MXPA97001465A - Formulation of acetaminofeno, liberacion sosten - Google Patents
Formulation of acetaminofeno, liberacion sostenInfo
- Publication number
- MXPA97001465A MXPA97001465A MXPA/A/1997/001465A MX9701465A MXPA97001465A MX PA97001465 A MXPA97001465 A MX PA97001465A MX 9701465 A MX9701465 A MX 9701465A MX PA97001465 A MXPA97001465 A MX PA97001465A
- Authority
- MX
- Mexico
- Prior art keywords
- dosage form
- particles
- form according
- ester copolymer
- methacrylate ester
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 42
- 238000009472 formulation Methods 0.000 title description 8
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 70
- 229960005489 paracetamol Drugs 0.000 claims abstract description 70
- 229940022659 Acetaminophen Drugs 0.000 claims abstract description 69
- 239000002245 particle Substances 0.000 claims abstract description 60
- 230000002459 sustained Effects 0.000 claims abstract description 56
- 239000002552 dosage form Substances 0.000 claims abstract description 49
- 229920001577 copolymer Polymers 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 15
- 239000000463 material Substances 0.000 claims abstract description 15
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- 239000011248 coating agent Substances 0.000 claims description 32
- 238000000576 coating method Methods 0.000 claims description 32
- 239000004615 ingredient Substances 0.000 claims description 7
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 6
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 5
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- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
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- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
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- RXPRRQLKFXBCSJ-GIVPXCGWSA-N Vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 2
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- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
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- 229920002401 polyacrylamide Polymers 0.000 description 1
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- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000197 polyisopropyl acrylate Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000182 polyphenyl methacrylate Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
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- 239000004814 polyurethane Substances 0.000 description 1
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- 239000011118 polyvinyl acetate Substances 0.000 description 1
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- 239000004800 polyvinyl chloride Substances 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
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- ZMRUPTIKESYGQW-UHFFFAOYSA-N propranolol hydrochloride Chemical compound [H+].[Cl-].C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 ZMRUPTIKESYGQW-UHFFFAOYSA-N 0.000 description 1
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- XHKUDCCTVQUHJQ-LCYSNFERSA-N quinidine D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 XHKUDCCTVQUHJQ-LCYSNFERSA-N 0.000 description 1
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- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
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- 238000009492 tablet coating Methods 0.000 description 1
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- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
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- 235000010487 tragacanth Nutrition 0.000 description 1
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- 230000003424 uricosuric Effects 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
A orally administrable sustained release dosage form is provided which includes particles of an active pharmaceutical ingredient that is coated with a polymeric material that is insoluble in water, but water permeable and water swellable, so that the form of Sustained release dosage provides controlled release which is independent of certain physiological variable factors such as pH. According to one aspect of the invention, the active ingredient is acetaminophen and the coated acetaminophen particles are combined with uncoated acetaminophen particles to provide a combination of immediate release / sustained release dosage form. According to another aspect of the invention, the active pharmaceutical ingredient is coated with methacrylate ester copolymer, and the coated particles are combined with uncoated particles of an active pharmaceutical ingredient to provide a combination of immediate release / sustained release dosage form, wherein the sustained release component provides a rate of release which is substantially independent of physiological factors such as pH. The final dosage form, orally administrable, can be presented as compressed tablets, capsules or sac
Description
FORMULATION OF ACETMINDPHENE, RELEASE SOgTEMTDA
ANTii? KUENTES DE LA INVBJCIQN
This invention relates to sustained release pharmaceutical formulations and more particularly to sustained release oral acetaminophen formulations - to provide prolonged therapeutic relief. Many medical conditions or disorders are best treated by administering a pharmaceutical substance in a manner that sustains its action for a prolonged period of time. For example, this class of pharmaceutical administration may be useful for treating chronic pain such as that associated with rheumatic or arthritic conditions. Sustained-release dosage forms can also be used beneficially in the administration of antiarrhythmics, antihypertensives and other drugs whose sustained action is important for their efficacy. Many physiological factors influence both the gastrointestinal transit time and the release of a medicament from a controlled release dosage form, and therefore affect the uptake of the drug into the systemic circulation. Therefore, the dosage forms should be designed so that REF: 24160 such variable factors do not compromise the efficacy and safety of the product. Ideally, such sustained release dosage forms should release the reactive pharmaceutical ingredient at a controlled rate so that the amount of active pharmaceutical ingredient which is available in the body to treat the condition is maintained at a relatively constant level for a period of time. of prolonged time. That is, it is desirable that the active pharmaceutical ingredient be released at a reproducible and predictable rate which is substantially independent of physiological factors which can vary considerably between different individuals and even over time for a particular individual. The release of the active pharmaceutical ingredient from a controlled release dosage form is generally controlled by diffusion through a coating, by diffusion of the agent from a monolithic device, or by erosion of the coating by a process which depends on the enzymes or of pH. Because such factors may vary from one moment to another for a particular individual, and may also vary from one individual to another, pharmaceutical sustained release formulations dependent on enzyme or pH do not provide a reproducible release rate of the active pharmaceutical ingredient. and therefore do not minimize intrasubject and intersubject pairing in the bioavailability of the active ingredient. Certain medical disorders are treated more desirably with a dosage form which provides a therapeutic effect - both immediate and extended while reducing the amount of doses needed, thereby making the therapy more convenient. Known examples of pharmaceutical formulations which provide both immediate and sustained release of an active pharmaceutical ingredient are described in U.S. Patent No. 4,574,080 to Roswall et al and U.S. Patent No. 4,971,805 to Kitanishi et al. Each of these patents describes a pharmaceutical formulation consisting of a rapid release component and a slow release component, wherein the release of the active pharmaceutical ingredient from the slow release component is based on a pH dependent diffusion control mechanism. for example an enteric coating. Such formulations have the disadvantage of releasing the active ingredient at a variable rate depending on the pH of the gastrointestinal fluids with which they make contact, which may vary from one subject to another and may vary in a particular subject.
The North American patent number 4, 666,703 to Kopf discloses a fast disintegrating pharmaceutical tablet containing an active substance in a granular delayed release form comprising the pharmaceutically active substance in granular form which is coated with a polyacrylate mixture, for example an aqueous dispersion of a copolymer of ethyl acrylate-methyl methacrylate, and ethylcellulose, which is subsequently compressed into tablets. However, Kopf does not provide both immediate and sustained release of the active pharmaceutical ingredient. Roswall et al. (U.S. Patent No. 4,574,080) discloses an orally administrable, controlled release multi-unit formulation in which the individual units comprise coated cores containing an active substance which is subject to controlled release as a result of the coating of the cores with a controlled release coating insoluble in water but diffusible in water. The units include instant release particles of an active substance adhered to the surface of a controlled release coating, the particles at least being a power of 10 smaller than the coated core.
U.S. Patent No. 5,055,306 for
Barry et al. , describe a pharmaceutical tablet constituted of granules having a core including an active substance and a encapsulating coating comprising 100 parts by weight of water-swellable acrylic polymer and 20 to 70 parts of hydroxylated cellulose derivative soluble in water. The combination of swellable acrylic polymer with water and a water soluble hydroxylated cellulose derivative provides a coating having release characteristics which are pH dependent, ie, an enteric coating. A two-layer acetaminophen tablet is available in which one layer is constituted by acetaminophen fast release, uncoated particles, and the other layer consists of sustained release acetaminophen. Two compression steps are required to make the tablet and the sustained release coating depends on the pH.
BRIEF DESCRIPTION OF THE INVENTION
The present invention comprises a mixture of polymerically coated sustained release acetaminophen particles and uncoated acetaminophen fast release particles which are pressed together into a tablet. Preferably, the coating is permeable to water, but is not soluble or pH dependent. In another aspect of the invention, other pharmaceutical agents can be substituted in place of acetaminophen in the above mixture, using the water-permeable, water-insoluble coating independent of pH. Finally, the invention alternatively encompasses acetaminophen in sustained release form per se, coated with a water-permeable, water-insoluble coating, independent of pH.
According to a first embodiment of the invention, a sustained release acetaminophen formulation is provided. Acetaminophen is preferably provided in finely divided form for example in small particles or granules. Preferably, the acetaminophen particles have an average particle size between about 180 microns to about 425 microns. The acetaminophen particles may contain excipients, adjuvants or other active ingredients in minor amounts, if desired, but more preferably they consist of at least 80, 90 or 95% acetaminophen.
According to the first aspect of the invention, the sustained release acetaminophen formulations are provided with sustained release coating formulations comprising a water-insoluble, water-permeable coating and a slightly water-swellable polymer. The polymeric coating is not soluble in gastrointestinal fluids and is not sensitive to the pH thereof. The term "pH independent" as used herein means that the water permeability of the coating, and therefore its ability to release pharmaceutical ingredients, is not a function of pH or is only pH dependent in a very light manner. Accordingly, the sustained release acetaminophen formulations of the present invention are capable of delivering acetaminophen to the gastrointestinal tract at a controlled rate which is independent of physiological factors such as pH, which may vary from subject to subject, and may vary from one moment to another in a particular subject. Preferably, the polymeric coating comprises a copolymer of ester methacrylate having the general formula:
wherein R is an alkyl or aminoalkyl group having 1 to about 12 carbon atoms, and wherein n1? n2 and n3 are selected so that the polymer has a molecular weight of from about 100,000 to about 1,000,000. The ratio nx, n2 is from about 1: 2 to about 2: 1, and the ratio of + n2) is from about 0 to about 1:15. Particularly preferred are the copolymers of ethyl acrylate and methyl methacrylate, although terpolymers and other polymers comprising three or more different monomer units having similar properties to the copolymers of ethyl acrylate-methylene acrylate are also preferred. The preferred methacrylate-ethyl acrylate copolymer has a molecular weight of about 800,000. A particularly preferred methyl methacrylate-acrylate copolymer is Eudragrit1® NE30D, which is commercially available from Rómh Pharma.
The polymeric film coating can be applied to the acetaminophen particles in any suitable manner. Preferably, the polymeric film is applied as a uniform coating having a smooth surface structure and a relatively constant thickness. A particularly preferred method for applying the polymer coating to the acetaminophen particles is by the use of pneumatic spray guns. Pneumatic spray guns preferably have a nozzle diameter of about 0.8 mm to about 2 mm and are operated at an air pressure from about 0.5 to about 3 bar. The spray speed of the spray guns can be easily regulated by the use of persitálticas pumps or pressure vessels. Ideally, the spray should be continuous with simultaneous drying, so that the particles do not become too wet (or even get wet). The newly spread polymeric film should be dried as quickly as possible to avoid particle agglomeration. The fluidized bed process is particularly suitable for coating small particles. For example, fluidized bed systems such as Aeromatic, Glatt with Wurster HS Column, operate in closed cylindrical devices in which a stream of air is introduced through the bottom to fluidize acetaminophen particles and dry the films during spraying or spraying. aspersion. In addition to the fluidized bed process, modified coating drums (usually horizontally rotating cylindrical units with a perforated wall) are also suitable for coating small particles. Acetaminophen particles that have a controlled release to polymeric coating can be further manufactured in various types of oral dosage forms. For example, acetaminophen particles coated for release can be compressed, either alone or in combination with containers, adjuvants and / or other active ingredients, in pills, tablets or the like. As another example, release coated particles can be filled into capsules such as soft gelatin capsules or hard gelatin capsules. As another example, the release coated particles can be packaged in a bag with other active or inactive ingredients. They can be dispersed in water to form a suspension. The coating composition may include minor amounts of emulsifiers, wetting agents and stabilizers such as isononylphenyl-polyoxyethylene glycol ethers. Minor amounts of talc may be incorporated into the coating composition or subsequently applied to improve or increase the flow properties of the coated particles. Suitable coating thicknesses can vary from about 2 microns to about 15 microns, based on the desired diffusion properties. The weight of the coating is generally between 2 and 15% by weight of the acetaminophen particles. According to another embodiment of the invention, release coated acetaminophen particles can be combined with uncoated acetaminophen particles to provide an orally administrable pharmaceutical formulation having both immediate release and sustained release components. The acetaminophen particles not generally coated have substantially the same characteristics as the coated release particles before coating. Like the coated release particles, the uncoated particles may contain minor amounts of excipients, adjuvants and / or active ingredients. In the broader aspects of the invention, a wide variety of different release coatings including soluble, insoluble coatings, permeable, impermeable or biodegradable, can be replaced by water-insoluble, water-permeable and water-swellable polymer coatings, as previously established. The polymer coating may be comprised of one or more polymers including copolymers, terpolymers and other polymers having three or more different monomer units. The polymers may include natural or synthetic polymers. Natural polymers which can be used in the sustained release coating include polypeptides, polysaccharides and alginic acid. Representative synthetic polymers include aqueous cellulose, hydroxy acyl cellulose, cellulose ether, cellulose esters, nitrocellulose, polymers of acrylic and methacrylic acids and esters thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene glycol, polyalkylene oxides, polyalkylene terephthalates, alcohols polyvinyl ethers, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinyl pyrrolidone, polyglycolides, polysiloxanes and polyurethanes and copolymers thereof. Particular examples of polymers suitable for use in the sustained release coating of the combined release immediate release / sustained release acetaminophen formulations include: methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate (weight low, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polybutyl methacrylate, polyisobutylmethacrylate, polyexomethacrylate, polyisodecyl methacrylate, poly (lauryl methacrylate), poly (phenyl methacrylate), polymethacrylate, polyisopropylacrylate, polyisobutalacrylate, polyoctadecyl acrylate, polyethylene (low or high density), polypropylene, polyethylene glycol, polyethylene oxide, tereft polyethylene wing, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate, polyvinyl chloride and polyvinyl pyrrolidone. Examples of suitable copolymers include: high molecular weight butyl methacrylate / isobutyl methacrylate copolymer, methylvinyl ether / maleic acid copolymer, methylvinyl ether / maleic acid, monoethyl ester copolymer, such as methyl vinyl ether / maleic acid copolymer and anhydride and vinyl alcohol / vinyl acetate copolymer. Examples of biodegradable polymers include: polylactides, polyglycolides, teratctic polyethylene and polyurethanin. Examples of acrylate and methacrylate are polyacrylic and methacrylic polymer such as those sold under the trademark Eudragit "1 *.
The combination of an immediate release / sustained release acetaminophen formulation can be constituted of substantially any amount of acetaminophen in the immediate release form which is effective and non-toxic, and any amount of acetaminophen in a sustained release form which is therapeutically effective and non-toxic compared to the sustained release period when used in combination with the selected amount of immediate-release acetaminophen. Specific examples include approximately 162.5 milligrams of acetaminophen in sustained release form, in combination with approximately 487.5 milligrams of acetaminophen in immediate release form. Another specific example comprises about 325 milligrams of acetaminophen in immediate release form and about 325 milligrams of acetaminophen in sustained release form. The uncoated and coated acetaminophen particles can be combined in various oral pharmaceutical dosage forms or in formulations such as capsules, tablets, pouches or the like. Acetaminophen particles coated with sustained release and uncoated acetaminophen particles can be combined with various excipients, adjuvants and / or other active ingredients.
Another embodiment of the invention includes particles of a pharmaceutically active ingredient which are coated with a water-insoluble, water-permeable, and slightly water-swellable polymer coating which provides controlled sustained-release diffusion of the active ingredient at a highly reproducible and predictable rate which is independent of the inter-subject and intra-subject physiological variations such as pH, combined with a pharmaceutically uncoated active ingredient which may be the same as or different from the sustained release coated pharmaceutically active ingredient. The resulting immediate release / sustained release formulation provides greater reproducibility of drug release rates compared to other sustained release dosage forms using conventional enteric sustained release coating compositions, and at the same time provides immediate release and sustained of medications. Examples of such other active ingredients include antacids, anti-inflammatory substances, coronary dilators, brain dilators, peripheral vasodilators, anti-infective psychotropics, antimaniacs, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, anti-diarrhea preparations, anti-angina drugs, vasodilators, antiarrhythmics and antihypertensive drugs, vasoconstrictors and to treat migraine, anticoagulants and antithrombotic, analgesic, antipyretic, hypnotic, sedative, antihemiatic, anti-nausea, anticonvulsant, neuromuscular drugs, hyperglycemic and hypoglycemic agents, thyroid and antithyroid preparations , diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic medications, erythropoietic drugs, antiasthmatics, bronchodilators, expectorants, cough suppressants, mucolytics and anti-thermal drugs. Typical active ingredients include gastrointestinal sedatives such as metoclopramide and propantheline bromide; antacids such as aluminum trisilcate, aluminum hydroxide and cimetidine; anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, fluriprofen, diclofenac, dexamethasone, prednisone and prednisolone; coronary vasodilator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate; peripheral and cerebral vasodilators such as solocidilium, vincamine, naftidrofuryl oxalate, co-dergocrine mesylate, cycladelate, papaverine and nicotinic acid; anti-infective substances such as erythromycin stearate, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, flucloxacillin sodium, hexamine mandelate and hexamine hippurate; neuroeleptic measurements such as flurazepam, diazepam, temazepam, amitriptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluoperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and desmethylimipramine; central nervous system stimulants such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate and amphetamine hydrochloride; antihistamine drugs such as diphenylhydramine, diphenylpyraline, chlorpheniramine and brompheniramine; laxative medications such as bisacodyl and magnesium hydroxide; dioctylsodium sulfosuccinate; nutritional supplements such as ascorbic acid, alpha tocopherol, thiamin and pyridoxine; antispasmodic drugs such as dicyclomine and diphenoxylate; medicines that affect heart rhythm such as verapamil, nifedipinia, diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate, and quinidine gluconate; medications used in the treatment of hypertension such as propranolol hydrochloride, guanethyntin monosulfate, methyldopa, oxprenolol hydrochloride, captopril and hydralazine; medications used in the treatment of migraine such as ergotamine; drugs that affect the ability of blood to clot such as epsilon aminocaproic acid and protamine sulfate, - analgesic drugs such as acetylsalicylic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxicodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazacin, pethidine, buprenorphine and mefenamic acid; antiepileptic drugs such as sodium phenytoin and sodium valproate; neuromuscular medications such as dantrolene sodium; substances used in the treatment of diabetes such as tolbutamide, disbenase glucagon and insulin; medicines used in the treatment of dysfunction of the thyroid gland such as triiodothyronine, thyroxine and propylthiouracil, diuretic drugs such as furosemide, chlortralidone, hydroclortiazide, spironolactone and triamterene; uterine relaxing medications such as ritodrine; appetite suppressants such as fenfluramine hydrochloride, phentermine and diethylpropion hydrochloride; antiasthmatic and bronchodilator drugs such as aminophylline, theophylline, salbutamol, orciprenaline sulfate and terbutaline sulfate; preserving medications such as guaifenesin; cough suppressants such as dextromethorphan and noscapine; mucolytic drugs such as carbocysteine; antiseptics such as cetylpyridinium chloride, thyrothricin and chlorhexidine; decongestant medications such as phenylpropanolamine and pseudoephedrine, hypnotic drugs such as dicloralphenazone and nitrazepam; anti-nausea medications such as promethazine teoclate; hemopoietic drugs such as ferrous sulfate, folic acid and calcium gluconate; uricosuric drugs such as sulfilpyrazone, alopulinol and probenecid. Although any of the foregoing embodiments of the invention can be formulated generally in any of a variety of different types of orally administrable pharmaceutical dosage forms such as capsules, the pharmaceutical compositions of the invention are most preferably pressed into tablets, pills. or similar. Preferably, the tablets have a hardness of from about 11 to about 19 SCU, and more preferably a hardness of about 15 SCU. Preferably, the tablets have a friability of less than about 0.8% in weight loss after 6 minutes. Suitable excipients and adjuvants which can be used in the preparation of the sustained release therapeutic compositions of the present invention generally include those conventionally used in the pharmaceutical industry. Examples include fillers and diluents such as lactose, sucrose, dextrose, mannitol, calcium sulfate, dicalcium sulfate, tricalcium sulfate, starches such as rice starch and microcrystalline cellulose. Useful binders include acacia, tragacanth, gelatin, sucrose, pregelatinized starch, starch, sodium alginate, calcium and ammonium alginate, methylcellulose, sodium carboxymethylcellulose, ethel cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, aluminum mechanism ciliate and polyacrylamide. Examples of disintegrants include cross-linked polyvinylpyrrolidone, starch derivatives such as carboxymethylcellulose and cellulose derivatives. Lubricants, lubricating agents and anti-adhesives including metallic stearates such as magnesium stearate, talcum, waxes with high melting point and color-silicate. For the various functions of acetaminophen described herein, the preferred combination of disintegrants / binders includes cross-linked polyvinylpyrrolidone such as Polyplasdone XL * available from GAF or croscarmellose sodium such as Ac-Di-Sol "* available from FMC Corporation. binders which are preferably used in combination with cross-linked polyvinylpyrrolidone or with croscarmellose sodium are microcrystalline cellulose The preferred disintegrants / binders can be used in effective amounts which can be determined easily using known techniques. Typical are tabletted directly using a conventional tabletting machine, for example, Manesty Rotary Press, a Stokes Rotary Press, etc., at a temperature of about 15 ° C to about 30 ° C and a pressure of about 0.4 to about 3.0 tons The tab Lets are desirably provided with a coating which helps prevent the formation of powder from the tablets during handling and in the bottle, which improves the appearance and ability to swallow the tablets. A preferred tablet coating is established in the examples. Preferably coated tablets are also provided with a carnauba wax jacket which provides the tablets with an added lustrous appearance. The following examples illustrate the preferred combination of immediate release / sustained release acetaminophen formulations according to the invention.
EXAMPLE 1
In Table 1 a combined preferred formulation of immediate release / sustained release acetaminophen containing 650 milligrams of acetaminophen is established. The tablets are prepared according to the formulations. which are set forth in Table 1 by mixing microcrystalline cellulose with a acetaminophen coated for sustained release containing acetaminophen, ethers of isononylphenyl polyoxyethylene glycol, methacrylate ester copolymer and talc in a weight ratio of 20,790; 0.023; 1.531; 1,167. A suitable mixing time for acetaminophen particles of sustained release coating and microcrystalline cellulose is about 1 minute. The mixture of coated acetaminophen and microcrystalline cellulose is preferably combined with the crosslinked polyvinylpyrrolidone and uncoated acetaminophen. Uncoated acetaminophen (Compap WSE 95%) is mainly acetaminophen and contains minor amounts of maltodextrin (a filler) and polyvinylpyrrolidone (povidone). A suitable mixing time for the acetaminophen coated with premixed sustained release and the acetaminophen not coated with microcrystalline cellulose and crosslinked polyvinylpyrrolidone is about 10 minutes. Subsequently, magnesium stearate is mixed with the above ingredients. A suitable mixing time for the magnesium stearate with the above ingredients is from about 3 minutes. The above mixture is compressed into tablets in the form of capsules (caplets) having a weight of about 0.77 grams, a thickness of about 6.6 mm (0.26 inches) plus or minus 0.13 mm (0.005 inches), a hardness of about 11 to 19. SCU (preferably about 15 SCU), a friability of no more than 0.8% by weight loss after 6 minutes and a single tablet weight variation of 0.732 to 0.809 grams. The tablets can be coated or coated by placing them in a 60 cm "accela-cota container and sprayed with a coating such as Opadry W-YS-1-7003.
EXAMPLE 2
Another preferred formulation of immediate release / sustained release acetaminophen contains 325 milligrams of acetaminophen in immediate release form and 325 milligrams of acetaminophen in sustained release form per tablet, as set forth in Table 2. The tablet is prepared in accordance with formulations set out in Table 2 and can be prepared in any manner substantially identical to the manner in which the tablets of Example 1 are prepared.
TABLE 1
^ ft T? IBKR? T) ftMPMA OF A AP 650 mg
MATERIAL INGREDIENT INDICATED% OF UNDETERMINED IN THE ETI-PÓRM0IA QUETA
7578R APA-SR ACETAMINOFENO, USP 162.50 mg 20,790
3520 COMPAP WSE 95% ACETAMINOFEN, USP 487.50 mg 62.370 3075 CARNAUBE WAX CARNAUBA WAX, NF 0.010 8897 CROSPOVIDONE XL CROSPOVIDONE XL 1.970
8796 OPADRY W-YS-1-7003 HIDROXIPROPILMETILCELLULOSA 0.883 7578R APAP-SR ISONOYLPHENILPOLIOXETILEN GLYCOL ETHERIES 0.023
3241 ESTEARATE MG MAGNESIUM ESTEARATE, NF 0.499 3520 COMPAP WSE 95% MALTODEXTRINE < 3,305 7578R APA-SR METACRYLIC ACID COPOLYMERS 1,531 8871 CELLULOSE MICROCRYSTALLINE CELLULOSE MICROCRYSTALLINE 6,856 8796 OPADRY W-YS-1-7003 POLYETHYLENE GLYCOL 400 0.118 8796 OPADRY W-YS-1-7003 POLYSORBATE 80, NF 0.115 3520 COMPAP WSE 95% POVIDONE, USP < 3,305 7578R APAP-SR TALCO # 127 1,167 8796 OPADRY W-YS-1-7003 TITANIUM DIOXIDE, USP 0-462 TOTAL 100,000
TABLE 2
TENTATIVE DESCRIPTION OF 544XB RELIEF _6_5J mg
MATERIAL INGREDIENT INDICATED% OF UNDETERMINED IN THE QUIT ETIFORMULA
7578R APA-SR ACETAMINOFENO, USP 325.00 MG 41,580 3520 COMPAP WSE 95% ACETAMINOFENO, USP 325.00 MG 41,580
3075 WAX OF CARNAUBA WAX OF CARNAUBA, NF 0.010
8897 CROSPOVIDONE XL CROSPOVIDONE XL 1.970
8796 OPADRY W-YS-1-7003 HIDROXIPROPILMETILCELLULOSA 0.883 7578R APAP-SR IS0N0ILFENIL- POLIOXETILENGLICOL 0.050 ETHERIES
3241 ESTEARATE MG ESTEARATE OF MAGNESIUM, NF 0.493
3520 COMPAP WSE 95% MALTODEXTRINE < 2.188 7578R APA-SR METACRYLIC ACID COPOLYMERS 3,291 8871 MICROCRYSTALLINE CELLULOSE MICROCRYSTALLINE CELLULOSE. 4.855
8796 OPADRY W-YS-1-7003 POLYETHYLENE GLYCOL 400 0.118
8796 OPADRY W-YS- 1-7003 POLYSORBATE 80, NF 0.115 3520 COMPAP WSE 95% POVIDONE, USP < 2.188
7578R APAP-SR TALCO # 127 2.506
8796 OPADRY W-YS-1-7003 TITANIUM DIOXIDE, USP 0.462 TOTAL 100,000
It will become apparent to a person skilled in the art that various modifications may be made to the preferred embodiment of the invention described herein without departing from the spirit or scope of the invention as defined in the appended claims. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as above, property is claimed as contained in the following:
Claims (32)
1. An orally administrable sustained release dosage form characterized in that it comprises acetaminophen particles coated with a polymeric material which is insoluble in water, the polymeric material is permeable to water.
2. The dosage form according to claim 1, characterized in that the polymeric material comprises methacrylate ester copolymer.
3. The dosage form according to claim 2, characterized in that the methacrylate ester copolymer has the general formula: wherein R is an alkyl or aminoalkyl group having from 1 to about 12 carbon atoms, and wherein nl t n2 and n3 are selected such that the methacrylate ester copolymer has a molecular weight of from about 100,000 to about 1,000,000.
4. The dosage form according to claim 3, characterized in that the ratio of 'n1, n2 is from about 1: 2 to about 2: 1, and the ratio of n3: (nx + n2) is approximately 1:15 or lower. *
5. The dosage form according to claim 4, characterized in that the methacrylate ester copolymer consists substantially of methyl methacrylate and ethyl acrylate.
6. The dosage form according to claim 5, characterized in that the methacrylate ester copolymer has a molecular weight of about 800,000.
7. The dosage form according to claim 2, characterized in that the acetaminophen particles have an average size from about 180 microns to about 425 microns.
8. The dosage form according to claim 7, characterized in that it is a compressed tablet.
9. An orally administrable sustained release dosage form characterized in that it comprises a mixture of uncoated acetaminophen particles and acetaminophen particles coated with a polymeric material which is insoluble in water, the polymeric material is permeable to water.
10. The dosage form according to claim 9, characterized in that the polymeric material comprises methacrylate ester copolymer.
11. The dosage form according to claim 10, characterized in that the methacrylate ester copolymer has the general formula: n3 wherein R is an alkyl or aminoalkyl group having from 1 to about 12 carbon atoms, and wherein nlf n2 and n3 are selected such that the methacrylate ester copolymer has a molecular weight of from about 100,000 to about 1,000,000.
12. The dosage form according to claim 11 ,. characterized in that the ratio of n1, n2 is from about 1: 2 to about 2: 1, and the ratio of n3: (nx + n2) is about 1:15 or lower.
13. The dosage form according to claim 12, characterized in that the methacrylate ester copolymer consists substantially of methyl methacrylate and ethyl acrylate.
14. The dosage form according to claim 13, characterized in that the methacrylate ester copolymer has a molecular weight of about 800,000.
15. The dosage form according to claim 14, characterized in that the acetaminophen particles have an average size from about 180 microns to about 425 microns.
16. The dosage form according to claim 15, characterized in that the uncoated particles and the coated particles, before being coated, have an average size from about 180 micrometers up to approximately 425 micrometers.
17. An orally administrable combination of an immediate release / sustained release form, characterized in that it comprises uncoated acetaminophen particles and acetaminophen particles provided with a polymeric coating for sustained release.
18. A combination, orally administrable, of an immediate release / sustained release dosage form, characterized in that it comprises a mixture of particles not cd with a pharmaceutically active ingredient and particles of an active pharmaceutical ingredient cd with a polymeric material which is insoluble in water , the polymeric material is water permeable and inflatable with water.
19. The dosage form according to claim 18, characterized in that the polymeric material comprises methacrylate ester copolymer.
20. The dosage form according to claim 19, characterized in that the methacrylate ester copolymer has the general formula: wherein R is an alkyl or aminoalkyl group having from about 1 to about 12 carbon atoms, and wherein nx, n2 and n3 are selected such that the methacrylate ester copolymer has a molecular weight of from about 100,000. up to approximately 1,000,000.
21. The dosage form according to claim 20, characterized in that the ratio of nlf n2 is from about 1: 2 to about 2: 1, and the ratio of n3: (nx + n2) is approximately 1:15 or less.
22. The dosage form according to claim 21, characterized in that the methacrylate ester copolymer consists substantially of methyl methacrylate and ethyl acrylate.
23. The dosage form according to claim 22, characterized in that the methacrylate ester copolymer has a molecular weight of about 800,000.
24. The dosage form according to claim 23, characterized in that the acetaminophen particles have an average size from about 180 microns to about 425 microns.
25. An orally administrable combination of an immediate release / sustained release dosage form characterized in that it comprises a mixture of uncd particles of an active pharmaceutical ingredient and particles of the same ingredient which are cd with a polymeric material which is insoluble to water and permeable the water.
26. The dosage form according to claim 25, characterized in that the polymeric material comprises methacrylate ester copolymer.
27. The dosage form according to claim 26, characterized in that the methacrylate ester copolymer has the general formula: wherein R is an alkyl or aminoalkyl group having from 1 to about 12 carbon atoms, and wherein n1, n2 and n3 are selected such that the methacrylate ester copolymer has a molecular weight of from about 100,000 to about 1,000,000.
28. The dosage form according to claim 26, characterized in that the ratio of n1 (n2 is from about 1: 2 to about 2: 1, and the ratio of n3: (nx + n2) is about 1:15 or less .
29. The dosage form according to claim 28, characterized in that the methacrylate ester copolymer consists substantially of methyl methacrylate and ethyl acrylate.
30. The dosage form according to claim 29, characterized in that the methacrylate ester copolymer has a molecular weight of about 800,000.
31. The dosage form according to claim 30, characterized in that the acetaminophen particles have an average size from about 180 microns to about 425 microns.
32. The dosage form according to claim 31, characterized in that the uncd particles and the cd particles, before being cd, have an average size from about 180 microns to about 425 microns. SUMMARY OF THE INVENTION A orally administrable sustained release dosage form is provided which includes particles of an active pharmaceutical ingredient which is coated with a polymeric material which is insoluble in water, but water permeable and water swellable, so that the Sustained-release dosage form provides controlled release which is independent of certain physiological variables such as pH. According to one aspect of the invention, the active pharmaceutical ingredient is acetaminophen and the coated acetaminophen particles are combined with uncoated acetaminophen particles to provide a combination of immediate release / sustained release dosage form. According to another aspect of the invention, the active pharmaceutical ingredient is coated with methacrylate ester copolymer, and the coated particles are combined with uncoated particles of an active pharmaceutical ingredient to provide a combination of immediate release dosage form / release sustained, in which the sustained release component provides a rate of release which is substantially independent of physiological factors such as pH. The final dosage form, which can be administered orally, can be presented as compressed tablets, capsules or sacks.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/608,839 US5773031A (en) | 1996-02-27 | 1996-02-27 | Acetaminophen sustained-release formulation |
US08608839 | 1996-02-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
MXPA97001465A true MXPA97001465A (en) | 1998-04-01 |
MX9701465A MX9701465A (en) | 1998-04-30 |
Family
ID=24438247
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX9701465A MX9701465A (en) | 1996-02-27 | 1997-02-26 | Acetaminophen sustained-release formulation. |
Country Status (5)
Country | Link |
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US (2) | US5773031A (en) |
JP (1) | JPH1029936A (en) |
CA (1) | CA2198630C (en) |
GB (1) | GB2310601B (en) |
MX (1) | MX9701465A (en) |
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- 1997-02-26 CA CA002198630A patent/CA2198630C/en not_active Expired - Lifetime
- 1997-02-26 MX MX9701465A patent/MX9701465A/en not_active IP Right Cessation
- 1997-02-27 GB GB9704069A patent/GB2310601B/en not_active Expired - Lifetime
- 1997-10-31 US US08/962,599 patent/US6126969A/en not_active Expired - Lifetime
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