US20030129234A1 - Methods of making sustained release formulations of oxymorphone - Google Patents
Methods of making sustained release formulations of oxymorphone Download PDFInfo
- Publication number
- US20030129234A1 US20030129234A1 US10/190,383 US19038302A US2003129234A1 US 20030129234 A1 US20030129234 A1 US 20030129234A1 US 19038302 A US19038302 A US 19038302A US 2003129234 A1 US2003129234 A1 US 2003129234A1
- Authority
- US
- United States
- Prior art keywords
- sustained release
- delivery system
- oxymorphone
- weight
- release delivery
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000013268 sustained release Methods 0.000 title claims abstract description 177
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 177
- 229960005118 oxymorphone Drugs 0.000 title claims abstract description 171
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 title claims abstract description 167
- 239000000203 mixture Substances 0.000 title claims abstract description 120
- 238000000034 method Methods 0.000 title claims abstract description 96
- 238000009472 formulation Methods 0.000 title claims abstract description 70
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- 239000003431 cross linking reagent Substances 0.000 claims description 32
- 125000002091 cationic group Chemical group 0.000 claims description 31
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- 238000004132 cross linking Methods 0.000 claims description 28
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- -1 alkali metal borate Chemical class 0.000 claims description 22
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- BCGJBQBWUGVESK-KCTCKCTRSA-N Oxymorphone hydrochloride Chemical compound Cl.O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BCGJBQBWUGVESK-KCTCKCTRSA-N 0.000 claims description 18
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the invention provides sustained release formulations of oxymorphone and pharmaceutically acceptable salts thereof; methods for making the sustained release formulations of oxymorphone and pharmaceutically acceptable salts thereof; and methods for using the sustained release formulations of oxymorphone and pharmaceutically acceptable salts thereof to treat patients suffering from pain.
- Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride) is a semi-synthetic phenanthrene-derivative opioid agonist, used in the treatment of acute and chronic pain, with analgesic efficacy comparable to other opioid analgesics.
- Oxymorphone is currently marketed as an injection (1 mg/ml in 1 ml ampules; 1.5 mg/ml in 1 ml ampules; 1.5 mg/ml in 10 ml multiple dose vials) for intramuscular, subcutaneous, and intravenous administration, and as 5 mg rectal suppositories.
- a 10 mg oral immediate release tablet formation of oxymorphone HCl was marketed.
- Oxymorphone HCl is metabolized principally in the liver and undergoes conjugation with glucuronic acid and reduction to 6 alpha and beta hydroxy epimers.
- An important goal of analgesic therapy is to achieve continuous relief of chronic pain.
- Regular administration of an analgesic is generally required to ensure that the next dose is given before the effects of the previous dose have worn off.
- Compliance with opioids increases as the required dosing frequency decreases.
- Non-compliance results in suboptimal pain control and poor quality of life outcomes.
- Scheduled rather than “as needed” administration of opioids is currently recommended in guidelines for their use in treating chronic non-malignant pain.
- evidence from prior clinical trials and clinical experience suggests that the short duration of action of immediate release oxymorphone would necessitate 4-hourly administrations in order to maintain optimal levels of analgesia in patients with chronic pain.
- immediate release oxymorphone exhibits low oral bioavailability, because oxymorphone is extensively metabolized in the liver.
- the invention provides compositions comprising oxymorphone or a pharmaceutically acceptable salt thereof and a sustained release delivery system, where the sustained release delivery system comprises at least one hydrophilic compound, at least one cross-linking agent (which may be cationic) and at least one pharmaceutical diluent.
- the sustained release delivery system may further comprise one or more additional hydrophobic polymers or cross-linking compounds.
- the compositions may optionally comprise an outer coating comprising at least one water insoluble compound, and optionally one or more plasticizers and/or water soluble compounds.
- compositions comprising an inner core and an outer sustained release coating, where the inner core comprises oxymorphone or a pharmaceutically acceptable salt thereof and the outer sustained release coating comprises at least one water insoluble compound.
- the outer sustained release coating may optionally further comprise one or more plasticizers and/or water soluble compounds.
- the invention provides methods for treating pain in patients by administering an effective amount of any of the compositions of the invention.
- the pain may be moderate to severe, and may be acute or chronic.
- the invention also provides methods for making such compositions.
- FIG. 1 is a linear scale graph, without standard deviations, showing the mean oxymorphone plasma concentration versus time for patients treated with the sustained release oxymorphone tablets of the invention after fasting (A), for patients treated with sustained release oxymorphone tablets of the invention after a high fat meal (B), for patients treated with an oxymorphone solution after fasting (C), and for patients treated with an oxymorphone solution after a high fat meal (D).
- the invention provides an oral sustained release formulation of oxymorphone comprising an analgesically effective amount of oxymorphone or a pharmaceutically acceptable salt thereof.
- the bioavailability of the oral sustained release formulations of the invention is sufficiently high that the sustained release formulations can be used to treat patients suffering from pain with only once or twice daily dosing.
- the invention provides compositions comprising oxymorphone or a pharmaceutically acceptable salt thereof and a sustained release delivery system, wherein the sustained release delivery system comprises (i) at least one hydrophilic compound, at least one cross-linking agent, and at least one pharmaceutical diluent; (ii) at least one hydrophilic compound, at least one cross-linking agent, at least one pharmaceutical diluent, and at least one hydrophobic polymer; (iii) at least one hydrophilic compound, at least one cross-linking agent, at least one pharmaceutical diluent, and at least one cationic cross-linking agent different from the first cross-linking agent; (iv) at least one hydrophilic compound, at least one cross-linking agent, at least one pharmaceutical diluent, at least one cationic cross-linking compound different from the first cross-linking agent, and at least one hydrophobic polymer; (v) at least one hydrophilic compound, at least one cationic cross-linking compound, and at least one pharmaceutical
- the oxymorphone may be homogeneously dispersed in the sustained release delivery system.
- the oxymorphone or pharmaceutically acceptable salt thereof may be present in the composition in an amount of about 1 mg to about 200 mg, more preferably in an amount of about 1 mg to about 100 mg, even more preferably in an amount of about 5 mg to about 80 mg.
- the sustained release delivery system may be present in the composition in an amount from about 80 mg to about 420 mg, more preferably from about 80 mg to about 360 mg, even more preferably from about 80 mg to about 200 mg.
- “Oxymorphone” includes oxymorphone, metabolites thereof, derivatives thereof, and/or pharmaceutically acceptable salts thereof. Metabolites of oxymorphone include, for example, 6-hydroxy-oxymorphone (e.g., 6- ⁇ -hydroxy-oxymorphone and/or 6- ⁇ -hydroxy-oxymorphone).
- Oxymorphone may be in the form of any pharmaceutically acceptable salt known in the art.
- exemplary pharmaceutically acceptable salts include hydrochloric, sulfuric, nitric, phosphoric, hydrobromic, maleric, malic, ascorbic, citric, tartaric, pamoic, lauric, stearic, palmitic, oleic, myristic, lauryl sulfuric, napthalinesulfonic, linoleic, linolenic acid, and the like.
- the hydrochloride salt of oxymorphone is preferred.
- the sustained release delivery system comprises at least one hydrophilic compound.
- the hydrophilic compound preferably forms a gel matrix that releases the oxymorphone or the pharmaceutically acceptable salt thereof at a sustained rate upon exposure to liquids.
- the rate of release of the oxymorphone or the pharmaceutically acceptable salt thereof from the gel matrix depends on the drug's partition coefficient between the components of the gel matrix and the aqueous phase within the gastrointestinal tract.
- the weight ratio of oxymorphone to hydrophilic compound is generally in the range of about 1:0.5 to about 1:25, preferably in the range of about 1:0.5 to about 1:20.
- the sustained release delivery system generally comprises the hydrophilic compound in an amount of about 20% to about 80% by weight, preferably in an amount of about 20% to about 60% by weight, more preferably in an amount of about 40% to about 60% by weight, still more preferably in an amount of about 50% by weight.
- the hydrophilic compound may be any known in the art.
- Exemplary hydrophilic compounds include gums, cellulose ethers, acrylic resins, polyvinyl pyrrolidone, protein-derived compounds, and mixtures thereof.
- Exemplary gums include heteropolysaccharide gums and homopolysaccharide gums, such as xanthan, tragacanth, pectins, acacia, karaya, alginates, agar, guar, hydroxypropyl guar, carrageenan, locust bean gums, and gellan gums.
- Exemplary cellulose ethers include hydroxyalkyl celluloses and carboxyalkyl celluloses.
- Preferred cellulose ethers include hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropylmethyl-celluloses, carboxy methylcelluloses, and mixtures thereof.
- Exemplary acrylic resins include polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate.
- the hydrophilic compound is preferably a gum, more preferably a heteropolysaccharide gum, most preferably a xanthan gum or derivative thereof.
- Derivatives of xanthan gum include, for example, deacylated xanthan gum, the carboxymethyl esters of xanthan gum, and the propylene glycol esters of xanthan gum.
- the sustained release delivery system may further comprise at least one cross-linking agent.
- the cross-linking agent is preferably a compound that is capable of cross-linking the hydrophilic compound to form a gel matrix in the presence of liquids.
- liquids includes, for example, gastrointestinal fluids and aqueous solutions, such as those used for in vitro dissolution testing.
- the sustained release delivery system generally comprises the cross-linking agent in an amount of about 0.5% to about 80% by weight, preferably in an amount of about 2% to about 54% by weight, more preferably in an amount of about 20% to about 30% by weight more, still more preferably in an amount of about 25% by weight.
- Exemplary cross-linking agents include homopolysaccharides.
- Exemplary homopolysaccharides include galactomannan gums, such as guar gum, hydroxypropyl guar gum, and locust bean gum.
- the cross-linking agent is preferably a locust bean gum or a guar gum.
- the cross-linking agents may be alginic acid derivatives or hydrocolloids.
- the ratio of hydrophilic compound to cross-linking agent may be from about 1:9 to about 9:1, preferably from about 1:3 to about 3:1.
- the sustained release delivery system of the invention may comprise one or more cationic cross-linking compounds.
- Cationic cross-linking compound may be used instead of or in addition to the cross-linking agent.
- the cationic cross-linking compounds may be used in an amount sufficient to cross-link the hydrophilic compound to form a gel matrix in the presence of liquids.
- the cationic cross-linking compound is present in the sustained release delivery system in an amount of about 0.5% to about 30% by weight, preferably from about 5% to about 20% by weight.
- Exemplary cationic cross-linking compounds include monovalent metal cations, multivalent metal cations, and inorganic salts, including alkali metal and/or alkaline earth metal sulfates, chlorides, borates, bromides, citrates, acetates, lactates, and mixtures thereof.
- the cationic cross-linking compound may be one or more of calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, or mixtures thereof.
- the sustained release delivery system comprises at least one hydrophilic compound and at least one cationic cross-linking compound
- the ratio of hydrophilic compound to cationic cross-linking compound may be from about 1:9 to about 9:1, preferably from about 1:3 to about 3:1.
- Two properties of desirable components of this system e.g., the at least one hydrophilic compound and the at least one cross-linking agent; or the at least one hydrophilic compound and at least one cationic cross-linking compound
- fast hydration of the compounds/agents and the ability to form a gel matrix having a high gel strength.
- These two properties, which are needed to achieve a slow release gel matrix, are maximized in the invention by the particular combination of compounds (e.g., the at least one hydrophilic compound and the at least one cross-linking agent; or the at least one hydrophilic compound and the at least one cationic cross-linking compound).
- hydrophilic compounds e.g., xanthan gum
- hydrophilic compounds have excellent water-wicking properties which provide fast hydration.
- materials that are capable of cross-linking the rigid helical ordered structure of the hydrophilic compound e.g., cross-linking agents and/or cationic cross-linking compounds
- the sustained release delivery system further comprises one or more pharmaceutical diluents known in the art.
- exemplary pharmaceutical diluents include monosaccharides, disaccharides, polyhydric alcohols and mixtures thereof.
- Preferred pharmaceutical diluents include, for example, starch, lactose, dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol, fructose, and mixtures thereof.
- the pharmaceutical diluent is water-soluble, such as lactose, dextrose, sucrose, or mixtures thereof.
- the ratio of pharmaceutical diluent to hydrophilic compound is generally from about 1:8 to about 8:1, preferably from about 1:3 to about 3:1.
- the sustained release delivery system generally comprises one or more pharmaceutical diluents in an amount of about 20% to about 80% by weight, preferably about 35% by weight. In other embodiments, the sustained release delivery system comprises one or more pharmaceutical diluents in an amount of about 40% to about 80% by weight.
- the sustained release delivery system of the invention may comprise one or more hydrophobic polymers.
- the hydrophobic polymers may be used in an amount sufficient to slow the hydration of the hydrophilic compound without disrupting it.
- the hydrophobic polymer may be present in the sustained release delivery system in an amount of about 0.5% to about 20% by weight, preferably in an amount of about 2% to about 10% by weight, more preferably in an amount of about 3% to about 7% by weight, still more preferably in an amount of about 5% by weight.
- Exemplary hydrophobic polymers include alkyl celluloses (e.g., C 1-6 alkyl celluloses, carboxymethylcellulose), other hydrophobic cellulosic materials or compounds (e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers (e.g., polyvinyl acetate phthalate), polymers or copolymers derived from acrylic and/or methacrylic acid esters, zein, waxes, shellac, hydrogenated vegetable oils, and mixtures thereof.
- the hydrophobic polymer is preferably methyl cellulose, ethyl cellulose or propyl cellulose, more preferably ethyl cellulose.
- compositions of the invention may be further admixed with one or more wetting agents (such as polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid from castor oil, polyethoxylated fatty acid from hydrogenated castor oil) one or more lubricants (such as magnesium stearate), one or more buffering agents, one or more colorants, and/or other conventional ingredients.
- wetting agents such as polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid from castor oil, polyethoxylated fatty acid from hydrogenated castor oil
- lubricants such as magnesium stearate
- buffering agents such as magnesium stearate
- the invention provides oral sustained release solid dosage formulations comprising from about 1 mg to 200 mg oxymorphone hydrochloride, preferably from about 5 mg to about 80 mg oxymorphone hydrochloride; and about 80 mg to about 200 mg of a sustained release delivery system, preferably from about 120 mg to about 200 mg of a sustained release delivery system, more preferably about 160 mg of a sustained release delivery system; where the sustained release delivery system comprises about 8.3 to about 41.7% locust bean gum, preferably about 25% locust bean gum; about 8.3 to about 41.7% xanthan gum, preferably about 25% xanthan gum; about 20 to about 55% dextrose, preferably about 35% dextrose; about 5 to about 20% calcium sulfate dihydrate, preferably about 10% calcium sulfate dihydrate; and about 2 to 10% ethyl cellulose, preferably about 5% ethyl cellulose.
- the invention provides oral sustained release solid dosage formulations comprising from about 1 mg to 200 mg oxymorphone hydrochloride, preferably from about 5 mg to about 80 mg oxymorphone hydrochloride; and about 200 mg to about 420 mg of a sustained release delivery system, preferably from about 300 mg to about 420 mg of a sustained release delivery system, more preferably about 360 mg of a sustained release delivery system; where the sustained release delivery system comprises about 8.3 to about 41.7% locust bean gum, preferably about 25% locust bean gum; about 8.3 to about 41.7% xanthan gum, preferably about 25% xanthan gum; about 20 to about 55% dextrose, preferably about 35% dextrose; about 5 to about 20% calcium sulfate dihydrate, preferably about 10% calcium sulfate dihydrate; and about 2 to 10% ethyl cellulose, preferably about 5% ethyl cellulose.
- the sustained release formulations of oxymorphone are preferably orally administrable solid dosage formulations which may be, for example, tablets, capsules comprising a plurality of granules, sublingual tablets, powders, or granules; preferably tablets.
- the tablets may be an enteric coating or a hydrophilic coating.
- the sustained release delivery system in the compositions of the invention may be prepared by dry granulation or wet granulation, before the oxymorphone or pharmaceutically acceptable salt thereof is added, although the components may be held together by an agglomeration technique to produce an acceptable product.
- the components e.g., hydrophilic compounds, cross-linking agents, pharmaceutical diluents, cationic cross-linking compounds, hydrophobic polymers, etc.
- one or more liquids e.g., water, propylene glycol, glycerol, alcohol
- the dried mass is then milled with conventional equipment into granules of the sustained release delivery system.
- the sustained release delivery system is mixed in the desired amounts with the oxymorphone or the pharmaceutically acceptable salt thereof and, optionally, one or more wetting agents, one or more lubricants, one or more buffering agents, one or more coloring agents, or other conventional ingredients, to produce a granulated composition.
- the sustained release delivery system and the oxymorphone may be blended with, for example, a high shear mixer.
- the oxymorphone is preferably finely and homogeneously dispersed in the sustained release delivery system.
- the granulated composition in an amount sufficient to make a uniform batch of tablets, is subjected to tableting in a conventional production scale tableting machine at normal compression pressures, i.e., about 2,000-16,000 psi.
- the mixture should not be compressed to a point where there is subsequent difficulty with hydration upon exposure to liquids.
- the average particle size of the granulated composition is from about 50 ⁇ m to about 400 ⁇ m, preferably from about 185 ⁇ m to about 265 ⁇ m.
- the average density of the granulated composition is from about 0.3 g/ml to about 0.8 ⁇ g/ml, preferably from about 0.5 g/ml to about 0.7 g/ml.
- the tablets formed from the granulations are generally from about 6 to about 8 kg hardness.
- the average flow of the granulations are from about 25 to about 40 g/sec.
- the invention provides sustained release coatings over an inner core comprising oxymorphone or a pharmaceutically acceptable salt thereof.
- the inner core comprising oxymorphone or a pharmaceutically acceptable salt thereof may be coated with a sustained release film which, upon exposure to liquids, releases the oxymorphone or the pharmaceutically acceptable salt thereof from the core at a sustained rate.
- the sustained release coating comprises at least one water insoluble compound.
- the water insoluble compound is preferably a hydrophobic polymer.
- the hydrophobic polymer may be the same as or different from the hydrophobic polymer used in the sustained release delivery system.
- hydrophobic polymers include alkyl celluloses (e.g., C 1-6 alkyl celluloses, carboxymethylcellulose), other hydrophobic cellulosic materials or compounds (e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers (e.g., polyvinyl acetate phthalate), polymers or copolymers derived from acrylic and/or methacrylic acid esters, zein, waxes (alone or in admixture with fatty alcohols), shellac, hydrogenated vegetable oils, and mixtures thereof.
- alkyl celluloses e.g., C 1-6 alkyl celluloses, carboxymethylcellulose
- other hydrophobic cellulosic materials or compounds e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate
- polyvinyl acetate polymers e.g., polyvinyl acetate phthalate
- the hydrophobic polymer is preferably, methyl cellulose, ethyl cellulose or propyl cellulose, more preferably ethyl cellulose.
- the sustained release formulations of the invention may be coated with a water insoluble compound to a weight gain from about 1 to about 20% by weight.
- the sustained release coating may further comprise at least one plasticizer such as triethyl citrate, dibutyl phthalate, propylene glycol, polyethylene glycol, or mixtures thereof.
- plasticizer such as triethyl citrate, dibutyl phthalate, propylene glycol, polyethylene glycol, or mixtures thereof.
- the sustained release coating may also contain at least one water soluble compound, such as polyvinylpyrrolidones, hydroxypropylmethylcelluloses, or mixtures thereof.
- the sustained release coating may comprise at least one water soluble compound in an amount from about 1% to about 6% by weight, preferably in an amount of about 3% by weight.
- the sustained release coating may be applied to the oxymorphone core by spraying an aqueous dispersion of the water insoluble compound onto the oxymorphone core.
- the oxymorphone core may be a granulated composition made, for example, by dry or wet granulation of mixed powders of oxymorphone and at least one binding agent; by coating an inert bead with oxymorphone and at least one binding agent; or by spheronizing mixed powders of oxymorphone and at least one spheronizing agent.
- Exemplary binding agents include hydroxypropylmethylcelluloses.
- Exemplary spheronizing agents include microcrystalline celluloses.
- the inner core may be a tablet made by compressing the granules or by compressing a powder comprising oxymorphone or the pharmaceutically acceptable salt thereof.
- compositions comprising oxymorphone or a pharmaceutically acceptable salt thereof and a sustained release delivery system are coated with a sustained release coating, as described herein.
- compositions comprising oxymorphone or a pharmaceutically acceptable salt thereof and a sustained release delivery system, as described herein are coated with a hydrophobic polymer, as described herein.
- compositions comprising oxymorphone or a pharmaceutically acceptable salt thereof and a sustained release delivery system are coated with an enteric coating, such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimelliate, or mixtures thereof.
- enteric coating such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimelliate, or mixtures thereof.
- the compositions comprising oxymorphone or a pharmaceutically acceptable salt thereof and a sustained release delivery system are coated with a hydrophobic polymer, as described herein, and further coated with an enteric coating, as described herein.
- compositions comprising oxymorphone or a pharmaceutically acceptable salt thereof and a sustained release delivery system may optionally be coated with a hydrophilic coating which may be applied above or beneath the sustained release film, above or beneath the hydrophobic coating, and/or above or beneath the enteric coating.
- a hydrophilic coating comprise hydroxypropylmethylcellulose.
- the invention provides methods for treating pain by administering an effective amount of the sustained release formulations of oxymorphone to a patient in need thereof.
- An effective amount is an amount sufficient to eliminate all pain or to alleviate the pain (i.e., reduce the pain compared to the pain present prior to administration of the oxymorphone sustained release formulation).
- sustained release means that the oxymorphone or pharmaceutically acceptable salt thereof is released from the formulation at a controlled rate so that therapeutically beneficial blood levels (but below toxic levels) of the oxymorphone or pharmaceutically acceptable salt thereof are maintained over an extended period of time.
- the sustained release formulations of oxymorphone are administered in an amount sufficient to alleviate pain for an extended period of time, preferably about 8 hours to about 24 hours, more preferably for a period of about 12 hours to about 24 hours.
- the oxymorphone sustained release oral solid dosage formulations of the invention may be administered one to four times a day, preferably once or twice daily, more preferably once daily.
- the pain may be minor to moderate to severe, and is preferably moderate to severe.
- the pain may be acute or chronic.
- the pain may be associated with, for example, cancer, autoimmune diseases, infections, surgical traumas, accidental traumas or osteoarthritis.
- the patient may be an animal, preferably a mammal, more preferably a human.
- the sustained release formulation upon oral ingestion of the oxymorphone sustained release formulation and contact of the formulation with gastrointestinal fluids, the sustained release formulation swells and gels to form a hydrophilic gel matrix from which the oxymorphone is released.
- the swelling of the gel matrix causes a reduction in the bulk density of the formulation and provides the buoyancy necessary to allow the gel matrix to float on the stomach contents to provide a slow delivery of the oxymorphone.
- the hydrophilic matrix the size of which is dependent upon the size of the original formulation, can swell considerably and become obstructed near the opening of the pylorus.
- oxymorphone Since the oxymorphone is dispersed throughout the formulation (and consequently throughout the gel matrix), a constant amount of oxymorphone can be released per unit time in vivo by dispersion or erosion of the outer portions of the hydrophilic gel matrix. The process continues, with the gel matrix remaining bouyant in the stomach, until substantially all of the oxymorphone is released.
- the chemistry of certain of the components of the formulation is such that the components are considered to be self-buffering agents which are substantially insensitive to the solubility of the oxymorphone and the pH changes along the length of the gastrointestinal tract.
- the chemistry of the components is believed to be similar to certain known muco-adhesive substances, such as polycarbophil. Muco-adhesive properties are desirable for buccal delivery systems.
- the sustained release formulation can loosely interact with the mucin in the gastrointestinal tract and thereby provide another mode by which a constant rate of delivery of the oxymorphone is achieved.
- the sustained release formulations of the invention exhibit an in vitro dissolution rate of about 15% to about 50% by weight oxymorphone after 1 hour, about 45% to about 80% by weight oxymorphone after 4 hours, and at least about 80% by weight oxymorphone after 10 hours.
- the in vitro and in vivo release characteristics of the sustained release formulations of the invention may be modified using mixtures of one or more different water insoluble and/or water soluble compounds, using different plasticizers, varying the thickness of the sustained release film, including providing release-modifying compounds in the coating, and/or by providing passageways through the coating.
- the sustained release formulations of the invention exhibit the following in vivo characteristics: (a) a peak plasma level of oxymorphone occurs within about 2 to about 6 hours after administration; (b) the duration of the oxymorphone analgesic effect is about 8 to about 24 hours; and (c) the relative oxymorphone bioavailability is about 0.5 to about 1.5 compared to an orally administered aqueous solution of oxymorphone.
- compositions of the invention may be administered as the sole active pharmaceutical compound in the methods described herein, they can also be used in combination with one or more compounds which are known to be therapeutically effective against pain.
- the invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the compositions of the invention.
- the kits may further comprise other pharmaceutical compounds known in the art to be therapeutically effective against pain, and instructions for use.
- Two sustained release delivery systems were prepared by dry blending xanthan gum, locust bean gum, calcium sulfate dehydrate, and dextrose in a high speed mixed/granulator for 3 minutes.
- a slurry was prepared by mixing ethyl cellulose with alcohol. While running choppers/impellers, the slurry was added to the dry blended mixture, and granulated for another 3 minutes. The granulation was then dried to a LOD (loss on drying) of less than about 10% by weight. The granulation was then milled using 20 mesh screen.
- the relative quantities of the ingredients are listed in Table 1.
- Example 2 Excipient % % Locust Bean Gum, FCC 25.0 30.0 Xanthan Gum, NF 25.0 30.0 Dextrose, USP 35.0 40.0 Calcium Sulfate Dihydrate, NF 10.0 0.0 Ethylcellulose, NF 5.0 0.0 Alcohol, SD3A (Anhydrous) 1 (10) 1 (20.0) 1 Total 100.0 100.0
- Example 9 slow release fast release Ingredients mg/tablet mg/tablet Oxymorphone HCl, USP 20 20 Sustained Release Delivery System 360 160 Silicified Microcrystalline 20 20 Cellulose, NF Sodium stearyl fumarate, NF 4 2 Coating (color) 12.12 12.12 Total weight 416.12 214.12
- Example 9 Time (hr) slow release fast release 0.5 18.8% 21.3% 1 27.8% 32.3% 2 40.5% 47.4% 3 50.2% 58.5% 4 58.1% 66.9% 5 64.7% 73.5% 6 70.2% 78.6% 8 79.0% 86.0% 10 85.3% 90.6% 12 89.8% 93.4%
- a clinical study was conducted to (1) assess the relative bioavailability (rate and extent of absorption) of oxymorphone sustained release (20 mg) (fast release formulation of Example 9) compared to oral solution oxymorphone (10 mg) under fasted conditions, (2) to assess the relative bioavailability of oxymorphone sustained release (20 mg) compared to oral solution oxymorphone (10 mg) under fed conditions, (3) to assess the relative bioavailability of oxymorphone sustained release (20 mg) fed compared to oxymorphone sustained release (20 mg) fasted, (4) to assess the relative bioavailability of oral solution oxymorphone fed compared to oral solution oxymorphone fasted, and (5) to assess the relative safety and tolerability of sustained release oxymorphone (20 mg) under fed and fasted conditions.
- This study had a single-center, open-label, analytically blinded, randomized, four-way crossover design. Subjects randomized to Treatment A and Treatment C, as described below, were in a fasted state following a 10-hour overnight fast. Subjects randomized to Treatment B and Treatment D, as described below, were in the fed state, having had a high fat meal, completed ten minutes prior to dosing. There was a 14-day washout interval between the four dose administrations. The subjects were confined to the clinic during each study period. Subjects assigned to receive Treatment A and Treatment B were discharged from the clinic on Day 3 following the 48-hour procedures, and subjects assigned to receive Treatment C and Treatment D were discharged from the clinic on Day 2 following the 36-hour procedures. On Day 1 of each study period the subjects received one of four treatments:
- Treatments A and B were of oxymorphone sustained release 20 mg tablets. Subjects randomized to Treatment A received a single oral dose of one 20 mg oxymorphone sustained release tablet taken with 240 ml of water after a 10-hour fasting period. Subjects randomized to Treatment B received a single oral dose of one 20 mg oxymorphone sustained release tablet taken with 240 ml of water 10 minutes after a standardized high fat meal.
- Treatments C and D were of oxymorphone HCl solutions, USP, 1.5 mg/mil injection 10 ml vials.
- Subjects randomized to Treatment C received a single oral dose of 10 mg (6.7 ml) oxymorphone solution taken with 240 ml of water after a 10-hour fasting period.
- Subjects randomized to Treatment D received a single oral dose of 10 mg (6.7 ml) oxymorphone solution taken with 240 ml of water 10 minutes after a standardized high-fat meal.
- a total of 28 male subjects were enrolled in the study, and 24 subjects completed the study.
- the mean age of the subjects was 27 years (range of 19 through 38 years), the mean height of the subjects was 69.6 inches (range of 64.0 through 75.0 inches), and the mean weight of the subjects was 169.0 pounds (range 117.0 through 202.0 pounds).
- the subjects were not to consume any alcohol-, caffeine-, or xanthine-containing foods or beverages for 24 hours prior to receiving study medication for each study period.
- Subjects were to be nicotine and tobacco free for at least 6 months prior to enrolling in the study.
- over-the-counter medications were prohibited 7 days prior to dosing and during the study. Prescription medications were not allowed 14 days prior to dosing and during the study.
- the subjects were screened within 14 days prior to study enrollment.
- the screening procedure included medical history, physical examination (height, weight, frame size, vital signs, and ECG), and clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody screen, Hepatitis B surface antigen screen, Hepatitis C antibody screen, and a screen for cannabinoids).
- Blood samples (7 ml) were collected during each study period at the 0 hour (predose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, and 48 hours post-dose (19 samples) for subjects randomized to Treatment A and Treatment B.
- Blood samples (7 mi) were collected during each study period at the 0 hour (predose), and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, and 36 hours post-dose (21 samples) for subjects randomized to Treatment C and Treatment D.
- a total of 80 blood samples (560 ml) per subject were drawn during the study for drug analysis. Plasma samples were separated by centrifugation, and then frozen at ⁇ 70° C., and kept frozen until assayed.
- Terminal elimination rate constants were computed using linear regression of a minimum of three time points, at least two of which were consecutive. Kel values for which correlation coefficients were less than or equal to 0.8 were not reported in the pharmacokinetic parameter tables or included in the statistical analysis. Thus, T1/2el, AUC(0-inf), C1/F, MRT, and LN-transformed T1/2el, AUC(0-inf), and C1/F were also not reported in these cases.
- a parametric (normal-theory) general linear model was applied to each of the above parameters (excluding Tmax and Frel), and the LN-transformed parameters Cmax, AUC(0-24), AUC(0-t), AUC(0-inf), C1/F, and T1/2el.
- the analysis of variance (ANOVA) model included the following factors: treatment, sequence, subject within sequence, period, and carryover effect. If carryover effect was not significant, it was dropped from the model. The sequence effect was tested using the subject within sequence mean square, and all other main effects were tested using the residual error (error mean square). The following treatment comparisons of relative rate and extent of absorption were made: Treatment B versus Treatment A, Treatment A versus Treatment C (dose normalized to 20 mg).
- Treatment B versus Treatment D (dose normalized to 20 mg), and Treatment D versus Treatment C (dose normalized to 20 mg for both treatments).
- the 90% confidence intervals of the ratios of the treatment least squares parameter means were calculated.
- Tmax was analyzed using the Wilcoxon Signed Ranks test. Summary statistics were presented for Frel.
- Plasma oxymorphone concentrations were listed by subject at each collection time and summarized using descriptive statistics. Pharmacokinetic parameters were also listed by subject and summarized using descriptive statistics.
- the objectives of this study were to assess the relative bioavailability of oxymorphone from oxymorphone sustained release (20 mg) compared to oxymorphone oral solution (10 mg) under both fasted and fed conditions, and to determine the effect of food on the bioavailability of oxymorphone from the sustained release formulation and from the oral solution.
- LS mean Cmax was 49% lower for oxymorphone sustained release tablets compared to the dose-normalized oral solution, based on LN-transformed data.
- Half-value duration was significantly longer for the sustained release formulation (means, 12 hours versus 2.5 hours).
- oxymorphone availability from oxymorphone sustained release 20 mg was similar compared to 10 mg oxymorphone oral solution normalized to a 20 mg dose (Treatment B versus Treatment D).
- LS mean AUC(0-inf) was 12% lower for oxymorphone sustained release.
- Mean Frel values calculated from AUC(0-inf) and AUC(0-24), (0.89 and 0.83 respectively) also showed similar extent of oxymorphone availability from the tablet. There were differences in parameters reflecting rate of absorption.
- LS mean Cmax was 46% lower for oxymorphone sustained release tablets compared to the dose-normalized oral solution, based on LN-transformed data.
- Mean Tmax was 5.7 hours for the tablet compared to 1.1 hours for the oral solution.
- Half-value duration was significantly longer for the sustained release formulation (means, 7.8 hours versus 3.1 hours).
- LS mean ratios were 97% for AUC(0-t) and 91% for Cmax (Treatment B versus A), based on LN-transformed data. This was consistent with the relative bioavailability determination from AUC(0-24), since mean Frel was 0.97.
- AUC(0-inf) was not a reliable measure for bioavailability since half-life could not be estimated accurately, and in many cases at all.
- Half-life estimates were not accurate because in the majority of subjects, the values for half-life were nearly as long or longer (up to 2.8 times longer) as the sampling period.
- Mean Tmax was later for the fed treatment compared to the fasted treatment (5.2 and 3.6 hours, respectively), and difference was significant.
- oxymorphone sustained release 20 mg tablets Under fasted conditions, oxymorphone sustained release 20 mg tablets exhibited similar availability compared to 10 mg oxymorphone oral solution normalized to a 20 mg dose (Treatment A versus Treatment C). From LN-transformed data, LS mean ratio for AUC (0-t) was 104.5%. Mean Frel (0.83) calculated from AUC(0-24) also showed similar extent of oxymorphone availability between the two treatments. There were differences in parameters reflecting rate of absorption. LS mean Cmax was 57% lower for oxymorphone sustained release tablets compared to the dose-normalized oral solution. Mean Tmax was 3.6 hours for the tablet compared to 0.88 for the oral solution. Half-value duration was significantly longer for the sustained release formulation (means, 11 hours versus 2.2 hours).
- oxymorphone sustained release tablets Under both fed and fasted conditions, oxymorphone sustained release tablets exhibited similar extent of oxymorphone availability compared to oxymorphone oral solution since there was less than a 20% difference in LS mean AUC(0-t) and AUC(0-inf) values for each treatment.
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US20030129230A1 (en) * | 2001-07-06 | 2003-07-10 | Penwest Pharmaceuticals Company | Sustained release formulations of oxymorphone |
US20030157167A1 (en) * | 2001-07-06 | 2003-08-21 | Endo Pharmaceuticals, Inc. | Oxymorphone controlled release formulations |
US20060269604A1 (en) * | 1993-11-23 | 2006-11-30 | Purdue Pharma L.P. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
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US9120800B2 (en) | 2013-08-02 | 2015-09-01 | Johnson Matthey Public Limited Company | Process for the preparation of oxymorphone alkaloid and oxymorphone salts |
WO2016123202A1 (en) | 2015-01-29 | 2016-08-04 | Johnson Matthey Public Limited Company | Process of preparing low abuk oxymorphone hydrochloride |
US9730885B2 (en) | 2012-07-12 | 2017-08-15 | Mallinckrodt Llc | Extended release, abuse deterrent pharmaceutical compositions |
Families Citing this family (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002100382A2 (en) * | 2001-06-08 | 2002-12-19 | Endo Pharmaceuticals, Inc. | Controlled release dosage forms using acrylic polymer, and process for making the same |
US20030068375A1 (en) | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
US10004729B2 (en) | 2002-07-05 | 2018-06-26 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
WO2004004693A1 (en) | 2002-07-05 | 2004-01-15 | Collgegium Pharmaceutical | Abuse-deterrent pharmaceutical compositions of opiods and other drugs |
US8557291B2 (en) | 2002-07-05 | 2013-10-15 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
US8840928B2 (en) | 2002-07-05 | 2014-09-23 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
CA2533165A1 (en) * | 2003-07-21 | 2005-01-27 | Bio-Dar Ltd. | Gellan gum based oral controlled release dosage forms- a novel platform technology for gastric retention |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
DE10361596A1 (de) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
DE10336400A1 (de) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
DE102005005446A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Bruchfeste Darreichungsformen mit retardierter Freisetzung |
ES2653568T3 (es) | 2004-06-12 | 2018-02-07 | Collegium Pharmaceutical, Inc. | Formulaciones de fármacos para la prevención del abuso |
DE102004032049A1 (de) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
DE102005005449A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
US20080119501A1 (en) * | 2006-04-28 | 2008-05-22 | Hein William A | Immediate release oxymorphone compositions and methods of using same |
EP2079453A1 (de) * | 2006-10-10 | 2009-07-22 | Penwest Pharmaceuticals Co. | Robuste formulierungen mit verzögerter freisetzung |
MX2009003772A (es) * | 2006-10-10 | 2009-07-22 | Penwest Pharmaceuticals Co | Formulaciones de oximorfona robustas, de liberacion sostenida. |
JP2010505948A (ja) * | 2006-10-10 | 2010-02-25 | ペンウェスト ファーマシューティカルズ カンパニー | オキシモルフォンのロバスト性持続放出製剤およびその使用方法 |
US20080227805A1 (en) * | 2007-02-28 | 2008-09-18 | Abbott Laboratories | Sustained release parenteral formulations of buprenorphine |
DE102007011485A1 (de) | 2007-03-07 | 2008-09-11 | Grünenthal GmbH | Darreichungsform mit erschwertem Missbrauch |
EP2249811A1 (de) | 2008-01-25 | 2010-11-17 | Grünenthal GmbH | Pharmazeutische dosierform |
JP2011511782A (ja) | 2008-02-12 | 2011-04-14 | アボット・ラボラトリーズ | 長期放出性ヒドロコドンアセトアミノフェンならびにその関連方法および用途 |
CA2723438C (en) | 2008-05-09 | 2016-10-11 | Gruenenthal Gmbh | Process for the preparation of an intermediate powder formulation and a final solid dosage form under usage of a spray congealing step |
BR112012001244A2 (pt) | 2009-07-22 | 2020-12-08 | Gruünenthal Gmbh | Forma de dosagem resitente à adulteração, seu processo de produção, e embalagem contendo tal forma |
WO2011009602A1 (en) | 2009-07-22 | 2011-01-27 | Grünenthal GmbH | Hot-melt extruded controlled release dosage form |
CZ302789B6 (cs) | 2009-11-25 | 2011-11-09 | Zentiva, K. S. | Zpusob zvýšení rozpustnosti farmaceuticky aktivních látek a cílený (kontrolovaný) transport do streva |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US9579285B2 (en) | 2010-02-03 | 2017-02-28 | Gruenenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of an extruder |
AR082862A1 (es) | 2010-09-02 | 2013-01-16 | Gruenenthal Gmbh | Forma de dosificacion resistente a alteracion que comprende un polimero anionico |
RU2604676C2 (ru) | 2010-09-02 | 2016-12-10 | Грюненталь Гмбх | Устойчивая к разрушению лекарственная форма, содержащая неорганическую соль |
MY166034A (en) | 2010-12-22 | 2018-05-21 | Purdue Pharma Lp | Encased tamper resistant controlled release dosage forms |
JP5638151B2 (ja) | 2010-12-23 | 2014-12-10 | パーデュー、ファーマ、リミテッド、パートナーシップ | 不正加工抵抗性の(tamperresistant)固形経口剤形 |
PT2736497T (pt) | 2011-07-29 | 2017-11-30 | Gruenenthal Gmbh | Comprimido resistente a adulteração proporcionando libertação imediata de fármaco |
BR112014002022A2 (pt) | 2011-07-29 | 2017-02-21 | Gruenenthal Gmbh | comprimido resistente à violação proporcionando liberação de fármaco imediata |
FR2983409B1 (fr) * | 2011-12-06 | 2013-12-27 | Ethypharm Sa | Comprime susceptible de lutter contre le detournement par voie injectable |
CA2864949A1 (en) | 2012-02-28 | 2013-09-06 | Grunenthal Gmbh | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
ES2692944T3 (es) | 2012-04-18 | 2018-12-05 | Grünenthal GmbH | Forma de dosificación farmacéutica resistente a la manipulación y resistente a la descarga rápida de la dosis |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
MX2015016254A (es) | 2013-05-29 | 2016-04-20 | Gruenenthal Gmbh | Forma de dosificacion resistente al uso indebido con perfil de liberacion bimodal. |
MX371432B (es) | 2013-05-29 | 2020-01-30 | Gruenenthal Gmbh | Forma de dosificacion resistente al uso indebido que contiene una o mas particulas. |
US10624862B2 (en) | 2013-07-12 | 2020-04-21 | Grünenthal GmbH | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
CN105934241B (zh) | 2013-11-26 | 2020-06-05 | 格吕伦塔尔有限公司 | 通过低温研磨制备粉末状药物组合物 |
WO2015173195A1 (en) | 2014-05-12 | 2015-11-19 | Grünenthal GmbH | Tamper resistant immediate release capsule formulation comprising tapentadol |
AU2015266117A1 (en) | 2014-05-26 | 2016-11-24 | Grunenthal Gmbh | Multiparticles safeguarded against ethanolic dose-dumping |
CN107889459A (zh) | 2015-04-24 | 2018-04-06 | 格吕伦塔尔有限公司 | 具有立即释放和对溶剂萃取的抗性的抗篡改剂型 |
US10842750B2 (en) | 2015-09-10 | 2020-11-24 | Grünenthal GmbH | Protecting oral overdose with abuse deterrent immediate release formulations |
US9861629B1 (en) | 2015-10-07 | 2018-01-09 | Banner Life Sciences Llc | Opioid abuse deterrent dosage forms |
US10335405B1 (en) | 2016-05-04 | 2019-07-02 | Patheon Softgels, Inc. | Non-burst releasing pharmaceutical composition |
WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
US10335375B2 (en) | 2017-05-30 | 2019-07-02 | Patheon Softgels, Inc. | Anti-overingestion abuse deterrent compositions |
Citations (88)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2806033A (en) * | 1955-08-03 | 1957-09-10 | Lewenstein | Morphine derivative |
US3393197A (en) * | 1966-01-19 | 1968-07-16 | Endo Lab | Nu-substituted-14-hydroxydihydronormorphines |
US3879555A (en) * | 1970-11-16 | 1975-04-22 | Bristol Myers Co | Method of treating drug addicts |
US3966940A (en) * | 1973-11-09 | 1976-06-29 | Bristol-Myers Company | Analgetic compositions |
US3980766A (en) * | 1973-08-13 | 1976-09-14 | West Laboratories, Inc. | Orally administered drug composition for therapy in the treatment of narcotic drug addiction |
US4070494A (en) * | 1975-07-09 | 1978-01-24 | Bayer Aktiengesellschaft | Enteral pharmaceutical compositions |
US4457933A (en) * | 1980-01-24 | 1984-07-03 | Bristol-Myers Company | Prevention of analgesic abuse |
US4464376A (en) * | 1982-07-22 | 1984-08-07 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4479856A (en) * | 1982-08-09 | 1984-10-30 | Meidensha Electric Mfg. Co., Ltd. | Zinc dendrite inhibitor |
US4567183A (en) * | 1983-03-11 | 1986-01-28 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same |
US4569937A (en) * | 1985-02-11 | 1986-02-11 | E. I. Du Pont De Nemours And Company | Analgesic mixture of oxycodone and ibuprofen |
US4582835A (en) * | 1983-12-06 | 1986-04-15 | Reckitt & Colman Products Limited | Analgesic compositions |
US4587249A (en) * | 1982-07-22 | 1986-05-06 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4599114A (en) * | 1985-02-11 | 1986-07-08 | Atkinson George K | Treatment of titanium dioxide and other pigments to improve dispersibility |
US4656177A (en) * | 1982-07-22 | 1987-04-07 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4661492A (en) * | 1984-11-30 | 1987-04-28 | Reckitt & Colman Products Limited | Analgesic compositions |
US4777174A (en) * | 1982-07-22 | 1988-10-11 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4844909A (en) * | 1986-10-31 | 1989-07-04 | Euroceltique, S.A. | Controlled release hydromorphone composition |
US4861598A (en) * | 1986-07-18 | 1989-08-29 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
US4935428A (en) * | 1987-12-03 | 1990-06-19 | Reckitt & Colman Products Limited | Treating opiate dependence |
US4994276A (en) * | 1988-09-19 | 1991-02-19 | Edward Mendell Co., Inc. | Directly compressible sustained release excipient |
US5128143A (en) * | 1988-09-19 | 1992-07-07 | Edward Mendell Co., Inc. | Sustained release excipient and tablet formulation |
US5135757A (en) * | 1988-09-19 | 1992-08-04 | Edward Mendell Co., Inc. | Compressible sustained release solid dosage forms |
US5236714A (en) * | 1988-11-01 | 1993-08-17 | Alza Corporation | Abusable substance dosage form having reduced abuse potential |
US5399358A (en) * | 1993-11-12 | 1995-03-21 | Edward Mendell Co., Inc. | Sustained release formulations for 24 hour release of metroprolol |
US5431922A (en) * | 1991-03-05 | 1995-07-11 | Bristol-Myers Squibb Company | Method for administration of buspirone |
US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
US5512578A (en) * | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
US5543434A (en) * | 1994-02-25 | 1996-08-06 | Weg; Stuart L. | Nasal administration of ketamine to manage pain |
US5556837A (en) * | 1994-08-01 | 1996-09-17 | Regeneron Pharmaceuticals Inc. | Methods for treating addictive disorders |
US5567754A (en) * | 1995-08-23 | 1996-10-22 | Kerr-Mcgee Corporation | Pigments with improved dispersibility in thermoplastic resins |
US5612053A (en) * | 1995-04-07 | 1997-03-18 | Edward Mendell Co., Inc. | Controlled release insufflation carrier for medicaments |
US5633000A (en) * | 1994-06-23 | 1997-05-27 | Axxia Technologies | Subcutaneous implant |
US5639476A (en) * | 1992-01-27 | 1997-06-17 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5662933A (en) * | 1993-09-09 | 1997-09-02 | Edward Mendell Co., Inc. | Controlled release formulation (albuterol) |
US5672360A (en) * | 1993-11-23 | 1997-09-30 | Purdue Pharma, L.P. | Method of treating pain by administering 24 hour oral opioid formulations |
US5891474A (en) * | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
US5914131A (en) * | 1994-07-07 | 1999-06-22 | Alza Corporation | Hydromorphone therapy |
US5948438A (en) * | 1995-01-09 | 1999-09-07 | Edward Mendell Co., Inc. | Pharmaceutical formulations having improved disintegration and/or absorptivity |
US5958459A (en) * | 1991-12-24 | 1999-09-28 | Purdue Pharma L.P. | Opioid formulations having extended controlled released |
US5958452A (en) * | 1994-11-04 | 1999-09-28 | Euro-Celtique, S.A. | Extruded orally administrable opioid formulations |
USRE36547E (en) * | 1992-09-21 | 2000-02-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
US6093420A (en) * | 1996-07-08 | 2000-07-25 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
US6103258A (en) * | 1996-04-12 | 2000-08-15 | Simon; David Lew | Salts and bases of the 17-(Cyclopropylmethyl)-4,5 alpha-epoxy-6-Methylenemorphinan-3,14 diol molecule for optimizing dopamine homeostasis during administration of opioid analgesics |
US6103261A (en) * | 1993-07-01 | 2000-08-15 | Purdue Pharma Lp | Opioid formulations having extended controlled release |
US6221393B1 (en) * | 1995-01-27 | 2001-04-24 | Rhodia Chimie | Pharmaceutical compositions in the form of sustained-release tablets based on high molecular weight polysaccharide granules |
US6245357B1 (en) * | 1998-03-06 | 2001-06-12 | Alza Corporation | Extended release dosage form |
US6248789B1 (en) * | 1996-08-29 | 2001-06-19 | Stuart L. Weg | Administration of ketamine to manage pain and to reduce drug dependency |
US6277384B1 (en) * | 1997-12-22 | 2001-08-21 | Euro-Celtique S.A. | Opioid agonist/antagonist combinations |
US6294195B1 (en) * | 1991-12-24 | 2001-09-25 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
US6340475B2 (en) * | 1997-06-06 | 2002-01-22 | Depomed, Inc. | Extending the duration of drug release within the stomach during the fed mode |
US20020010127A1 (en) * | 2000-02-08 | 2002-01-24 | Benjamin Oshlack | Controlled-release compositions containing opioid agonist and antagonist |
US6375957B1 (en) * | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
US6391336B1 (en) * | 1997-09-22 | 2002-05-21 | Royer Biomedical, Inc. | Inorganic-polymer complexes for the controlled release of compounds including medicinals |
US6413494B1 (en) * | 1998-07-23 | 2002-07-02 | Samyang Corporation | Composition and pharmaceutical dosage form for colonic drug delivery using polysaccharides |
US6432438B1 (en) * | 1997-10-29 | 2002-08-13 | Atul J. Shukla | Biodegradable vehicle and filler |
US20030004177A1 (en) * | 2001-05-11 | 2003-01-02 | Endo Pharmaceuticals, Inc. | Abuse-resistant opioid dosage form |
US6506730B1 (en) * | 1999-08-17 | 2003-01-14 | Kang Choon Lee | Nasal transmucosal delivery of peptide conjugated with biocompatible polymers |
US6514531B1 (en) * | 1998-12-04 | 2003-02-04 | Sanofi-Synthelabo | Controlled-release dosage forms comprising zolpidem or a salt thereof |
US20030044458A1 (en) * | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
US20030049272A1 (en) * | 2001-08-30 | 2003-03-13 | Yatindra Joshi | Pharmaceutical composition which produces irritation |
US20030059397A1 (en) * | 2001-09-17 | 2003-03-27 | Lyn Hughes | Dosage forms |
US20030065008A1 (en) * | 2000-01-28 | 2003-04-03 | Endorecherche, Inc. | Selective estrogen receptor modulators in combination with estrogens |
US20030064122A1 (en) * | 2001-05-23 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse resistant pharmaceutical composition containing capsaicin |
US20030065002A1 (en) * | 2001-05-11 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse-resistant controlled-release opioid dosage form |
US20030064099A1 (en) * | 2001-08-06 | 2003-04-03 | Benjamin Oshlack | Pharmaceutical formulation containing bittering agent |
US20030068392A1 (en) * | 2001-08-06 | 2003-04-10 | Richard Sackler | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
US20030068375A1 (en) * | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
US20030069263A1 (en) * | 2001-07-18 | 2003-04-10 | Breder Christopher D. | Pharmaceutical combinations of oxycodone and naloxone |
US20030068370A1 (en) * | 2001-08-06 | 2003-04-10 | Richard Sackler | Pharmaceutical formulation containing irritant |
US20030068371A1 (en) * | 2001-08-06 | 2003-04-10 | Benjamin Oshlack | Pharmaceutical formulation containing opioid agonist,opioid antagonist and gelling agent |
US20030068276A1 (en) * | 2001-09-17 | 2003-04-10 | Lyn Hughes | Dosage forms |
US20030073714A1 (en) * | 2001-08-06 | 2003-04-17 | Christopher Breder | Opioid agonist formulations with releasable and sequestered antagonist |
US6555127B2 (en) * | 2000-01-19 | 2003-04-29 | Pharmaceutical Discovery Corporation | Multi-spike release formulation for oral drug delivery |
US20030091635A1 (en) * | 2001-09-26 | 2003-05-15 | Baichwal Anand R. | Opioid formulations having reduced potential for abuse |
US20030124185A1 (en) * | 2001-08-06 | 2003-07-03 | Benjamin Oshlack | Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent |
US20030125347A1 (en) * | 2001-11-02 | 2003-07-03 | Elan Corporation Plc | Pharmaceutical composition |
US20030124061A1 (en) * | 2003-01-10 | 2003-07-03 | Roberts Richard H. | Pharmaceutical safety dosage forms |
US20030129230A1 (en) * | 2001-07-06 | 2003-07-10 | Penwest Pharmaceuticals Company | Sustained release formulations of oxymorphone |
US20030143269A1 (en) * | 2000-02-08 | 2003-07-31 | Benjamin Oshlack | Tamper-resistant oral opioid agonist formulations |
US20030152638A1 (en) * | 1999-08-27 | 2003-08-14 | Southern Research | Injectable opioid partial agonist or opioid antagonist microparticle compositions and their use in reducing consumption of abused substances |
US20030158264A1 (en) * | 2002-02-20 | 2003-08-21 | Ramachandran Radhakrishnan | Orally administrable pharmaceutical formulation comprising ephedrine hydrochloride and process for preparing the same |
US20030157168A1 (en) * | 2001-08-06 | 2003-08-21 | Christopher Breder | Sequestered antagonist formulations |
US20030157167A1 (en) * | 2001-07-06 | 2003-08-21 | Endo Pharmaceuticals, Inc. | Oxymorphone controlled release formulations |
US20030163099A1 (en) * | 2000-08-15 | 2003-08-28 | Wermeling Daniel P | Programmable multi-dose intranasal drug delivery device |
US20030170181A1 (en) * | 1999-04-06 | 2003-09-11 | Midha Kamal K. | Method for preventing abuse of methylphenidate |
US20030177975A1 (en) * | 2000-09-18 | 2003-09-25 | Akio Ikesue | Rare earth-iron garnet single crystal material and method for preparation thereof and device using rare earth-iron garnet single crystal material |
US6627635B2 (en) * | 1997-12-22 | 2003-09-30 | Euro-Celtique S.A. | Method of preventing abuse of opioid dosage forms |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US4366159A (en) | 1981-09-08 | 1982-12-28 | Michael Richard Magruder | Nalbuphine-narcotic analgesic composition and method of producing analgesia |
US4486436A (en) | 1982-07-22 | 1984-12-04 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4479956A (en) * | 1983-04-26 | 1984-10-30 | Analgeic Associates | Analgesic compositions comprising propiram and methods of using same |
US4558051A (en) | 1983-10-11 | 1985-12-10 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same |
JPS60100516A (ja) * | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | 徐放型マイクロカプセルの製造法 |
IT1191674B (it) * | 1986-03-07 | 1988-03-23 | Eurand Spa | Formulazioni per la preparazione di farmaci a rilascio prolungato adatte alla somministrazione per via orale |
US5286497A (en) | 1991-05-20 | 1994-02-15 | Carderm Capital L.P. | Diltiazem formulation |
US5266331A (en) * | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
US5681585A (en) | 1991-12-24 | 1997-10-28 | Euro-Celtique, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
US5248789A (en) * | 1992-03-26 | 1993-09-28 | Ppg Industries, Inc. | Epoxy silicone |
KR100354702B1 (ko) | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | 약학조성물의제조방법및서방형조성물 |
GB9401894D0 (en) * | 1994-02-01 | 1994-03-30 | Rhone Poulenc Rorer Ltd | New compositions of matter |
US5958458A (en) * | 1994-06-15 | 1999-09-28 | Dumex-Alpharma A/S | Pharmaceutical multiple unit particulate formulation in the form of coated cores |
US6143325A (en) | 1998-06-05 | 2000-11-07 | Bristol-Myers Squibb Company | Nefazodone dosage form |
DE29818454U1 (de) * | 1998-10-15 | 1999-01-14 | Euroceltique S.A., Luxemburg/Luxembourg | Opioid-Analgetikum |
US6806294B2 (en) | 1998-10-15 | 2004-10-19 | Euro-Celtique S.A. | Opioid analgesic |
US6306425B1 (en) | 1999-04-09 | 2001-10-23 | Southern Research Institute | Injectable naltrexone microsphere compositions and their use in reducing consumption of heroin and alcohol |
JP2003522127A (ja) * | 1999-07-29 | 2003-07-22 | ロクセニ ラボラトリーズ インコーポレイテッド | オピオイド徐放性製剤 |
US6296842B1 (en) | 2000-08-10 | 2001-10-02 | Alkermes Controlled Therapeutics, Inc. | Process for the preparation of polymer-based sustained release compositions |
US20020187192A1 (en) | 2001-04-30 | 2002-12-12 | Yatindra Joshi | Pharmaceutical composition which reduces or eliminates drug abuse potential |
US20030024172A1 (en) * | 2001-06-05 | 2003-02-06 | Jerold Lyons | Method and apparatus for providing a modular shielded enclosure |
EP1455763B1 (de) * | 2001-12-21 | 2007-10-03 | Supernus Pharmaceuticals, Inc. | Orale kapselformulierung mit verbesserter physikalischer stabilität |
-
2002
- 2002-07-03 EP EP02748085A patent/EP1404332A1/de not_active Withdrawn
- 2002-07-03 DE DE60223254T patent/DE60223254T2/de not_active Expired - Lifetime
- 2002-07-03 WO PCT/US2002/021354 patent/WO2003004029A1/en not_active Application Discontinuation
- 2002-07-03 US US10/189,932 patent/US7276250B2/en not_active Expired - Lifetime
- 2002-07-03 BR BR0205722-0A patent/BR0205722A/pt not_active IP Right Cessation
- 2002-07-03 AT AT02744835T patent/ATE376832T1/de active
- 2002-07-03 DK DK02744835T patent/DK1404331T3/da active
- 2002-07-03 US US10/190,383 patent/US20030129234A1/en not_active Abandoned
- 2002-07-03 PL PL366430A patent/PL207748B1/pl unknown
- 2002-07-03 EP EP02744835A patent/EP1404331B1/de not_active Expired - Lifetime
- 2002-07-03 KR KR10-2003-7003334A patent/KR20030048026A/ko not_active Application Discontinuation
- 2002-07-03 WO PCT/US2002/021403 patent/WO2003004033A1/en active IP Right Grant
- 2002-07-03 BR BRPI0210855-0A patent/BR0210855A/pt not_active IP Right Cessation
- 2002-07-03 PL PL367277A patent/PL208484B1/pl unknown
- 2002-07-03 ES ES02744835T patent/ES2292775T3/es not_active Expired - Lifetime
-
2003
- 2003-03-05 NO NO20031019A patent/NO326375B1/no not_active IP Right Cessation
-
2004
- 2004-09-23 HK HK04107358A patent/HK1064921A1/xx not_active IP Right Cessation
-
2007
- 2007-08-13 US US11/891,775 patent/US20080050431A1/en not_active Abandoned
Patent Citations (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2806033A (en) * | 1955-08-03 | 1957-09-10 | Lewenstein | Morphine derivative |
US3393197A (en) * | 1966-01-19 | 1968-07-16 | Endo Lab | Nu-substituted-14-hydroxydihydronormorphines |
US3879555A (en) * | 1970-11-16 | 1975-04-22 | Bristol Myers Co | Method of treating drug addicts |
US3980766A (en) * | 1973-08-13 | 1976-09-14 | West Laboratories, Inc. | Orally administered drug composition for therapy in the treatment of narcotic drug addiction |
US3966940A (en) * | 1973-11-09 | 1976-06-29 | Bristol-Myers Company | Analgetic compositions |
US4070494A (en) * | 1975-07-09 | 1978-01-24 | Bayer Aktiengesellschaft | Enteral pharmaceutical compositions |
US4457933A (en) * | 1980-01-24 | 1984-07-03 | Bristol-Myers Company | Prevention of analgesic abuse |
US4656177A (en) * | 1982-07-22 | 1987-04-07 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4587249A (en) * | 1982-07-22 | 1986-05-06 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4464376A (en) * | 1982-07-22 | 1984-08-07 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4777174A (en) * | 1982-07-22 | 1988-10-11 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
US4479856A (en) * | 1982-08-09 | 1984-10-30 | Meidensha Electric Mfg. Co., Ltd. | Zinc dendrite inhibitor |
US4567183A (en) * | 1983-03-11 | 1986-01-28 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same |
US4582835A (en) * | 1983-12-06 | 1986-04-15 | Reckitt & Colman Products Limited | Analgesic compositions |
US4661492A (en) * | 1984-11-30 | 1987-04-28 | Reckitt & Colman Products Limited | Analgesic compositions |
US4569937A (en) * | 1985-02-11 | 1986-02-11 | E. I. Du Pont De Nemours And Company | Analgesic mixture of oxycodone and ibuprofen |
US4599114A (en) * | 1985-02-11 | 1986-07-08 | Atkinson George K | Treatment of titanium dioxide and other pigments to improve dispersibility |
US4861598A (en) * | 1986-07-18 | 1989-08-29 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
US4844909A (en) * | 1986-10-31 | 1989-07-04 | Euroceltique, S.A. | Controlled release hydromorphone composition |
US4935428A (en) * | 1987-12-03 | 1990-06-19 | Reckitt & Colman Products Limited | Treating opiate dependence |
US4994276A (en) * | 1988-09-19 | 1991-02-19 | Edward Mendell Co., Inc. | Directly compressible sustained release excipient |
US5128143A (en) * | 1988-09-19 | 1992-07-07 | Edward Mendell Co., Inc. | Sustained release excipient and tablet formulation |
US5135757A (en) * | 1988-09-19 | 1992-08-04 | Edward Mendell Co., Inc. | Compressible sustained release solid dosage forms |
US5236714A (en) * | 1988-11-01 | 1993-08-17 | Alza Corporation | Abusable substance dosage form having reduced abuse potential |
US5431922A (en) * | 1991-03-05 | 1995-07-11 | Bristol-Myers Squibb Company | Method for administration of buspirone |
US6294195B1 (en) * | 1991-12-24 | 2001-09-25 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
US5958459A (en) * | 1991-12-24 | 1999-09-28 | Purdue Pharma L.P. | Opioid formulations having extended controlled released |
US5639476A (en) * | 1992-01-27 | 1997-06-17 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5512578A (en) * | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
USRE36547E (en) * | 1992-09-21 | 2000-02-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
US6103261A (en) * | 1993-07-01 | 2000-08-15 | Purdue Pharma Lp | Opioid formulations having extended controlled release |
US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
US5958456A (en) * | 1993-09-09 | 1999-09-28 | Edward Mendell Co., Inc. | Controlled release formulation (albuterol) |
US5662933A (en) * | 1993-09-09 | 1997-09-02 | Edward Mendell Co., Inc. | Controlled release formulation (albuterol) |
US5554387A (en) * | 1993-09-09 | 1996-09-10 | Edward Mendell Co., Ltd. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
US5512297A (en) * | 1993-09-09 | 1996-04-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
US5399358A (en) * | 1993-11-12 | 1995-03-21 | Edward Mendell Co., Inc. | Sustained release formulations for 24 hour release of metroprolol |
US5672360A (en) * | 1993-11-23 | 1997-09-30 | Purdue Pharma, L.P. | Method of treating pain by administering 24 hour oral opioid formulations |
US5543434A (en) * | 1994-02-25 | 1996-08-06 | Weg; Stuart L. | Nasal administration of ketamine to manage pain |
US5633000A (en) * | 1994-06-23 | 1997-05-27 | Axxia Technologies | Subcutaneous implant |
US5858388A (en) * | 1994-06-23 | 1999-01-12 | Axxia Technologies | Subcutaneous implant for delivery of hydromorphone |
US5914131A (en) * | 1994-07-07 | 1999-06-22 | Alza Corporation | Hydromorphone therapy |
US5556837A (en) * | 1994-08-01 | 1996-09-17 | Regeneron Pharmaceuticals Inc. | Methods for treating addictive disorders |
US6261599B1 (en) * | 1994-11-04 | 2001-07-17 | Euro-Celtique, S.A. | Melt-extruded orally administrable opioid formulations |
US5958452A (en) * | 1994-11-04 | 1999-09-28 | Euro-Celtique, S.A. | Extruded orally administrable opioid formulations |
US5948438A (en) * | 1995-01-09 | 1999-09-07 | Edward Mendell Co., Inc. | Pharmaceutical formulations having improved disintegration and/or absorptivity |
US6221393B1 (en) * | 1995-01-27 | 2001-04-24 | Rhodia Chimie | Pharmaceutical compositions in the form of sustained-release tablets based on high molecular weight polysaccharide granules |
US6387394B1 (en) * | 1995-04-07 | 2002-05-14 | Penwest Pharmaceuticals Co. | Controlled release insufflation carrier for medicaments |
US20020090345A1 (en) * | 1995-04-07 | 2002-07-11 | Penwest Pharmaceuticals Co. | Controlled release insufflation carrier for medicaments |
US5738865A (en) * | 1995-04-07 | 1998-04-14 | Edward Mendell Co., Inc. | Controlled release insufflation carrier for medicaments |
US5612053A (en) * | 1995-04-07 | 1997-03-18 | Edward Mendell Co., Inc. | Controlled release insufflation carrier for medicaments |
US5567754A (en) * | 1995-08-23 | 1996-10-22 | Kerr-Mcgee Corporation | Pigments with improved dispersibility in thermoplastic resins |
US6103258A (en) * | 1996-04-12 | 2000-08-15 | Simon; David Lew | Salts and bases of the 17-(Cyclopropylmethyl)-4,5 alpha-epoxy-6-Methylenemorphinan-3,14 diol molecule for optimizing dopamine homeostasis during administration of opioid analgesics |
US6093420A (en) * | 1996-07-08 | 2000-07-25 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
US6248789B1 (en) * | 1996-08-29 | 2001-06-19 | Stuart L. Weg | Administration of ketamine to manage pain and to reduce drug dependency |
US5891474A (en) * | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
US6340475B2 (en) * | 1997-06-06 | 2002-01-22 | Depomed, Inc. | Extending the duration of drug release within the stomach during the fed mode |
US6391336B1 (en) * | 1997-09-22 | 2002-05-21 | Royer Biomedical, Inc. | Inorganic-polymer complexes for the controlled release of compounds including medicinals |
US6432438B1 (en) * | 1997-10-29 | 2002-08-13 | Atul J. Shukla | Biodegradable vehicle and filler |
US20030031712A1 (en) * | 1997-12-22 | 2003-02-13 | Kaiko Robert F. | Opioid agonist /antagonist combinations |
US6375957B1 (en) * | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
US20020058673A1 (en) * | 1997-12-22 | 2002-05-16 | Kaiko Robert F. | Opioid agonist/opioid antagonist/acetaminophen combinations |
US6277384B1 (en) * | 1997-12-22 | 2001-08-21 | Euro-Celtique S.A. | Opioid agonist/antagonist combinations |
US6627635B2 (en) * | 1997-12-22 | 2003-09-30 | Euro-Celtique S.A. | Method of preventing abuse of opioid dosage forms |
US6245357B1 (en) * | 1998-03-06 | 2001-06-12 | Alza Corporation | Extended release dosage form |
US6413494B1 (en) * | 1998-07-23 | 2002-07-02 | Samyang Corporation | Composition and pharmaceutical dosage form for colonic drug delivery using polysaccharides |
US6514531B1 (en) * | 1998-12-04 | 2003-02-04 | Sanofi-Synthelabo | Controlled-release dosage forms comprising zolpidem or a salt thereof |
US20030170181A1 (en) * | 1999-04-06 | 2003-09-11 | Midha Kamal K. | Method for preventing abuse of methylphenidate |
US6506730B1 (en) * | 1999-08-17 | 2003-01-14 | Kang Choon Lee | Nasal transmucosal delivery of peptide conjugated with biocompatible polymers |
US20030152638A1 (en) * | 1999-08-27 | 2003-08-14 | Southern Research | Injectable opioid partial agonist or opioid antagonist microparticle compositions and their use in reducing consumption of abused substances |
US6555127B2 (en) * | 2000-01-19 | 2003-04-29 | Pharmaceutical Discovery Corporation | Multi-spike release formulation for oral drug delivery |
US20030065008A1 (en) * | 2000-01-28 | 2003-04-03 | Endorecherche, Inc. | Selective estrogen receptor modulators in combination with estrogens |
US20020010127A1 (en) * | 2000-02-08 | 2002-01-24 | Benjamin Oshlack | Controlled-release compositions containing opioid agonist and antagonist |
US20030143269A1 (en) * | 2000-02-08 | 2003-07-31 | Benjamin Oshlack | Tamper-resistant oral opioid agonist formulations |
US20030163099A1 (en) * | 2000-08-15 | 2003-08-28 | Wermeling Daniel P | Programmable multi-dose intranasal drug delivery device |
US20030177975A1 (en) * | 2000-09-18 | 2003-09-25 | Akio Ikesue | Rare earth-iron garnet single crystal material and method for preparation thereof and device using rare earth-iron garnet single crystal material |
US20030065002A1 (en) * | 2001-05-11 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse-resistant controlled-release opioid dosage form |
US20030004177A1 (en) * | 2001-05-11 | 2003-01-02 | Endo Pharmaceuticals, Inc. | Abuse-resistant opioid dosage form |
US20030064122A1 (en) * | 2001-05-23 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse resistant pharmaceutical composition containing capsaicin |
US20030157167A1 (en) * | 2001-07-06 | 2003-08-21 | Endo Pharmaceuticals, Inc. | Oxymorphone controlled release formulations |
US20030129230A1 (en) * | 2001-07-06 | 2003-07-10 | Penwest Pharmaceuticals Company | Sustained release formulations of oxymorphone |
US20030069263A1 (en) * | 2001-07-18 | 2003-04-10 | Breder Christopher D. | Pharmaceutical combinations of oxycodone and naloxone |
US20030064099A1 (en) * | 2001-08-06 | 2003-04-03 | Benjamin Oshlack | Pharmaceutical formulation containing bittering agent |
US20030157168A1 (en) * | 2001-08-06 | 2003-08-21 | Christopher Breder | Sequestered antagonist formulations |
US20030044458A1 (en) * | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
US20030124185A1 (en) * | 2001-08-06 | 2003-07-03 | Benjamin Oshlack | Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent |
US20030068392A1 (en) * | 2001-08-06 | 2003-04-10 | Richard Sackler | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
US20030068375A1 (en) * | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
US20030073714A1 (en) * | 2001-08-06 | 2003-04-17 | Christopher Breder | Opioid agonist formulations with releasable and sequestered antagonist |
US20030068371A1 (en) * | 2001-08-06 | 2003-04-10 | Benjamin Oshlack | Pharmaceutical formulation containing opioid agonist,opioid antagonist and gelling agent |
US20030068370A1 (en) * | 2001-08-06 | 2003-04-10 | Richard Sackler | Pharmaceutical formulation containing irritant |
US20030049272A1 (en) * | 2001-08-30 | 2003-03-13 | Yatindra Joshi | Pharmaceutical composition which produces irritation |
US20030068276A1 (en) * | 2001-09-17 | 2003-04-10 | Lyn Hughes | Dosage forms |
US20030059397A1 (en) * | 2001-09-17 | 2003-03-27 | Lyn Hughes | Dosage forms |
US20030091635A1 (en) * | 2001-09-26 | 2003-05-15 | Baichwal Anand R. | Opioid formulations having reduced potential for abuse |
US20030125347A1 (en) * | 2001-11-02 | 2003-07-03 | Elan Corporation Plc | Pharmaceutical composition |
US20030158264A1 (en) * | 2002-02-20 | 2003-08-21 | Ramachandran Radhakrishnan | Orally administrable pharmaceutical formulation comprising ephedrine hydrochloride and process for preparing the same |
US20030124061A1 (en) * | 2003-01-10 | 2003-07-03 | Roberts Richard H. | Pharmaceutical safety dosage forms |
Cited By (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070237833A1 (en) * | 1993-11-23 | 2007-10-11 | Purdue Pharma L.P. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
US20100209514A1 (en) * | 1993-11-23 | 2010-08-19 | Sackler Richard S | Method of treating pain by administering 24 hour oral oploid formulations exhibiting rapid rate of initial rise of plasma drug level |
US20100209351A1 (en) * | 1993-11-23 | 2010-08-19 | Sackler Richard S | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
US20060269604A1 (en) * | 1993-11-23 | 2006-11-30 | Purdue Pharma L.P. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
US20080031963A1 (en) * | 1993-11-23 | 2008-02-07 | Purdue Pharma L.P. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
US20070237832A1 (en) * | 1993-11-23 | 2007-10-11 | Purdue Pharma L.P. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
US9820982B2 (en) | 2001-07-06 | 2017-11-21 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
US20070134328A1 (en) * | 2001-07-06 | 2007-06-14 | Endo Pharmaceuticals, Inc. | Oxymorphone controlled release formulations |
US20070098794A1 (en) * | 2001-07-06 | 2007-05-03 | Haui-Hung Kao | Oxymorphone controlled release formulations |
US20070098793A1 (en) * | 2001-07-06 | 2007-05-03 | Haui-Hung Kao | Oxymorphone controlled release formulations |
US20030157167A1 (en) * | 2001-07-06 | 2003-08-21 | Endo Pharmaceuticals, Inc. | Oxymorphone controlled release formulations |
US8329216B2 (en) | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
US8309122B2 (en) | 2001-07-06 | 2012-11-13 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
US20030129230A1 (en) * | 2001-07-06 | 2003-07-10 | Penwest Pharmaceuticals Company | Sustained release formulations of oxymorphone |
US20070140975A1 (en) * | 2001-09-26 | 2007-06-21 | Penwest Pharmaceuticals Co. | Opioid formulations having reduced potential for abuse |
US20030091635A1 (en) * | 2001-09-26 | 2003-05-15 | Baichwal Anand R. | Opioid formulations having reduced potential for abuse |
US20070212414A1 (en) * | 2006-03-08 | 2007-09-13 | Penwest Pharmaceuticals Co. | Ethanol-resistant sustained release formulations |
US9775811B2 (en) | 2006-08-25 | 2017-10-03 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9492393B2 (en) | 2006-08-25 | 2016-11-15 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US11964056B1 (en) | 2006-08-25 | 2024-04-23 | Purdue Pharma L.P | Tamper resistant dosage forms |
US11938225B2 (en) | 2006-08-25 | 2024-03-26 | Purdue Pharm L.P. | Tamper resistant dosage forms |
US20090081290A1 (en) * | 2006-08-25 | 2009-03-26 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US11904055B2 (en) | 2006-08-25 | 2024-02-20 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US11826472B2 (en) | 2006-08-25 | 2023-11-28 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US8815289B2 (en) | 2006-08-25 | 2014-08-26 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US8821929B2 (en) | 2006-08-25 | 2014-09-02 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US8834925B2 (en) | 2006-08-25 | 2014-09-16 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US8846086B2 (en) | 2006-08-25 | 2014-09-30 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US11304908B2 (en) | 2006-08-25 | 2022-04-19 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US8894987B2 (en) | 2006-08-25 | 2014-11-25 | William H. McKenna | Tamper resistant dosage forms |
US8894988B2 (en) | 2006-08-25 | 2014-11-25 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US8911719B2 (en) | 2006-08-25 | 2014-12-16 | Purdue Pharma Lp | Tamper resistant dosage forms |
US11304909B2 (en) | 2006-08-25 | 2022-04-19 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9084816B2 (en) | 2006-08-25 | 2015-07-21 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9095614B2 (en) | 2006-08-25 | 2015-08-04 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9095615B2 (en) | 2006-08-25 | 2015-08-04 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9101661B2 (en) | 2006-08-25 | 2015-08-11 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US11298322B2 (en) | 2006-08-25 | 2022-04-12 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US10076498B2 (en) | 2006-08-25 | 2018-09-18 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US10076499B2 (en) | 2006-08-25 | 2018-09-18 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9775808B2 (en) | 2006-08-25 | 2017-10-03 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9486413B2 (en) | 2006-08-25 | 2016-11-08 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9486412B2 (en) | 2006-08-25 | 2016-11-08 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9492390B2 (en) | 2006-08-25 | 2016-11-15 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9492389B2 (en) | 2006-08-25 | 2016-11-15 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9492392B2 (en) | 2006-08-25 | 2016-11-15 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9775810B2 (en) | 2006-08-25 | 2017-10-03 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9492391B2 (en) | 2006-08-25 | 2016-11-15 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9545380B2 (en) | 2006-08-25 | 2017-01-17 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9775812B2 (en) | 2006-08-25 | 2017-10-03 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9763933B2 (en) | 2006-08-25 | 2017-09-19 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9763886B2 (en) | 2006-08-25 | 2017-09-19 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9770417B2 (en) | 2006-08-25 | 2017-09-26 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9770416B2 (en) | 2006-08-25 | 2017-09-26 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US9775809B2 (en) | 2006-08-25 | 2017-10-03 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US20080146601A1 (en) * | 2006-12-14 | 2008-06-19 | Johnson Matthey Public Limited Company | Method for making analgesics |
US7851482B2 (en) | 2006-12-14 | 2010-12-14 | Johnson Matthey Public Limited Compnay | Method for making analgesics |
CN102391271B (zh) * | 2006-12-14 | 2015-12-09 | 约翰逊马西有限公司 | 生产镇痛药的改进方法 |
US11389443B2 (en) * | 2007-06-21 | 2022-07-19 | Endo Pharmaceuticals Inc. | Method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for renal impairment |
US20220313688A1 (en) * | 2007-06-21 | 2022-10-06 | Endo Pharmaceuticals Inc. | Method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for renal impairment |
US20090124650A1 (en) * | 2007-06-21 | 2009-05-14 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol |
US20100151027A1 (en) * | 2007-06-21 | 2010-06-17 | Endo Pharmaceuticals, Inc. | Method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for renal impairment |
US20180098985A1 (en) * | 2007-06-21 | 2018-04-12 | Endo Pharmaceuticals Inc. | Method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for renal impairment |
US20080318993A1 (en) * | 2007-06-21 | 2008-12-25 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instruction on Dosing for Hepatic Impairment |
US20080318994A1 (en) * | 2007-06-21 | 2008-12-25 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instruction on Dosing for Renal Impairment |
US8808737B2 (en) | 2007-06-21 | 2014-08-19 | Endo Pharmaceuticals Inc. | Method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for renal impairment |
US9789103B2 (en) * | 2007-06-21 | 2017-10-17 | Endo Pharmaceuticals Inc. | Method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for renal impairment |
US20140329847A1 (en) * | 2007-06-21 | 2014-11-06 | Endo Pharmaceuticals Inc. | Method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for renal impairment |
US9730885B2 (en) | 2012-07-12 | 2017-08-15 | Mallinckrodt Llc | Extended release, abuse deterrent pharmaceutical compositions |
US11096887B2 (en) | 2012-07-12 | 2021-08-24 | SpecGx LLC | Extended release, abuse deterrent pharmaceutical compositions |
US10485753B2 (en) | 2012-07-12 | 2019-11-26 | SpecGx LLC | Extended release, abuse deterrent pharmaceutical compositions |
US9120800B2 (en) | 2013-08-02 | 2015-09-01 | Johnson Matthey Public Limited Company | Process for the preparation of oxymorphone alkaloid and oxymorphone salts |
US9062063B1 (en) | 2014-03-21 | 2015-06-23 | Johnson Matthey Public Limited Company | Forms of oxymorphone hydrochloride |
WO2015143253A1 (en) | 2014-03-21 | 2015-09-24 | Johnson Matthey Public Limited Company | Crystalle forms of oxymorphone hydrochloride |
US9918979B2 (en) | 2015-01-29 | 2018-03-20 | Johnson Matthey Public Limited Company | Process of preparing low ABUK oxymorphone hydrochloride |
WO2016123202A1 (en) | 2015-01-29 | 2016-08-04 | Johnson Matthey Public Limited Company | Process of preparing low abuk oxymorphone hydrochloride |
Also Published As
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PL366430A1 (en) | 2005-01-24 |
ES2292775T3 (es) | 2008-03-16 |
US7276250B2 (en) | 2007-10-02 |
WO2003004033A1 (en) | 2003-01-16 |
NO20031019D0 (no) | 2003-03-05 |
PL208484B1 (pl) | 2011-05-31 |
NO326375B1 (no) | 2008-11-17 |
ATE376832T1 (de) | 2007-11-15 |
EP1404331B1 (de) | 2007-10-31 |
DE60223254T2 (de) | 2008-08-14 |
PL367277A1 (en) | 2005-02-21 |
US20030129230A1 (en) | 2003-07-10 |
US20080050431A1 (en) | 2008-02-28 |
DK1404331T3 (da) | 2008-01-28 |
PL207748B1 (pl) | 2011-01-31 |
HK1064921A1 (en) | 2005-02-08 |
EP1404332A1 (de) | 2004-04-07 |
NO20031019L (no) | 2003-05-05 |
WO2003004029A1 (en) | 2003-01-16 |
DE60223254D1 (de) | 2007-12-13 |
BR0210855A (pt) | 2006-10-24 |
BR0205722A (pt) | 2005-04-05 |
EP1404331A1 (de) | 2004-04-07 |
KR20030048026A (ko) | 2003-06-18 |
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