 9 within a bubble 12. Active ingredient 14 is deposited on substrate 8.
• Unit form 6 comprises a deposit of active ingredient 14, bubble 12, and a region of substrate 8 within bonds 7.
• Unit form 6 is a stable "core" (hereinafter, an "AccudepTM Core"), which may be further processed into a dosage form resembling a conventional tablet, capsule, caplet and the like or processed into a non-conventional wafer or stamp-like presentation.
• the preferred dosage forms may be suitable for oral, transdermal or buccal dosing of appropriate drugs.
• active ingredient 14 Suitable means of electrostatic deposition of active ingredient 14 are described in, for example, U.S. Patent Nos. 5,714,007, 5,846,595 and 6,074,688, the disclosures of which are incorporated by reference herein in their entireties.
• active ingredient may be coated onto the substrate in the form of a solution or a suspension of finely divided medicament; e.g., a collodial suspension.
• the liquid utilized for these operations can be water, an organic solvent, e.g., ethanol, or a hydroalcoholic solvent.
• One method of loading active ingredient in a liquid form onto a substrate is by electrostatic jet spray deposition. In this method, the active ingredient containing solution or suspension is metered into an apparatus which projects a spray of microdroplets which are concentrated on a particular area of the substrate through the use of a defined area electrostatic field.
• certain other coating techniques recognized in other arts as being amenable to the coating of a substrate with a liquid may be utilized in loading a pharmaceutically acceptable substrate with active ingredient.
• the substrate may be passed under a roll which is immersed in a bath of saturating fluid. As the substrate passes the roller, the excess fluid is "wiped" from the substrate by another roller, a jet of air, a rubber wiping bar, a wire-wound rod, e.g., a Meier rod, or the like.
• the present invention improves upon the prior art dosage forms depicted in FIGS. 1 through 4 by providing a dissolution-enhancing amount of a surfactant, disposed within a carrier that is segregated from, but in contact with, the active ingredient.
• the invention is based on the surprising finding that, contrary to the teachings in the prior art, a surfactant can improve the dissolution (and, consequently, the bioavailability) of a hydrophobic drag even though the drug and the surfactant are not co-formulated in intimate admixture with one another. Certain embodiments of the present invention are depicted in FIG. 5.
• active ingredient (“drag") 14 is shown after being deposited on substrate 8, prior to sealing with cover layer 9.
• cover layer 9 covers film
• cover layer 9 is aligned to place the pouch 16 in contact with active ingredient 14.
• the pouch material may be any polymer, and preferably the same material as substrate 8 or cover layer 9.
• pouch 16 Upon administration of the dosage form, during dissolution of cover layer 9 and/or substrate 8, pouch 16 similarly dissolves and releases the surfactant in the immediate vicinity of the drag, thereby improving drug dissolution.
• An alternative embodiment of the present invention is depicted in the second drawing in FIG.
• the surfactant is incorporated in an ingestible adhesive 10 that is applied to cover layer 9. After sealing cover layer 9 to substrate 8, the surfactant is in contact with, but segregated from, active ingredient 14. Upon administration of the dosage form and dissolution of cover layer 9 and/or substrate 8, the adhesive dissolves and releases the surfactant in the immediate vicinity of the drag, again improving drug dissolution.
• neither a pouch 16 nor a special adhesive 10 is required. Rather, the surfactant is incorporated directly in cover layer 9, so that the dissolving cover layer 9 releases the surfactant in the immediate vicinity of the encapsulated hydrophobic drug, allowing the surfactant to interact with the drug to help with dissolution.
• hydrophobic drag means a drag that ranges from “sparingly soluble” to “practically insoluble or insoluble,” as shown in the following table:
• Analgesics and anti-inflammatory agents acetaminophen, aloxiprin, auranofin, azapropazone, benorylate, celecoxib, diflunisal, etodolac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, salicylamide, salicylic acid, sulindac.
• Anthelmintics albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxantel embonate, oxfendazole, praziquantel, pyrantel embonate, thiabendazole.
• Anti-arrhythmic agents amiodarone, disopyramide, flecainide, quinidine.
• Anti-bacterial agents benethamine, cefaclor, cinoxacin, ciprofloxacin, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, penicillin, rifampicin, spiramycin, sulphabenzamide, sulphacetamide, sulphadiazine, sulphadoxine, sulphafurazole, sulphamerazine, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim.
• Anti-coagulants dicoumarol, dipyridamole, nicoumalone, phenindione.
• Anti-depressants amoxapine, maprotiline, mianserin, nortriptyline, oxypertine, trazodone, trimipramine.
• Anti-diabetics acetohexamide, chlo ⁇ ropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.
• Anti-epileptics beclamide, carbamazepine, clonazepam, ethotoin, metharbital, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phensuximide, phenytoin, primidone, sulthiame, valproic acid.
• Anti-fungal agents amphotericin, butoconazole, clotrimazole, econazole, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole, terbinafine, terconazole, tioconazole, undecenoic acid.
• Anti-gout agents allopurinol, probenecid, sulphinpyrazone.
• Anti-hypertensive agents amlodipine, benidipine, darodipine, diazoxide, dilitazem, felodipine, guanabenz, isradipine, methyldopa, minoxidil, nicardipine, nifedipine, nimodipine, phenoxybenzamine, prazosin, reserpine, terazosin.
• Anti-malarials amodiaquine, chloroquine, chlo ⁇ roguanil, halofantrine, mefloquine, proguanil, pyrimethamine, quinine.
• Anti-migraine agents dihydroergotamine, ergotamine, methysergide, pizotifen, sumatriptan.
• Anti-muscarinic agents atropine, benzhexol, biperiden, ethopropazine, hyoscyamine, mepenzolate, oxyphencylcimine, tropicamide.
• Anti-neoplastic agents and immunosuppressants aminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, finasteride, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine, raloxifene, tamoxifen, testolactone.
• Anti-Parkinsonian agents bromocriptine, lysuride.
• Anti-protazoal agents benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide, dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole.
• Anti-thyroid agents carbimazole, propylthiouracil.
• Anxiolytics sedatives, hypnotics and neuroleptics: allobarbitone, allylbarbituric acid, alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, ca ⁇ henazine, chlordiazepoxide, chlormethiazole, chlo ⁇ romazine, clobazam, clotiazepam, clozapine, cyclobarbitone, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, fluopromazine, flupenthixol, fluphenazine, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nit
• ⁇ -Blockers acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol.
• Cardiac Inotropic agents amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin.
• Corticosteroids beclomethasone, betamethasone, budesonide, cortisone, desoxymethasone, dexamethasone, flucortolone, fludrocortisone, flunisolide, fluticasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.
• Diuretics acetazolamide, amiloride, amisometradine, bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, furosemide, hydrochlorothiazide, metolazone, spironolactone, triamterene.
• Gastro-intestinal agents aminosalicylic acid, bisacodyl, cimetidine, cisapride, diphenoxylate, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron, ranitidine, sulphasalazine.
• Histamine Hi-Receptor Antagonists acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine, dimenhydrinate, fexofenadine, flunarizine, loratadine, meclozine, oxatomide.
• Lipid-regulating agents atorvastatin, bezafibrate, clofibrate, dextrothyroxine, fenofibrate, gemfibrozil, lovastatin, probucol, simvastatin.
• Nitrates and other anti-anginal agents amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.
• Nutritional agents betacarotene, vitamin A, vitamin B, vitamin D, vitamin E, vitamin K.
• Opioid analgesics codeine, dextropropyoxyphene, diamo ⁇ hine, dihydrocodeine, meptazinol, methadone, mo ⁇ hine, nalbuphine, pentazocine.
• Respiratory agents montelukast, pranlukast (CCN00401), zafirlukast, zileuton.
• Sex hormones clomiphene, conjugated estrogens, danazol, estradiol, ethinyloestradiol, medrogestone, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestimate, norgestrel, progesterone, stanozolol, stiboestrol, testosterone, tibolone.
• Stimulants amphetamine, cocaine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol.
• Thyroid agents levothyroxine.
• surfactant is meant, for pu ⁇ oses of the present invention, that the material is a surface active agent which displays wetting, detergent or soap-like qualities as those agents are understood by those of ordinary skill in the art.
• surfactant represents ionic and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, benzalkonium chloride, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium lauryl sulfate, magnesium lauryl sulfate, triethanolamine, cetrimide, sucrose laurate and other sucrose esters, glucose (dextrose) esters, simethicone,
• the surfactants of the invention may be classified by an "HLB number.”
• the HLB number provides a means for ranking surfactants based on the balance between the hydrophilic and lipophilic portions of the surfactant. That is, the higher the HLB number, the more hydrophilic the surfactant.
• many other types of pharmaceutical additives may be included in the dosage form disposed within a carrier that is segregated from, but in contact with, the deposited active ingredient.
• Such pharmaceutically acceptable additives include, but are not limited to, antioxidants, antimicrobial agents, complexing agents, acidity boosting agents, alkalinity boosting agents, buffering agents, carrier molecules, chelating compounds, preservatives and the like.
• “Pharmaceutically acceptable” here means that the additive may be introduced safely into the human or animal body, for example, taken orally and digested.
• Examples of such additives include, but are not limited to, the following: Acidifying agents: citric acid, maleic acid, lactic acid, malic acid, succinic acid, tartaric acid.
• Alkalinity buffering agents calcium carbonate, monoethanolamine, potassium citrate, sodium bicarbonate, sodium citrate, triethanolamine.
• Anti-microbial agents benzethonium chloride, benzoic acid, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, editic acid, ethylparaben, glycerol, imidurea, methylparaben, phenol, phenolic acid, phenoxyethanol, phenyl ethyl alcohol, phenylmercuric salts (acetate, borate and nitrate), potassium sorbate, propylene glycol, propylparaben, sodium benzoate, sodium propionate, sorbic acid, thimerosol.
• Anti-oxidants alpha tocopherol, ascorbic acid, ascorbic acid palmitate, butylated hydroxyanisole, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium metabisulfate.
• Complexing agents EDTA, potassium citrate, sodium citrate.
• Hydroxypropylmethylcellulose E50 (“HPMC”), available from Dow Chemical Company, Midland, Michigan. Hydroxypropylcellulose JFP (“HPC”), available from Hercules Inc., Wilmington, Delaware.
• PEG Polyethylene Glycol 400
• SLS Sodium lauryl sulfate
• SLS sodium lauryl sulfate
• Control AccudepTM Core Sealed a 1 mg deposition of CCN00401 between two polymer sheets with the following composition: 45% HPMC, 45% HPC, 10% PEG.
• SLS inco ⁇ orated in film AccudepTM Core Sealed a 1 mg deposition of CCN00401 between two polymer sheets with the following composition: 33.75% HPMC, 33.75% HPC, 7.5% PEG, 25% SLS (equivalent of about 1.2 mg SLS inco ⁇ orated in each AccudepTM Core).
• Dissolution profiles for the AccudepTM Cores listed above were generated under the following conditions: 50 rpm, paddles, pH 8.0 TRIS buffer.
• a set of Control AccudepTM Cores were tested in dissolution media that also contained Polysorbate 20.
• the addition of SLS in the polymer film or mixed directly with the drag led to significantly faster dissolution at 15 minutes (even faster than the case where Polysorbate 20 is present in the media).
• Hydrocortisone CCN90306A
• SLS and Polysorbate 80 were used to test the effect SLS and Polysorbate 80 have on dissolution of an AccudepTM Core.
• AccudepTM Cores were made as follows:
• Control AccudepTM Core Sealed a 1 mg deposition of CCN90306A between two polymer sheets with the following composition: 45% HPMC, 45% HPC, 10% PEG.
• HPMC HPMC, 36% HPC, 8% PEG, 20% SLS (equivalent of about 5 mg SLS inco ⁇ orated in each AccudepTM Core).
• Polysorbate 80 inco ⁇ orated in film AccudepTM Core Sealed a 1 mg deposition of CCN90306A between two polymer sheets with the following composition: 36% HPMC, 36% HPC, 8% PEG, 20% Polysorbate 80 (equivalent of about 5 mg Polysorbate 80 inco ⁇ orated in each AccudepTM Core).
• Dissolution profiles for the AccudepTM Cores listed above were generated under the following conditions: 75 rpm, paddles, distilled water.
• Glipizide, CCN90906A was used to test the effect SLS and Polysorbate 80 have on dissolution of an AccudepTM Core.
• AccudepTM Cores were made as follows:
• CCN90906A between two polymer sheets with the following composition: 36% HPMC, 36% HPC, 8% PEG, 20% SLS (equivalent of about 5 mg SLS inco ⁇ orated in each AccudepTM Core).
• Polysorbate 80 inco ⁇ orated in film AccudepTM Core Sealed a 1 mg deposition of CCN90906A between two polymer sheets with the following composition: 36% HPMC, 36% HPC, 8% PEG, 20% Polysorbate 80 (equivalent of about 5 mg Polysorbate 80 inco ⁇ orated in each AccudepTM Core).
• Dissolution profiles for the AccudepTM Cores listed above were generated under the following conditions: 50 ⁇ m, paddles, simulated intestinal fluid.

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