CN1469707A - Improved solid pharmaceutical dosage formulation of hydrophobic drugs - Google Patents
Improved solid pharmaceutical dosage formulation of hydrophobic drugs Download PDFInfo
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- CN1469707A CN1469707A CNA018171605A CN01817160A CN1469707A CN 1469707 A CN1469707 A CN 1469707A CN A018171605 A CNA018171605 A CN A018171605A CN 01817160 A CN01817160 A CN 01817160A CN 1469707 A CN1469707 A CN 1469707A
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- 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
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- 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
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- 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
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- 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
Abstract
A novel solid pharmaceutical dosage formulation of hydrophobic drugs is disclosed, which provides enhanced dissolution and improved bioavailability. The hydrophobic drug is deposited electrostatically on the base substrate. T he dosage form may include any pharmaceutically acceptable additive, disposed within a carrier that is segregated from, but in contact with, the deposit. Figure No. 1 depicts an isometric view of a product comprising a strip packa ge containing a plurality of unit forms in accordance with the prior art.
Description
Background of invention
The present invention relates to improved solid pharmaceutical dosage formulation.More specifically, the present invention relates to strengthen the stripping of hydrophobic drug.
Hydrophobic drug
As everyone knows, manyly be used for oral pharmaceutical active compounds and have relatively poor water-soluble.Hydrophobic drug is difficult for promptly being dissolved in intestines and stomach usually.This hydrophobic property often causes being difficult to compounding pharmaceutical, so that medicine shows gratifying bioavilability in vivo.Dosage and/or undesirable side effect that relatively poor bioavilability may cause effectively treating, needs are higher.
Have realized that now adding surfactant in the process of hydrophobic drug can improve the stripping of dosage unit in intestines and stomach.In addition, for some hydrophobic drug, add the bioavilability that surfactant also can improve product in process, this is owing to improved the wetability of hydrophobic active composition, causes the result of very fast stripping and absorption.
Therefore, for remedying the poorly soluble defective of some hydrophobic drug, existing people has advised various carrier systems, wherein this class medicine is fully mixed jointly with some surfactant and other compositions and prepares.
For example, United States Patent (USP) 4344934 discloses the medicine of poorly water-soluble and the mixture or the solution of pharmaceutically acceptable water soluble polymer, and wherein said mixture or solution are to use the wetting agent that is selected from anion surfactant and cationic surfactant on a small quantity to handle.This based composition is following formation: at first, form the mixture or the solution of medicine and water-soluble polymer.This mixture can be at the solvent that is medicine, also is simultaneously to form in a kind of solvent of solvent of polymer or the solvent mixture.After in solvent, forming drug-polymer mixture or solution, it is carried out drying by atomized drying, rapid evaporation or air drying means.This powdery medicine-polymeric blends is handled with a certain amount of wetting agent solution then, and this wetting agent solution mainly comprises the wetting agent that is selected from anion surfactant and cationic surfactant.The mixture that to handle carries out drying more then, and if desired, after its grinding, sieving or pulverize, is mixed with suitable formulation with pharmaceutically acceptable excipient.
United States Patent (USP) 5827541 discloses a kind of preparation method of oral rapidly disintegrating dosage form of hydrophobic drug.This method comprises the suspension of formation hydrophobic drug in the solvent that comprises pharmaceutically acceptable surfactant and water-soluble or water-dispersible carrier material; Form the suspension of individual; Desolvate with from the suspension of individual, removing under the condition of the mesh carrier material of the hydrophobic drug that is loaded with doses in formation.
Therefore, common method known in the art is tending towards concentrating in the exploitation of carrier system, and wherein hydrophobic drug must mix fully with surfactant and other components.A series of shortcomings of this method are all to need to develop independent carrier system according to experience more or less for each hydrophobic drug.Moreover because the interaction between medicine and the wetting agent/solubilizer, wetting agent/solubilizer can cause the product instability with mixing of active component.It is obviously time-consuming and expensive to design independent carrier system for each medicine.Therefore still need a kind of special pharmaceutical carrier system that extensively is suitable for all kinds of different hydrophobic drugs.
The deposition of medicine
By active pharmaceutical ingredient being deposited on the solid dosage forms that can obtain unique types on the pharmaceutically acceptable matrix.Be used to deposit the various means of pure active component, all can be used for forming the formulation of instructing in for example following patent and the patent publications as weight, spraying or coating: United States Patent (USP) 5,845,463,5,240,049,5,018,335 and 4,640,322 and WO 00/09249, SU 1803328 and GB 223878, the full text that is incorporated herein these documents for your guidance.
In a preferred embodiment, can use the electrostatic precipitation method.In electrostatic deposition process, the electrically charged particle of cloud or steam-like active component is contacted with matrix, perhaps directive matrix, opposite electric charge has distributed on the surface of described matrix.By this way, can make the active component of determining dosage be adhered to matrix.Preferably be disclosed in the International Patent Application WO 99/63972 of publication through the formulation of electrostatic precipitation, this application transfers assignee of the present invention, and the disclosure that is incorporated herein this application for your guidance.
Though static drug deposition method has some advantage usually, comprise and improve dose uniformity that when the medicine of wanting electrostatic precipitation was hydrophobic drug, also there was certain problem in this method.Particularly, final formulation can be caused the problem of stripping property difference and bioavilability difference, and these problems are identical with the problem of the conventional solid dosage forms of relevant hydrophobic drug discussed above.In addition, the art methods that comprises abundant mixing hydrophobic drug and surfactant is difficult to or may realize electrostatic precipitation.
For example,, may be difficult to the uniformity mixture that obtains to be fit to, perhaps electrically charged and send and during matrix, need to keep this uniformity if medicine and surfactant powder were mixed before on the matrix in electrostatic precipitation.In addition, the codeposition of two kinds of different powder requirement two kinds of powder between depositional stage have similar performance, but this is difficult to realization, because different powder often has the suitableeest different deposition parameter.Under extreme case, surfactant only just may deposit under the condition with electric charge opposite with active component.
A kind of feasible solution is sequential aggradation active component and surfactant.But because the dispersion of electric charge, be difficult to form deposition above sedimental being pre-existing in.
Therefore, need provide a kind of formulation of hydrophobic drug, wherein solve the technical matters described in poor solubility and bioavilability difference and top each section.
Summary of the invention
According to instruction of the present invention, improved solid pharmaceutical dosage formulation (solidpharmaceutical dosage formulations) is provided, be characterised in that the stripping that has improved hydrophobic drug.Said preparation comprises:
The bottom that contains first polymer;
The sediments that contains the hydrophobic drug of therapeutic dose, it is deposited on the bottom;
The cover layer that contains second polymer, this cover layer cover sediments and link to each other with bottom by centering on sedimental adhesive; And
The surfactant of stripping promotion amount, it is deposited on separates with sediments but in the contacted carrier.
Therefore, the solid pharmaceutical dosage formulation of hydrophobic drug that the purpose of this invention is to provide the bioavilability of stripping with improvement and improvement.
Description of drawings
Accompanying drawing 1 has described to comprise the stereogram (isometric view) of the product of splitting packing (strip package), the described unit dosage form that comprises a plurality of prior aries of splitting.
Accompanying drawing 2 has been described the cover layer that partly separates with bottom of splitting packing of prior art.
Accompanying drawing 3 has been described the end view of the exemplary cell formulation of prior art.
Accompanying drawing 4 has been described the top view of accompanying drawing 3 illustrational unit dosage forms.
Accompanying drawing 5 has been described the formation of the unit dosage form of different embodiments of the present invention.
Accompanying drawing 6 is stripping curve figure of medicine CCN00401.
Accompanying drawing 7 is stripping curve figure of medicine hydrocortisone.
Accompanying drawing 8 is stripping curve figure of medicine Glipizide.
Detailed Description Of The Invention
Accompanying drawing 1-4 has described the general structure of prior art formulation, and they will improve according to the present invention.In accompanying drawing 1, product 1 comprises the packing 2 that is considered to split packing 4, splits the unit dosage form 6 that packing 4 has arrangement.Split packing 4 and comprise bottom 8 and cover layer 9.
That bottom 8 and cover layer 9 respectively comprise is smooth basically, flexible film or thin slice.In some cases, one deck in bottom 8 or the cover layer 9 comprises the arrangement of hemispherical bubble-cap, recess, protruding bubble or the sunk part 12 (hereinafter referred to as " bubble-cap (bubble) ") advantageously arranged in length and breadth, in the example package that accompanying drawing 1 is described, cover layer 9 comprises 3 * 5 arrangements of bubble-cap 12, but the bubble-cap of more or less number can be provided aptly.Form thickness and be the bottom 8 of about 0.001 inch (0.0254mm) and cover layer 9 is favourable and they comprise thermoplastic usually.Be suitable for comprising as the material of bottom 8 and/or cover layer 9, but be not limited to following polymer and copolymer: polyvinyl alcohol, polyvinylpyrrolidone, polysaccharide polymer, acrylate polymer, methacrylate polymers, phthalate polymers, polyvinyl acetate, methylcellulose, carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, PEO, polypropylene, polyester and polyamide film, Eudragits (that is the polymer and the copolymer that, comprise methacrylic acid), starch-based polymer, gelatin etc.Being suitable for use as bottom and/or tectal polyvinyl alcohol film can be available from Polymer Films, Inc., West Haven, CT; Chris Craft, Gary, IN; Aquafilm, Winston-Salem, NC; Idroplast S.p.A., MontecatiniTerme (PT), Italy; Aicello Chemical Co., Ltd., Toyohashi; Japan; And Soltec, Paris, France.
Shown in accompanying drawing 2 (having shown the cover layer of " peeling off " with bottom 8 parts 9) and accompanying drawing 3, the sediments of the active component 14 of the drying of powder/granule (hereinafter referred to as " powder ") form is deposited in the bubble-cap 12 between bottom 8 and the cover layer 9.Active component 14 is deposited on the bottom 8.Shown in the vertical view of the cross sectional view of accompanying drawing 3 and accompanying drawing 4 (each figure has only shown single bubble-cap 12), bottom 8 and cover layer 9 are with 7 to be connected to each other by adhesive tape or welding, adhesive tape or welding band near and around bubble-cap 12.Bonding passing through for example heated or ultrasonic bonding carries out or undertaken bonding by suitable adhesive.Unit dosage form 6 comprises the zone of sediments, bubble-cap 12 and the bottom 8 in the adhesive tape 7 of active component 14.Unit dosage form 6 is stable " nuclear " (" Accudep hereinafter referred to as
TMNuclear "), it can further be processed to form formulation, resembles conventional sheet, capsule, capsule sheet (caplet) etc. or is processed as unconventional thin slice (wafer) or is punching press shape (stamp-like).Preferred formulation can be the form that is suitable for the suitable drugs of oral, transdermal or cheek administration.
The suitable means of electrostatic precipitation active component 14 are recorded in, and for example United States Patent (USP) 5,714, and in 007,5,846,595 and 6,074,688, the disclosure of these patents is incorporated herein by reference.Destatic outside the powder cloud and mist sedimentation (electrostatic powdercloud deposition), the suspension of active component with solution or particulate medicine can be coated on the bottom as the soliquid form.The liquid that is used for these operations can be water, organic solvent, as ethanol or water alcohols solvent.Is the electrostatic spraying spray deposition with liquid form with a kind of method that active component is loaded on the bottom.In the method, the solution or the suspension metering that will comprise active component are added in the device that sprays vaporific fine droplets, fine droplets are concentrated on the specific region of bottom by the electrostatic field that adopts the localized area.
Destatic outside the jet atomization sedimentation, also can utilize known being suitable for of other field active component to be loaded on the pharmaceutically acceptable bottom with some other coating technology of liquid coating basic unit.For example, pass through below the roll that bottom is flooded in saturated fluid bath.When bottom when the roll, with air, the rubber of another roll, injection wipe rod, wire twines rod, " wipes " fluid of surplus from bottom as Meier rod etc.
The present invention has improved the prior art formulation shown in accompanying drawing 1-4, and described improvement comprises the surfactant that stripping promotion amount is provided, and it is deposited in the carrier of separating with active component but contacting with it.The present invention is based on this beat all discovery, promptly opposite with the instruction of prior art, even medicine is not fully to prepare jointly each other with surfactant with mixing, surfactant also can promote the stripping (and therefore having improved bioavilability) of hydrophobic drug.
Embodiments more of the present invention have been described in the accompanying drawing 5.In the figure that indicates " sediments ", active component (" medicine ") 14 is shown is before with cover layer 9 sealings, be deposited on the bottom 8 after.In indicating first figure of " cover film " (" surfactant is in bag (pouch) "), surfactant is the bag in 16 that joins cover layer (" cover film ") 9, and discharging cover layer 9, so that bag 16 contacts with active component 14.The bag material can be any polymer, but preferably with bottom 8 or cover layer 9 identical materials.When this formulation administration, between 8 breaking-in periods, bag 16 is dissolving and release surface activating agent around next-door neighbour's medicine similarly, improves the stripping of medicine thus at cover layer 9 and/or bottom.
Second figure (" surfactant is in adhesive ") that indicates " cover film " in the accompanying drawing 5 described another embodiment of the invention.In this embodiment, surfactant is incorporated in the absorbable adhesive 10 that is applied to cover layer 9.After cover layer 9 and bottom 8 sealed, surfactant contacted with active component 14 but separates.When this formulation administration and cover layer 9 and/or bottom 8 dissolvings, adhesive is dissolving and release surface activating agent around next-door neighbour's medicine, has also improved the stripping of medicine.
In an embodiment preferred (specifically not showing in the accompanying drawing 5), neither need bag 16, do not need particular adhesive 10 yet.But surfactant is directly mixed in the cover layer 9, dissolve cover layer 9 like this and around the hydrophobic drug of next-door neighbour's packing, discharge surfactant, make surfactant and drug interaction and hydrotropy goes out.
In full text of the present invention, " hydrophobic drug " is meant the medicine from " slightly soluble " to " almost insoluble or insoluble " scope as shown in the table:
Descriptive item for 1 part of solute Solvent umber for 1 part of solute needsSlightly soluble 30-100 is the unusual slightly soluble 1000-10 of slightly soluble 100-1000 slightly, 000 almost insoluble or insoluble 10,000 and more than
Hydrophobic drug and the officinal salt thereof that can prepare according to the present invention include, but are not limited to following:
The analgesia class agent that disappears: paracetamol, Aloxiprin, Anranofin, apazone, benorylate, celecoxib, Diflunisal, Etodolac, fenbufen, fenoprofen, Flurbiprofen, brufen, indocin, Ketoprofen, Meclofenamic Acid, mefenamic acid, Nabumetone, naproxen, crovaril, phenylbutazone, piroxicam, rofecoxib, salicylamide, salicylic acid, sulindac.
Pest repellant: Albendazole, Bephenium Hydroxynaphthoate, cambendazole, two chlorine sweet smell, ivermectin, mebendazol, Oxamniquine, oxantel embonate, oxfendazole, praziquantel, pyrantel pamoate, thiabendazolum.
Antiarrhymic: amiodarone, disopyramide, Flecainide, quinindium.
Antibacterial agent: benapen (benethamine), Cefaclor, cinoxacin, Ciprofloxacin, Clarithromycin, Clofazimine, Cloxacillin, demeclocycline, Doxycycline, erythromycin, 2-ethylisonicotinthionamide, Imipenem, acidum nalidixicum, furantoin, penicillin, rifampin, spiramycin, sulfabenzamide (sulphabenzamide), sulfacetamide, sulphadiazine, sulfadoxine (sulphadoxine), sulfafurazole, sulfamerazine, Sulfamethoxazole, sulfapryidine, tetracycline, Trimethoprim.
Anticoagulant: bicoumarin, Dipyridamole, acenocoumarin (nicoumalone), phenindione.
Antidepressant: amoxapine, maprotiline, Mianserin, nortriptyline, Oxypertine, Trazodone, trimipramine.
Remedies for diabetes: Acetohexamide, chlorpropamide, glibenclamide, gliclazide, Glipizide, tolazamide, orinase.
Anti-epileptics: beclamide, carbamazepine, Clonazepam, Ethotoin, metharbital, mephenytoin, first amber amine, mebaral, Oxcarbazepine, paramethadione, phenacemide, phenobarbital, phensuximide, phenytoinum naticum, Primidone, easypro thiazine (sulthiame), valproic acid.
Antifungal agent: anphotericin, butoconazole, clotrimazole, econazole, Fluconazole, Flucytosine, griseofulvin, Itraconazole, ketoconazole, Miconazole, Natamycin, nystatin, sulconazole, Terbinafine, terconazole, tioconazole, undecenoic acid.
The gout treatment agent: Allopurinol, probenecid, sulfinpyrazone.
Antihypertensive: Amlodipine, Benidipine, darodipine, diazoxiide, diltiazem (dititazem), felodipine, guanabenz, Isradipine, ethyldopa, minoxidil, nicardipine, nifedipine, Nimodipine, phenoxybenzamine, prazosin, reserpine, Terazosin.
Antimalarial: amodiaquine, chloroquine, Chlorproguanil, halofantrine, Mefloquine, chloroguanide, pyrimethamine, quinine.
The migraine treatment agent: dihydroergotamine, ergotamine, methysergid, pizotifen, sumatriptan.
Anti-muscarine agent: atropine, benzhexol, Biperiden, profenamine, hyoscyamine, Mepenzolate, Oxyphencyclimine, Tropicamide.
Antitumor agent and immunodepressant: aminoglutethimide, amsacrine, imuran, busulfan, Chlorambucil, cyclosporin, Dacarbazine, Estramustine, Etoposide, Fei Nasi carry, lomustine, melphalan, mercaptopurine, methotrexate (MTX), mitomycin, mitotane, rice holder anthrone (mitozantrone), procarbazine, Raloxifene, Tamoxifen, testolactone.
Antiparkinsonian drug: bromocriptine, lisuride.
Antiprotozoal agent: benznidazole, clioquinol, Decoquinate, moebiquin, diloxanide, dinitolmide, furazolidone (furzolidone), metronidazole, Nimorazole, nitrofurazone, Ornidazole, Tinidazole.
Antithyroid drug: Carbimazole, propylthiouracil (PTU).
Antianxiety agent, sedative, hypnotic and Neuroleptic: allobarbital, butalbital, alprazolam, amytal, barbital, bentazepam, Bromazepam, Bromperidol, brotizolam, butobarbital, carbromal, Carfenazine (carphenazine), chlorine nitrogen , clormethiazole, chlorpromazine, Clobazam, Clotiazepam, Clozapine, cyclobarbital, diazepam, droperidol, ethinamate, flunanisone, Flunitrazepam, padil, Flupentixol, fluphenazinum, Flurazepam, haloperole, Lorazepam, Lormetazepam, medazepam, Meprobamate, Methaqualone, midazolam, nitrazepam, Oxazepam, amobarbital, perphenazine, Pimozide, prochlorperazine, Sulpiride, Temazepam, thioridazine, triazolam, zopiclone.
Beta-Blocking agent: acebutolol, alprenolol, atenolol, labetalol, metoprolol, Nadolol, oxprenolol, pindolol, Propranolol.
Influence the cardiac contractile force agent: Amrinone, foxalin, digoxin, Enoximone, cedilanid lanatoside C, metildigoxin.
Corticosteroid: beclomethasone, betamethasone, budesonide, cortisone, Desoximetasone, dexamethasone, fluocortolone, fludrocortison, flunisolide, fluticasone, hydrocortisone, methylprednisolone, prednisolone, metacortandracin, fluoxyprednisolone.
Diuretic: acetazolamide, amiloride, amisometradine, bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, Hydrochioro, metolazone, spirolactone, triamterene.
The intestines and stomach medicine: Para-amino-salicylic acid, Bisacodyl, Cimetidine, Cisapride, diphenoxylate, domperidone, famotidine, Loperamide, Mesalazine, nizatidine, Omeprazole, Ondansetron, ranitidine, salicylazosulfapyridine.
Histamine H 1 -receptor antagonist: Acrivastine, astemizole, cinnarizine, Cyclizine, cyproheptadine, dramamine, fexofenadine, flunarizine, Loratadine, meclozine, Oxatomide.
Lipid regulating agent: Atorvastatin, Bezafibrate, chlorine Bei Te, dexadrine, fenofibrate, Gemfibrozil, Lovastatin, probucol, Simvastatin.
Nitrate esters and other antianginal drug: amyl nitrate, monobel, isosorbide dinitrate, Ismo 20, four pentaerythritol tetranitrates.
Nutritional agents: Betacarotene, vitamin A, Cobastab, vitamin D, vitamin E, vitamin K.
Opium sample anodyne: codeine, dextropropoxyphene (dextropropyoxyphene), diamorphine, Dihydrocodeine, meptazinol, methadone, morphine, Nalbuphine, pentazocine.
The respiratory tract medicine: montelukast, Pranlukast (CCN00401), zafirlukast, Zileuton.
Sex hormone: Clomifene, premarin, reach that azoles, estradiol, ethinyloestradiol, Medrogestone, medroxyprogesterone acetate, mestranol, methyltestosterone, norethindrone, norgestimate, norgestrel, progesterone, Stanozolol, diethylstilbestrol (stiboestrol), testosterone, Tibolone.
Analeptic: amphetamine, ***e, dextro-amphetamine, Dexfenfluramine, fenfluramine, horse indoles.
Thyroid: Levothyroxine.
For purpose of the present invention, " surfactant " is meant the surfactant materials that demonstrates wetting, de-sludging or soap sample character, as known to the those of ordinary skill of this area those.Therefore; in term " surfactant " the expression pharmaceutical preparation that the present invention uses ion commonly used or non-ionic surfactant or wetting agent; the castor oil of ethoxylation for example; Benasept; polyethylene glycol glycerol ester (polyglycolyzed glycerides); acetylated monoglyceride; fatty acid esters of sorbitan; poloxamer (poloxamers); polyoxyethylene fatty acid ester; polyoxyethylene deriv; monoglyceride or its ethoxylated derivative; two glyceride or its polyoxyethylene deriv; sodium docusate; NaLS; lauryl magnesium sulfate; triethanolamine; bromine alkanamine (cetrimide); lauric acid sucrose ester and other sucrose esters; glucose (dextrose) ester; simethicone; ocoxynol; dioctyl sodium sulphosuccinate; the polyethylene glycol glycerol ester; neopelex; dialkyl sodium sulfosuccinate; fatty alcohol is as laruyl alcohol; cetanol and stearyl alcohol; the glyceryl ester; the cholic acid or derivatives thereof; lecithin and phosphatide.
Surfactant of the present invention can be classified by " HLB value ".The HLB value provides the means according to the balanced sort surfactant between the hydrophilic and lipophilic portion of surfactant.That is, the HLB value is high more, and the hydrophily of surfactant is strong more.
In wideer embodiment of the present invention, can comprise the medicated premix (substitution list surface-active agent or except that surfactant) of many other types in the formulation, it is deposited in the carrier of separating with the active component that deposits but contacting with it.The pharmaceutically acceptable additive of this class includes, but not limited to antioxidant, antimicrobial, complexant, acid reinforcing agent, alkaline reinforcing agent, buffer, carrier molecule, chelate compound, preservative etc.
Here " pharmaceutically acceptable " for example is meant that the additive that can introduce is safe for human or animal body when oral and digestion.The example of such additive includes, but not limited to following:
Acidulant: citric acid, maleic acid, lactic acid, malic acid, succinic acid, tartaric acid.
Ealkaline buffer: calcium carbonate, monoethanolamine, potassium citrate, sodium bicarbonate, sodium citrate, triethanolamine.
Antimicrobial: Benzethonium Chloride, benzoic acid, bronopol, butyl hydroxybenzoate, Cetrimide, chlohexidine, anesin, chloreresol, cresols, edetic acid(EDTA) (editic acid), ethylparaben, glycerine, imidurea, methyl hydroxybenzoate, phenol, carbolic acid, phenoxetol, phenylethanol, phenyl mercuric salt (acetate, borate and nitrate), potassium sorbate, propane diols, propylben, Sodium Benzoate, sodium propionate, sorbic acid, thimerosal.
Antioxidant: alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole (BHA), fumaric acid, malic acid, n-propyl gallate, sodium ascorbate, sodium metabisulphate.
Complexant: EDTA, potassium citrate, sodium citrate.
Embodiment
Use following material among the embodiment:
Hydroxypropyl methylcellulose E50 (" HPMC ") can be available from Dow Chemical Company, Midland, Michigan.
Hydroxypropyl cellulose JFP (" HPC ") can be available from Hercules Inc., Wilmington, Delaware.
PEG400 (" PEG " ＂) can be available from Union Carbide Corporation, Danbury, Connecticut.
NaLS (" SLS "), HLB=40 can be available from Spectrum Qualit Products, New Brunswick, New Jersey.
Polysorbate80 (Tween 80), HLB=15 can be available from Uniqema, ICI branch, Wilmington, Delaware.
Polysorbate20 (polysorbas20), HLB=16.7 can be available from Uniqema.
Hydrocortisone can be available from Spectrum Quality Products.
Glipizide can be available from Fine Chemicals Corporation, Capetown, South Africa.
Embodiment 1
Use representative compounds CCN00401 test NaLS (SLS) to Accudep
TMThe influence of the stripping of nuclear.Be prepared as follows the Accudep of a few types
TMNuclear:
Contrast Accudep
TMNuclear: 1mg sediments CCN00401 is sealed between the two layers of polymers film with following composition: 45%HPMC, 45%HPC, 10%PEG.
Mixed the Accudep of SLS in the film
TMNuclear: 1mg sediments CCN00401 is sealed between the two layers of polymers film with following composition: 33.75%HPMC, 33.75%HPC, 7.5%PEG, 25%SLS are (at each Accudep
TMMix identical about 1.2mg SLS in the nuclear).
The Accudep of the SLS that directly mixes with CCN00401
TMNuclear: 2mgCCN00401/SLS mixture (50/50) is sealed between the two layers of polymers film with following composition: 45%HPMC, 45%HPC, 10%PEG.
The Accudep that lists above under following condition, making
TMThe stripping curve of nuclear: 50rpm, oar formula, pH 8.0 TRIS buffer solutions.In addition, a series of Accudep in contrast of test in the dissolution medium that also comprises polysorbate20
TMNuclear.
Accompanying drawing 6 has shown the average stripping curve (n=3) of all CCN00401 stripping situations.As shown in Figure 6, in thin polymer film, add SLS or with its directly and medicine cause stripping obviously to accelerate (even also faster) when being blended in 15 minutes than the situation that has polysorbate20 in the medium.In the time of 30 minutes, except at Accudep
TMDo not have in the nuclear or in the dissolution medium outside the situation of surfactant, all experimental scheme all have medium to the average stripping up to 90% scope.
Embodiment 2
Use hydrocortisone, CCN90306A test SLS and polysorbate80 to Accudep
TMThe influence of the stripping of nuclear.Be prepared as follows Accudep
TMNuclear:
Contrast Accudep
TMNuclear: 1mg sediments CCN90306A is sealed between the two layers of polymers film with following composition: 45%HPMC, 45%HPC, 10%PEG.
Mixed the Accudep of SLS in the film
TMNuclear: 1mg sediments CCN90306A is sealed between the two layers of polymers film with following composition: 36%HPMC, 36%HPC, 8%PEG, 20%SLS are (at each Accudep
TMMix identical about 5mg SLS in the nuclear).
Mixed the Accudep of polysorbate80 in the film
TMNuclear: 1mg sediments CCN90306A is sealed between the two layers of polymers film with following composition: 36%HPMC, 36%HPC, 8%PEG, 20% polysorbate80 are (at each Accudep
TMMix identical about 5mg polysorbate80 in the nuclear).
The Accudep that lists above under following condition, making
TMThe stripping curve of nuclear: 75rpm, oar formula, distilled water.
Accompanying drawing 7 has shown the average stripping curve (n=3) of all CCN90306A stripping situations.As shown in Figure 7, adding SLS and polysorbate in thin polymer film causes stripping to be accelerated when 20 and 30 minutes sampled point.
Embodiment 3
Use Glipizide, CCN90906A test SLS and polysorbate80 to Accudep
TMThe influence of the stripping of nuclear.Be prepared as follows Accudep
TMNuclear:
Mix the Accudep of SLS in the film
TMNuclear: 1mg sediments CCN90906A is sealed between the two layers of polymers film with following composition: 36%HPMC, 36%HPC, 8%PEG, 20%SLS are (at each Accudep
TMMix identical about 5mg SLS in the nuclear).
Mixed the Accudep of polysorbate80 in the film
TMNuclear: 1mg sediments CCN90906A is sealed between the two layers of polymers film with following composition: 36%HPMC, 36%HPC, 8%PEG, 20% polysorbate80 are (at each Accudep
TMMix identical about 5mg polysorbate80 in the nuclear).
The Accudep that lists above under following condition, making
TMThe stripping curve of nuclear: 50rpm, oar formula, simulated intestinal fluid.
Accompanying drawing 8 has shown the average stripping curve (n=3) of all CCN90906A stripping situations.As shown in Figure 8, in thin polymer film, add SLS and polysorbate and cause stripping to be accelerated, particularly in 60 minutes of beginning.
Though the present invention uses some preferred embodiment of specific reference to be described, in the essence of following claims and scope, can change and modify the present invention.
Claims (16)
1. the solid pharmaceutical dosage formulation of an improved hydrophobic drug comprises:
The bottom that contains first polymer;
The sediments that contains the hydrophobic drug of therapeutic dose, it is deposited on the bottom;
The cover layer that contains second polymer, this cover layer cover sediments and link to each other with bottom by centering on sedimental adhesive tape; And
The surfactant of stripping promotion amount, it is deposited on separates with sediments but in the contacted carrier.
2. according to the dosage particles of claim 1, wherein bottom comprises smooth film.
3. according to the dosage particles of claim 1, wherein cover layer comprises smooth film.
4. according to the dosage particles of claim 3, wherein the shape of coverlay film comprises the hemispherical bubble-cap, and wherein sediments is deposited in the border of hemispherical bubble-cap.
5. according to the dosage particles of claim 2, wherein the shape of bottom film comprises the hemispherical bubble-cap, and wherein sediments is deposited in the border of hemispherical bubble-cap.
6. according to the dosage particles of claim 1, wherein sedimental shape is circular substantially, and sedimental diameter is about 3 millimeters to about 7 millimeters.
7. according to the dosage particles of claim 1, wherein first polymer or second polymer comprise thermoplastic.
8. according to the dosage particles of claim 1, wherein first polymer or second polymer are selected from following polymer and copolymer: polyvinyl alcohol, polyvinylpyrrolidone, polysaccharide polymer, acrylate polymer, methacrylate polymers, phthalate polymers, polyvinyl acetate, methylcellulose, carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, PEO, polypropylene, polyester and polyamide film, Eudragits, starch-based polymer and gelatin.
9. according to the dosage particles of claim 1, wherein first polymer and second polymer phase are together.
10. according to the dosage particles of claim 1, wherein bottom and cover layer are absorbable.
11. according to the dosage particles of claim 1, wherein carrier is a cover layer.
12. according to the dosage particles of claim 1, wherein carrier is absorbable adhesive, it imposes on cover layer.
13. according to the dosage particles of claim 1, wherein carrier is a bag, between sediments and cover layer, this bag comprises absorbable material.
14. according to the dosage particles of claim 1, wherein hydrophobic drug is by electrostatic precipitation.
15. an improved solid pharmaceutical dosage formulation, said preparation comprises:
The bottom that contains first polymer;
The sediments that contains the medicine of therapeutic dose, it is deposited on the bottom;
The cover layer that contains second polymer, this cover layer cover sediments and link to each other with bottom by centering on sedimental adhesive tape; And
Pharmaceutically acceptable additive, it is deposited on separates with sediments but in the contacted carrier.
16. according to the dosage particles of claim 15, its Chinese traditional medicine is by electrostatic precipitation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22427500P | 2000-08-10 | 2000-08-10 | |
| US60/224,275 | 2000-08-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1469707A true CN1469707A (en) | 2004-01-21 |
Family
ID=22839969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA018171605A Pending CN1469707A (en) | 2000-08-10 | 2001-08-09 | Improved solid pharmaceutical dosage formulation of hydrophobic drugs |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US20020036154A1 (en) |
| EP (1) | EP1307097A4 (en) |
| JP (1) | JP2004505996A (en) |
| KR (1) | KR20030024849A (en) |
| CN (1) | CN1469707A (en) |
| AU (1) | AU2001284772A1 (en) |
| CA (1) | CA2417813A1 (en) |
| HU (1) | HUP0301668A2 (en) |
| IL (1) | IL154268A0 (en) |
| WO (1) | WO2002013762A2 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0114532D0 (en) * | 2001-06-14 | 2001-08-08 | Jagotec Ag | Novel compositions |
| US20030068375A1 (en) | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
| SI21402A (en) * | 2003-02-12 | 2004-08-31 | LEK farmacevtska dru�ba d.d. | Lined particles and pharmaceutical forms |
| US20060018970A1 (en) * | 2003-12-12 | 2006-01-26 | Myogen, Inc. | Enoximone formulations and their use in the treatment of cardiac hypertrophy and heart failure |
| EP1765292B1 (en) | 2004-06-12 | 2017-10-04 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
| DE102004056576A1 (en) * | 2004-11-23 | 2006-05-24 | LABTEC Gesellschaft für technologische Forschung und Entwicklung mbH | Rapid Card |
| WO2008084828A1 (en) * | 2007-01-11 | 2008-07-17 | Kaneka Corporation | Method for producing coenzyme q10 particle |
| KR20080076382A (en) * | 2007-02-15 | 2008-08-20 | (주)아모레퍼시픽 | Controlled-release preparation containing cilostazol and process for the preparation thereof |
| EP2200613B1 (en) | 2007-09-21 | 2018-09-05 | The Johns Hopkins University | Phenazine derivatives and uses thereof |
| US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
| WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
| US11077134B1 (en) * | 2020-11-10 | 2021-08-03 | Mountain Valley Md Inc | Water dissolvable macrocyclic lactone cyclodextrin complexes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4344934A (en) * | 1978-11-20 | 1982-08-17 | American Home Products Corporation | Therapeutic compositions with enhanced bioavailability |
| US4690824A (en) * | 1983-07-07 | 1987-09-01 | Redi-Rowell, Inc. | Solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range |
| US4640322A (en) * | 1985-06-19 | 1987-02-03 | Cozzoli Machine Co. | Method and apparatus for filling a receptacle with a material |
| JPH02180265A (en) * | 1988-12-28 | 1990-07-13 | Nippon Eranko Kk | Charging device into capsule |
| US5046618A (en) * | 1990-11-19 | 1991-09-10 | R. P. Scherer Corporation | Child-resistant blister pack |
| IT1242614B (en) * | 1990-12-07 | 1994-05-16 | Macofar Spa | MACHINE FOR DOSING AND INTRODUCTION OF POLERULENT PRODUCTS IN CONTAINERS. |
| US5343672A (en) * | 1992-12-01 | 1994-09-06 | Scherer Ltd R P | Method for manufacturing freeze dried dosages in a multilaminate blister pack |
| US5811120A (en) * | 1994-03-02 | 1998-09-22 | Eli Lilly And Company | Solid orally administerable raloxifene hydrochloride pharmaceutical formulation |
| US5972383A (en) * | 1994-03-02 | 1999-10-26 | Eli Lilly And Company | Solid orally administerable raloxifene hydrochloride pharmaceutical formulation |
| GB9405304D0 (en) * | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
| GB9421836D0 (en) * | 1994-10-28 | 1994-12-14 | Scherer Corp R P | Process for preparing solid pharmaceutical dosage forms of hydrophobic substances |
| US5948438A (en) * | 1995-01-09 | 1999-09-07 | Edward Mendell Co., Inc. | Pharmaceutical formulations having improved disintegration and/or absorptivity |
| GB9608719D0 (en) * | 1996-04-26 | 1996-07-03 | Scherer Ltd R P | Pharmaceutical compositions |
| FR2748989B1 (en) * | 1996-05-22 | 1998-08-21 | Henaux Claude | MULTI-POCKET BAGING METHOD AND DEVICE AND BAGS THUS OBTAINED |
| US5993858A (en) * | 1996-06-14 | 1999-11-30 | Port Systems L.L.C. | Method and formulation for increasing the bioavailability of poorly water-soluble drugs |
| US5976574A (en) * | 1996-12-31 | 1999-11-02 | Inhale Therapeutic Systems | Processes for spray drying hydrophobic drugs in organic solvent suspensions |
| EP1014953B1 (en) * | 1997-03-05 | 2012-04-25 | Sugen, Inc. | Formulations for hydrophobic pharmaceutical agents |
| HUP0102753A2 (en) * | 1998-06-10 | 2001-11-28 | Delsys Pharmaceutical Corporation | Pharmaceutical product and methods and apparatus for making same |
| AU2001271875A1 (en) * | 2000-07-06 | 2002-01-21 | Delsys Pharmaceutical Corporation | Improved thyroid hormone formulations |
-
2001
- 2001-08-09 CA CA002417813A patent/CA2417813A1/en not_active Abandoned
- 2001-08-09 AU AU2001284772A patent/AU2001284772A1/en not_active Abandoned
- 2001-08-09 EP EP01963853A patent/EP1307097A4/en not_active Withdrawn
- 2001-08-09 JP JP2002518910A patent/JP2004505996A/en active Pending
- 2001-08-09 IL IL15426801A patent/IL154268A0/en unknown
- 2001-08-09 KR KR10-2003-7001940A patent/KR20030024849A/en not_active Application Discontinuation
- 2001-08-09 HU HU0301668A patent/HUP0301668A2/en unknown
- 2001-08-09 CN CNA018171605A patent/CN1469707A/en active Pending
- 2001-08-09 US US09/925,348 patent/US20020036154A1/en not_active Abandoned
- 2001-08-09 WO PCT/US2001/024949 patent/WO2002013762A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1307097A2 (en) | 2003-05-07 |
| IL154268A0 (en) | 2003-09-17 |
| HUP0301668A2 (en) | 2003-09-29 |
| WO2002013762A2 (en) | 2002-02-21 |
| WO2002013762A3 (en) | 2002-05-16 |
| JP2004505996A (en) | 2004-02-26 |
| EP1307097A4 (en) | 2004-01-28 |
| CA2417813A1 (en) | 2002-02-21 |
| US20020036154A1 (en) | 2002-03-28 |
| AU2001284772A1 (en) | 2002-02-25 |
| KR20030024849A (en) | 2003-03-26 |
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