CA2273272C - Immediate release drug delivery forms - Google Patents
Immediate release drug delivery forms Download PDFInfo
- Publication number
- CA2273272C CA2273272C CA002273272A CA2273272A CA2273272C CA 2273272 C CA2273272 C CA 2273272C CA 002273272 A CA002273272 A CA 002273272A CA 2273272 A CA2273272 A CA 2273272A CA 2273272 C CA2273272 C CA 2273272C
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- Prior art keywords
- microparticles
- dosage unit
- ibuprofen
- poloxamer
- agents
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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]
Abstract
A drug delivery system processed via thermoform techniques, having rapid, active agent release properties that are useful in pharmaceutical dosage forms. The delivery system may be utilized as particle s that contain active agents and solubilizing agents and which are contained in a dosage form.
Description
IMMEDIATE RELEASE DRUG DE1'I11ERY FORMS
Field of the Invention The invention deals with an active agent delivery system that has rapid release properties for active agents that are not normally readily water-soluble;
methods of making the delivery system and products made therefrom. The fast release of the active agents from pharmaceutical dosage forms is achieved by thermoforming the active along with a solubilizing agent prior to forming the dosage form.
Background of the Invention Melt-blended formulations containing active agents and solubilizers are known in the art.
U. S. Patent 4,944,949 discloses dissolving, or co-melting non-steroidal anti-inflammatory drugs (NSAIDs) in melts of nonionic surfactants such as poloxamers (cot. 5, line 31) to form micelles. Micelles are aggregates in which surfactant molecules are arranged in a spheroidal structure, with the hydrophobic regions at the core and the hydrophilic regions at the other surfaces.
Drugaurfactant ratios of 1:5.7 to 1:50 are disclosed at column 12, line 57.
U. S. Patent 5,281,420 shows tebufelone, an anti-inflammatory agent, in solid dispersions containing 15% to 75°/a tebufelone, 25% to 65% of a poloxamer surfactant (col. 1, lines 35-51 ) and other ingredients.
U. S. Patent 5,525,355 deals with laxative compositions that contain poloxamer surtactants, as stool softeners, melt-blended with stimulants. The ratio of surfactant to stimulant is 2:1 to 20:1 (cola 2, line 22+). The compositions ate administered in hard gelatin capsules.
i wo ~nrr~ rc~rrt~s9snoa,~
EPO Application 0 317 780, published May 31, 1989, shows quick-release and sustained-release formulations containing dihydropyridine calcium channel blodcers, poloxamer surfactants and other ingredients. The quick release compositions contain 0.15:1 to 0.5:1 of the water-soluble cellulosic derivative hydroxypropylmethylcelluiose to a poloxamerldihydropyridine complex (p. 6, I.
49). The complex contains 1:1 to 1:10 ratios of drug to surfactant (page 6, lines 25-27).
W097/02017, published January 23, 1997, discusses oral dosage forms that contain a solid dispersion of an active ingredient in a poloxamer polymer formed by solvent dissolution and melt blending. The ratio of active agent to poloxamer is 0.1:1.0 to 10.0:1.0 (page 3, line 280.
U.S. 4,727,109 shows liquid preparations containing an active agent and a carrier system consisting of a hydrophilic component, a hydrophobic component and a solubilizer. The hydrophilic component may be a polyethylene glycol or a polyoxyethylene/polyoxypropyiene copolymer. See column 2, lines 35-44.
U.S. 5,458,923 describes solid dispersions of dnrgs in polymers made by extruding the two materials and pulverizing the extrudate.
Polyoxyethylene/polyoxypropylene copolymers are disclosed, at column 3, fines 33-4, for use with the polymers as plasticizers.
U.S. 5,292,481 deals with pellets produced by spraying an active agent with a wetting agent. Polyethylene glycols are disclosed as lubricants (col.
7,1.
82) and agents that influence the release of the active ingredient (col. 8, I.
1-2).
Poloxamers are recited as surface-active agents (col. 7,1. 65).
Summary of the Invention The present invention is a thermoformed drug delivery system useful in making dosage forms having improved dissolution and shorter T""~ for the drug consisting essentwally of ftom about 50% to about 80% of an undissolved solid particulate form of at least one active agent in infimate contact with from about 20% to about 50% of a polymeric solubilizing agent wherein the sold particulate active agent is generally soluble in a melt of the polymeric solubitizing agent.
Field of the Invention The invention deals with an active agent delivery system that has rapid release properties for active agents that are not normally readily water-soluble;
methods of making the delivery system and products made therefrom. The fast release of the active agents from pharmaceutical dosage forms is achieved by thermoforming the active along with a solubilizing agent prior to forming the dosage form.
Background of the Invention Melt-blended formulations containing active agents and solubilizers are known in the art.
U. S. Patent 4,944,949 discloses dissolving, or co-melting non-steroidal anti-inflammatory drugs (NSAIDs) in melts of nonionic surfactants such as poloxamers (cot. 5, line 31) to form micelles. Micelles are aggregates in which surfactant molecules are arranged in a spheroidal structure, with the hydrophobic regions at the core and the hydrophilic regions at the other surfaces.
Drugaurfactant ratios of 1:5.7 to 1:50 are disclosed at column 12, line 57.
U. S. Patent 5,281,420 shows tebufelone, an anti-inflammatory agent, in solid dispersions containing 15% to 75°/a tebufelone, 25% to 65% of a poloxamer surfactant (col. 1, lines 35-51 ) and other ingredients.
U. S. Patent 5,525,355 deals with laxative compositions that contain poloxamer surtactants, as stool softeners, melt-blended with stimulants. The ratio of surfactant to stimulant is 2:1 to 20:1 (cola 2, line 22+). The compositions ate administered in hard gelatin capsules.
i wo ~nrr~ rc~rrt~s9snoa,~
EPO Application 0 317 780, published May 31, 1989, shows quick-release and sustained-release formulations containing dihydropyridine calcium channel blodcers, poloxamer surfactants and other ingredients. The quick release compositions contain 0.15:1 to 0.5:1 of the water-soluble cellulosic derivative hydroxypropylmethylcelluiose to a poloxamerldihydropyridine complex (p. 6, I.
49). The complex contains 1:1 to 1:10 ratios of drug to surfactant (page 6, lines 25-27).
W097/02017, published January 23, 1997, discusses oral dosage forms that contain a solid dispersion of an active ingredient in a poloxamer polymer formed by solvent dissolution and melt blending. The ratio of active agent to poloxamer is 0.1:1.0 to 10.0:1.0 (page 3, line 280.
U.S. 4,727,109 shows liquid preparations containing an active agent and a carrier system consisting of a hydrophilic component, a hydrophobic component and a solubilizer. The hydrophilic component may be a polyethylene glycol or a polyoxyethylene/polyoxypropyiene copolymer. See column 2, lines 35-44.
U.S. 5,458,923 describes solid dispersions of dnrgs in polymers made by extruding the two materials and pulverizing the extrudate.
Polyoxyethylene/polyoxypropylene copolymers are disclosed, at column 3, fines 33-4, for use with the polymers as plasticizers.
U.S. 5,292,481 deals with pellets produced by spraying an active agent with a wetting agent. Polyethylene glycols are disclosed as lubricants (col.
7,1.
82) and agents that influence the release of the active ingredient (col. 8, I.
1-2).
Poloxamers are recited as surface-active agents (col. 7,1. 65).
Summary of the Invention The present invention is a thermoformed drug delivery system useful in making dosage forms having improved dissolution and shorter T""~ for the drug consisting essentwally of ftom about 50% to about 80% of an undissolved solid particulate form of at least one active agent in infimate contact with from about 20% to about 50% of a polymeric solubilizing agent wherein the sold particulate active agent is generally soluble in a melt of the polymeric solubitizing agent.
SUBSTITUTE SKEET ( rule Z6 ) Preferably the solubilizing agent is a diblock copolymer containing polyoxyethyiene and potyoxypropylene units. More preferably the solubilizing agent is Poloxamer 188.
The active agent of the drug delivery system can be any drug that could benefit from the improved release properfles of the present invention and which is normally soluble, or dissolvable in a melt of the polymeric solubilizer.
Preferably the drug is selected from the group consisting of Hrantagonists, non-narcotic analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), anti-cholesterolemics, anti-allergy agents, anti-migraine agents and combinations thereof. Most preferably the active agent is ibuprofen.
Detailed Description of the Invention Fast release dosage forms include those in which T~, or time to maximum plasma drug concentration for the delivered drug or drug delivery form, is shortened. By "shorter T",~" or ushortened T""~" applicants refer to enhanced absorption of active agents) at earlier time points than would be found using conventional forms of, or delivery vehicles for, the drug. The product of the invention can generally release at least 80% of the active agents) in about 5 minutes or less in the appropriate pH environment.
The invention can utilize any appropriate processing techniques to make the drug delivery material, including liquiflash and extrusion processes. The drug delivery material comprises solid particles of active agents) in intimate contact with, embedded in, or at least partially encapsulated or enveloped by a polymeric solubilizing agent or combinations thereof, a melt of which would normally solubilize, or dissohre the active. The inventive material may then be processed into particles which in tum can be processed into conventional capsules or tablets or other dosage forms, all of which will exhibit fast release properties of the active.
Oral dosage forms are typical.
One aspect of the invention is dir~ecbed to drug delivery products made by subjecting at least one active agent and a solubilizing agent to them~oform w processing to form a drug delivery system.
The active agent of the drug delivery system can be any drug that could benefit from the improved release properfles of the present invention and which is normally soluble, or dissolvable in a melt of the polymeric solubilizer.
Preferably the drug is selected from the group consisting of Hrantagonists, non-narcotic analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), anti-cholesterolemics, anti-allergy agents, anti-migraine agents and combinations thereof. Most preferably the active agent is ibuprofen.
Detailed Description of the Invention Fast release dosage forms include those in which T~, or time to maximum plasma drug concentration for the delivered drug or drug delivery form, is shortened. By "shorter T",~" or ushortened T""~" applicants refer to enhanced absorption of active agents) at earlier time points than would be found using conventional forms of, or delivery vehicles for, the drug. The product of the invention can generally release at least 80% of the active agents) in about 5 minutes or less in the appropriate pH environment.
The invention can utilize any appropriate processing techniques to make the drug delivery material, including liquiflash and extrusion processes. The drug delivery material comprises solid particles of active agents) in intimate contact with, embedded in, or at least partially encapsulated or enveloped by a polymeric solubilizing agent or combinations thereof, a melt of which would normally solubilize, or dissohre the active. The inventive material may then be processed into particles which in tum can be processed into conventional capsules or tablets or other dosage forms, all of which will exhibit fast release properties of the active.
Oral dosage forms are typical.
One aspect of the invention is dir~ecbed to drug delivery products made by subjecting at least one active agent and a solubilizing agent to them~oform w processing to form a drug delivery system.
SUBSTITUTE SHEET ( rule 26 ) *rB
By thermoform, thermoforming, or thermoform processing the applicants mean a process that exposes the active and the solubilizing agent to only sufficient amounts of heat, or other energy, such that the majority of active does not co-melt and mingle with the solubilizing agent, or dissolve in the solubilizing agent (melt-blend), or otherwise form a single phase with the solubilizing agent, when the solubilizing agent forms a liquid, or liquiflash phase. An important aspect of thermoform processing is the control of the tendency of the solubilizer and the active agent to combine into a single phase or dispersion during the heating process. In the thermoformed delivery system the solubilizing agent should at-least partially encapsulate; envelop or~ otherwise-be°in intimate contact with, solid particles of the active agent. Co-melts, or solid solutions of the active and solubilizing agents) are to be minimized and avoided as much as possible.
It is believed that such forms interfere with the rapid release properties of the present invention. Solid particles of the active which have recrystallized from a co-melt of the active and solubiliter are also to be minimized.
Liquiflash processing is one thermoform process that is known in the art and useful in the practice of this invention. Liquiflash processing is disclosed, for example, in U.S. Patent 5,683,720, issued November 4, 1997. U.S. Patents 5,445,769 and 5,458,823 disclose some devices that can be utilized to make the inventive thermoformed delivery products by means of liquiflash processing.
In addition to liquiflash processing, extrusion processes or other methods which will not co-melt (melt-blend) the solubilizer and the active agent to any significant degree can be utilized for the practice of the present invention.
Compositions that are useful in the invention are feedstocks that contain:
(a) about 50% to about 80% of solid particles of at least one active ingredient or agent; and (b) about 50% to about 20% of a solubilizing agent.
By thermoform, thermoforming, or thermoform processing the applicants mean a process that exposes the active and the solubilizing agent to only sufficient amounts of heat, or other energy, such that the majority of active does not co-melt and mingle with the solubilizing agent, or dissolve in the solubilizing agent (melt-blend), or otherwise form a single phase with the solubilizing agent, when the solubilizing agent forms a liquid, or liquiflash phase. An important aspect of thermoform processing is the control of the tendency of the solubilizer and the active agent to combine into a single phase or dispersion during the heating process. In the thermoformed delivery system the solubilizing agent should at-least partially encapsulate; envelop or~ otherwise-be°in intimate contact with, solid particles of the active agent. Co-melts, or solid solutions of the active and solubilizing agents) are to be minimized and avoided as much as possible.
It is believed that such forms interfere with the rapid release properties of the present invention. Solid particles of the active which have recrystallized from a co-melt of the active and solubiliter are also to be minimized.
Liquiflash processing is one thermoform process that is known in the art and useful in the practice of this invention. Liquiflash processing is disclosed, for example, in U.S. Patent 5,683,720, issued November 4, 1997. U.S. Patents 5,445,769 and 5,458,823 disclose some devices that can be utilized to make the inventive thermoformed delivery products by means of liquiflash processing.
In addition to liquiflash processing, extrusion processes or other methods which will not co-melt (melt-blend) the solubilizer and the active agent to any significant degree can be utilized for the practice of the present invention.
Compositions that are useful in the invention are feedstocks that contain:
(a) about 50% to about 80% of solid particles of at least one active ingredient or agent; and (b) about 50% to about 20% of a solubilizing agent.
The active ingredients useful herein can be selected from a large group of therapeutic agents. Mixtures and pharmaceutically acceptable salts of these agents may also be used.
Active agents that are sparingly soluble in biological fluids (e.g., water) are examples of solid active agents whose dissolution and release properties are particularly enhanced by the delivery system described herein. These agents include, analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs).
Analgesics include, for example, non-narcotic analgesics such as aspirin, acetaminophen, acetaminophen plus caffeine, NSAIDs.
Useful NSAIDs include ibuprofen; diclofenac and its alkali metal. salts;
fenoprofen and its metal salts; ketoprofen, naproxen and its alkali metal salts; and piroxicam and its salts.
Combinations of various types of drugs in addition to analgesics; as well as combinations of individual drugs, are contemplated. In particular, combinations containing non-narcotic analgesics and non-toxic antagonists for the N-methyl-D-aspartate receptor, e.g. a morphinan such as dextromethorphan or dextrorphan, or a nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation, such as a ganglioside are contemplated herein.
The solubilizing agents, or solubilizers, used herein are commercially available solubilizers such as generaNy solid diblock copolymers containing only polyoxyethyiene units and polyoxypropylene units. Poloxamers containing polyoxyethylene and polyoxypropylene block segments ate particularly useful, with those having about 60% to about 90%, and particularly those having about 70% to about 80%, polyoxyethylene units being notable. Suitable polymers are sold using "L.utrol," °Monolan" and "Pluronic" trade marks (BASF
manufacturer).
Poloxamer 188 (Pluronic F68) is especially effective. This diblock copolymer surfactant has an average molecular weight of about 7680 to 9510. See Handbook of Pharmaceutical Excipients (2nd Edition), 1994, pages 352-354.
Other useful "Pluronic" polymers include those designated as F87, F108, F127 and F237.
*Trade-mark 5 Another group of useful solubilizers is polyethylene glycol esters sold as "Gelucire" (Gattefosse). "Gelucire 50113" is a polyethylene glycol-32 glyceryl palmitostearate (HLB 13).
Solid particles fomned from the inventive delivery system may optionally be coated with one or more pharmaceutical coatings after their formation.
However, any coating should not significantly alter the fast release properties of the particles or dosage forms, e.g., tablets, in which they are used. Useful coatings include aesthetic coatings, taste-masking coatings, enteric coatings and others conventionally used in the pharmaceutical field. Coatings will be present in _~1 p amounts_.consistent with their functions-i.e. .in.suitable pham~aceutical amounts.
Suitable amounts and types of pharmaceutical excipients, e.g., fillers, flavors, flow control agents, lubricants, diluents and the like, such as shown below in Table 1, may be blended with particles of the delivery systems before or during the preparation of suitable dosage forms. Such excipients are not combined, however, with the feedstock material of the delivery system prior to the thermoform processes. The excipients or combinations thereof may separately be subjected to thermoform processing, but they are not processed in the presence of the active/solubiiizing agent delivery system feedstock.
Solid diluents are a typical excipient useful in the formation of typical dosage forms and are generally bulking agents. They are typically present in a weight concentration which is 112 to 2l3 of the concentration of the delivery system.
Useful solid diluents are microcrystalline cellulose products having particle sizes of about 20 micrometers (pm) to about 200 micrometers. The Avicel products, especially Avicel PH101 (FMC) are especially effective.
Disintegrants can be used to assist in the release of the active agent from the dosage form after the tablet has been ingested. Useful disintegrants include croscarmellose sodium, polyvinylpolypyrrolidone (PVPP), and sodium starch glycolate. Ac-Di-Sol, a croscarrnellase sodium product made by FMC, is also very useful, as is Kollidon CL-M, a micronized crospovidone. Mixtures are operable.
*Trade-mark One or more glidants such as starch, talc, lactose, stearates and colloidal silica can be used. Cab-o-sil M5, a brand ofi colloidal silica made by Cabot;
is very useful.
Lubricants are used in the tablet compositions, among them stearic acid, adipic acid, fatty acid esters, talc, magnesium stearate, mineral oil and the like and mixtures thereof. Stearic acid powder, such as that made by Sherex Chemical Co., is highly effective.
Other conventional pharmaceutical dosage form additives may be employed. Ingredients such as colorants, flavors, taste-masking agents, flow controi.agents,-perfumes and stabilizers can be included in minor amounts.
Table 1. Tablet Ingredients BROAD NARROW
INGREDIENT RANGE (%) RANGE (%) Active System 40-80 53-63 Solid Diluent 15-55 30 -~ 40 Disintegrant 0.5-10 2 - 4 Glidant 0.2 - 5 1 - 3 Lubricant 0,2 - 5 1 ~~ 3 Other Additives 0 - 10 0 - 5 Optionally, particles of the inventive delivery system may be coated, or encapsulated, with materials which alter such properties as stability, taste, appearance and the like, but not the rapid release properties. Such coatings typically contain one or more pharmaceutically acceptable polymers, e.g., cellulosics.
Thermoform processing, and liquiflash processing in particular preferably involves providing the ingredients with a particle size of about 2 to about microns, and preferably (for ibuprofen) about 5 microns. Grinding/milling may be *Trade-mark 7 necessary as preliminary steps to prepare the active. The particles of active and solubilizer are then blended and used as a feedstock for a suitable thermoforming device wherein heat and centrifugal pressure conditions are controlled to effect morphological changes in the feedstock.
Inside the liquiflash thermoform device, the solubilizer particles of the feedstock lose their resistance to liquid flow and become "liquiform." In this state, the material is physically transformed from its original solid state, through a "liquid"
state and back to a solid state instantaneously. During this process the particles are also acted upon by centrifugal force, or another shearing force, which force further adds to the "tiquiform" condition and causes the solubilizer portion of the feedstock to, at least partially, encapsulate the solid particle of active.
U. S. Patents 5,445,769 and 5,458,823 set out the details of the liquiflash and flash flow processing.
The invention will now be described by way of example.
Example I
Ibuprofen Delivery S~ st tem Three kilograms micronized ibuprofen (IBP) and two kilograms milled Poloxamer 188 were added to a Stephan mixer in the following order: (1 ) one-half of the solubilizer, (2) all of the IBP, (3) the remaining portion of the solubilizer.
The ingredients were mixed for about three minutes. This mixture was used as a feedstock, as follows:
The feedstock was fed to a 5-inch spinning head .
The head speed was increased to 60Hz while the heating elements were raised to a temperature that produced liquiflash conditions (about 60°C to 75°C).
The spinning head forced the material through its orifices and the product was permitted to free fall a distance of from six to eight feet below the head. It consists of globules containing 60:40 IBPaolubilizer.
wo ~nrmt rc~rms9sizou~s After solidifying thoroughly the delivery system material was milled using a No. 6 screen.
Once milled, the solid particles can be used as is, e.g., in a sachet, or powder, delivery system. Attemativeiy, they can be used in liquid, gel, tablet or capsule forms. Solid dosage forms are very effective. Optionally, one or more coatings, such as aesthetic coating(s), taste-masking coatings) or enteric coating(s), can be applied before the particles are used to deliver active agents to individuals.
F.~.am~le II
Ibuo e~D,'~ssolution Studies A. 40:60 IBPIPoloxamer Using a procedure similar to that of Example I, particles containing 40%
IBP that had not been previously micronized and 60% milled Poloxamer 188 were produced. These spheres were subjected to dissolution testing using USP
Method Il in phosphate buffer adjusted to pH 6.0 (37° C).
The particles demonstrated the following dissolution properties in the pH 6 medium:
PERCENT
MINUTES DISSOLVED
Active agents that are sparingly soluble in biological fluids (e.g., water) are examples of solid active agents whose dissolution and release properties are particularly enhanced by the delivery system described herein. These agents include, analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs).
Analgesics include, for example, non-narcotic analgesics such as aspirin, acetaminophen, acetaminophen plus caffeine, NSAIDs.
Useful NSAIDs include ibuprofen; diclofenac and its alkali metal. salts;
fenoprofen and its metal salts; ketoprofen, naproxen and its alkali metal salts; and piroxicam and its salts.
Combinations of various types of drugs in addition to analgesics; as well as combinations of individual drugs, are contemplated. In particular, combinations containing non-narcotic analgesics and non-toxic antagonists for the N-methyl-D-aspartate receptor, e.g. a morphinan such as dextromethorphan or dextrorphan, or a nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation, such as a ganglioside are contemplated herein.
The solubilizing agents, or solubilizers, used herein are commercially available solubilizers such as generaNy solid diblock copolymers containing only polyoxyethyiene units and polyoxypropylene units. Poloxamers containing polyoxyethylene and polyoxypropylene block segments ate particularly useful, with those having about 60% to about 90%, and particularly those having about 70% to about 80%, polyoxyethylene units being notable. Suitable polymers are sold using "L.utrol," °Monolan" and "Pluronic" trade marks (BASF
manufacturer).
Poloxamer 188 (Pluronic F68) is especially effective. This diblock copolymer surfactant has an average molecular weight of about 7680 to 9510. See Handbook of Pharmaceutical Excipients (2nd Edition), 1994, pages 352-354.
Other useful "Pluronic" polymers include those designated as F87, F108, F127 and F237.
*Trade-mark 5 Another group of useful solubilizers is polyethylene glycol esters sold as "Gelucire" (Gattefosse). "Gelucire 50113" is a polyethylene glycol-32 glyceryl palmitostearate (HLB 13).
Solid particles fomned from the inventive delivery system may optionally be coated with one or more pharmaceutical coatings after their formation.
However, any coating should not significantly alter the fast release properties of the particles or dosage forms, e.g., tablets, in which they are used. Useful coatings include aesthetic coatings, taste-masking coatings, enteric coatings and others conventionally used in the pharmaceutical field. Coatings will be present in _~1 p amounts_.consistent with their functions-i.e. .in.suitable pham~aceutical amounts.
Suitable amounts and types of pharmaceutical excipients, e.g., fillers, flavors, flow control agents, lubricants, diluents and the like, such as shown below in Table 1, may be blended with particles of the delivery systems before or during the preparation of suitable dosage forms. Such excipients are not combined, however, with the feedstock material of the delivery system prior to the thermoform processes. The excipients or combinations thereof may separately be subjected to thermoform processing, but they are not processed in the presence of the active/solubiiizing agent delivery system feedstock.
Solid diluents are a typical excipient useful in the formation of typical dosage forms and are generally bulking agents. They are typically present in a weight concentration which is 112 to 2l3 of the concentration of the delivery system.
Useful solid diluents are microcrystalline cellulose products having particle sizes of about 20 micrometers (pm) to about 200 micrometers. The Avicel products, especially Avicel PH101 (FMC) are especially effective.
Disintegrants can be used to assist in the release of the active agent from the dosage form after the tablet has been ingested. Useful disintegrants include croscarmellose sodium, polyvinylpolypyrrolidone (PVPP), and sodium starch glycolate. Ac-Di-Sol, a croscarrnellase sodium product made by FMC, is also very useful, as is Kollidon CL-M, a micronized crospovidone. Mixtures are operable.
*Trade-mark One or more glidants such as starch, talc, lactose, stearates and colloidal silica can be used. Cab-o-sil M5, a brand ofi colloidal silica made by Cabot;
is very useful.
Lubricants are used in the tablet compositions, among them stearic acid, adipic acid, fatty acid esters, talc, magnesium stearate, mineral oil and the like and mixtures thereof. Stearic acid powder, such as that made by Sherex Chemical Co., is highly effective.
Other conventional pharmaceutical dosage form additives may be employed. Ingredients such as colorants, flavors, taste-masking agents, flow controi.agents,-perfumes and stabilizers can be included in minor amounts.
Table 1. Tablet Ingredients BROAD NARROW
INGREDIENT RANGE (%) RANGE (%) Active System 40-80 53-63 Solid Diluent 15-55 30 -~ 40 Disintegrant 0.5-10 2 - 4 Glidant 0.2 - 5 1 - 3 Lubricant 0,2 - 5 1 ~~ 3 Other Additives 0 - 10 0 - 5 Optionally, particles of the inventive delivery system may be coated, or encapsulated, with materials which alter such properties as stability, taste, appearance and the like, but not the rapid release properties. Such coatings typically contain one or more pharmaceutically acceptable polymers, e.g., cellulosics.
Thermoform processing, and liquiflash processing in particular preferably involves providing the ingredients with a particle size of about 2 to about microns, and preferably (for ibuprofen) about 5 microns. Grinding/milling may be *Trade-mark 7 necessary as preliminary steps to prepare the active. The particles of active and solubilizer are then blended and used as a feedstock for a suitable thermoforming device wherein heat and centrifugal pressure conditions are controlled to effect morphological changes in the feedstock.
Inside the liquiflash thermoform device, the solubilizer particles of the feedstock lose their resistance to liquid flow and become "liquiform." In this state, the material is physically transformed from its original solid state, through a "liquid"
state and back to a solid state instantaneously. During this process the particles are also acted upon by centrifugal force, or another shearing force, which force further adds to the "tiquiform" condition and causes the solubilizer portion of the feedstock to, at least partially, encapsulate the solid particle of active.
U. S. Patents 5,445,769 and 5,458,823 set out the details of the liquiflash and flash flow processing.
The invention will now be described by way of example.
Example I
Ibuprofen Delivery S~ st tem Three kilograms micronized ibuprofen (IBP) and two kilograms milled Poloxamer 188 were added to a Stephan mixer in the following order: (1 ) one-half of the solubilizer, (2) all of the IBP, (3) the remaining portion of the solubilizer.
The ingredients were mixed for about three minutes. This mixture was used as a feedstock, as follows:
The feedstock was fed to a 5-inch spinning head .
The head speed was increased to 60Hz while the heating elements were raised to a temperature that produced liquiflash conditions (about 60°C to 75°C).
The spinning head forced the material through its orifices and the product was permitted to free fall a distance of from six to eight feet below the head. It consists of globules containing 60:40 IBPaolubilizer.
wo ~nrmt rc~rms9sizou~s After solidifying thoroughly the delivery system material was milled using a No. 6 screen.
Once milled, the solid particles can be used as is, e.g., in a sachet, or powder, delivery system. Attemativeiy, they can be used in liquid, gel, tablet or capsule forms. Solid dosage forms are very effective. Optionally, one or more coatings, such as aesthetic coating(s), taste-masking coatings) or enteric coating(s), can be applied before the particles are used to deliver active agents to individuals.
F.~.am~le II
Ibuo e~D,'~ssolution Studies A. 40:60 IBPIPoloxamer Using a procedure similar to that of Example I, particles containing 40%
IBP that had not been previously micronized and 60% milled Poloxamer 188 were produced. These spheres were subjected to dissolution testing using USP
Method Il in phosphate buffer adjusted to pH 6.0 (37° C).
The particles demonstrated the following dissolution properties in the pH 6 medium:
PERCENT
MINUTES DISSOLVED
SUBSTITUTE SHEET ( rule 26 ) wo ~nrm rcrius9snoa~s B. 50'50 IBPIPoloxamer.
Using the procedure of Example I, particles of 5096 micronixed IBP and 50°~ milled Poloxamer 188 were made.
Using the testing method described in A, above, dissolution studies were run in pH 8.0 medium. The properties were:
PERCENT
MINUTES DISSOLVED*
g0 101 *Ca~ulated values 10 Examcle III
Ihuorofen Particle Studies In bioavailability tests, particles of the inventive delivery system made in accordance with Example f gave faster times to maximum plasma concentration 15 (T"",~) than times obtained using a commercial IBP tablet (NUPRIN, Bristol-Myers Squibb Co.).
The tests were designed to determine IBP plasma concentrations at various points in time. Enhanced absorption of ibuprofen was seen at earlier time points, with individual subject plasma concentration time profiles given below.
20 T"~ was determined from the concentration data, and was found to be 1.10 hours for the particles and 1.38 hours for the commercial product.
SUBSTTTUTE SHEET ( rule 26 ) Ten healthy male volunteers took part in a single dose, randomized crossover study. Plasma samples were collected pre dose and at 0.25, 0.5, 0.75, 1, 1,25, 1, 5, 1,75, 2, 2.25, 2.5, 3, 4, 6, 8, 10 and 12 hours post-dose.
The following tables show individual subject plasma concentration-time profiles at early time points comparing the fast release delivery system and NUPRIN tablets.
A. NUPRIN B Particles of the Invention Subiect .Q~,."5 hours ~~hours a ' ct 0. h urs 0; 5 hour 1 0 15.4 1 10.4 14.5 2 0 7.31 2 9.24 13 3 0.418 7.31 3 7.64 11.5 4 3.53 9.88 4 5.82 9.28 5 8.74 22.2 5 8.65 14.5 8 0.250 2.34 6 6.09 11.8 7 2.73 5.63 7 6.15 11.8 8 0.29 4.43 8 0.914 6.2 9 3.65 8 9 10.3 20 10 1.78 10.8 10 16:7 19.9 Average 2.1397 9.33 Average 7.9904 13.248 SD 2.735264 5.787295 SD 4.113166 4.290661 el~.l~l Ibuprofen Tablets Tablets were prepared containing 58% of 60:40 ibuprofen:Pluronic F-68 particles; 35% Avicel PH101; 3% croscam~ellose sodium; 2% Cab-o-sil and 2%
Stearic acid. The ingredients were blended in a V-blender and compressed on a Killian T200 rotary tablet press using 8 x 18 mm caplet tooling. ' .
SUBSTITUTE SKEET ( rude 26 ) *rB
Example V
Ibuprofen Tablet Dissolution Studies 200mg ibuprofen tablets containing 60:40 ibuprofenaolubilizer rapid release particle were subjected to dissolution testing using USP Method II, (50 rpm), phosphate buffer (900 rnl, 3?°C) adjusted to pH 5.2. They had the following dissolution profile:
TIME PERCENT
(MINUTES) DISSOLVED
10 For comparison, a dissolution study was run on 200 mg tablets of ADV11l, a commercially available preparation of Whitehall Labs (American Home Products Corp.).
Each tablet is believed to contain: ibuprofen, acetylated monoglyceride, beeswax andlor camauba wax, croscarmellose sodium, iron oxides, lecithin, 15 methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, propylparaben, silicon dioxide, simethicone, sodium benzoate, sodium lauryl sulfate, starch, stearic acid, sucrose, and titanium dioxide. See page 828 of the Physician's Desk Reference for Non-prescription Druqs_, 19th ed. (1998).
Using the same conditions as above, the ADVIL tablets had the following 20 dissolution profile:
*Trade-mark wo ~n~~~ PCTNS98J20266 TIME PERCENT
(MINUTES) DISSOLVED
g0 58 Clearly, the delivery system material containing the ibuprofen in the tablets of the invention dissolved faster than the commercial formulation. Seventy-seven 5 percent (7?%) of the ibuprofen in the particles was dissolved in 5 minutes, compared to 23% dissolution of ADVIL in the same time period.
Example Vf Ilbunrofen Delivery SVStem A 60:40 weight ratio mixture of micronized ibuprofen and Pluronic~ F68 was extruded in a MPV 2015,15 mm twin screw co-rotating Baker Perkins extruder.
During the initial phase of processing, only the Pluronic~ F68 surfactant was fed into the extruder. All four (4) temperature zones, namely bam3l, die, and zone 2 and 3, were set at 73° C. One a smooth extrudate flow was ensured, the 80:40 mixture was fed into the extruder. At this point the temperatures of the various zones were lowered to about 55° C. As the extrusion process continued, samples of the extrudate were collected on Teflon~ coated flat trays at various time intervals from the start of the run. During this time the processing temperatures were dropped from about 55° C to about 42° C.
The extrusion process was run at an average rotational speed of about 31 - _ _ rpm.
SUBSTITUTE SHEET ( rude 26 ) WO 99/17744 PCTlUS98/20266 After completion of these runs, another set of runs was carried out with the same mix but extruded at the higher temperature of 80° C. The processing run con5nued for approximately 15 minutes during which three (3) sample were collected.
The samples collected were misled in a Braun coffiee grinder and sieved through a 40 mesh sieve. These saved samples were then subjected to dissolution toting using USP Method II in phosphate buffer adjusted to pH 5.2 (37° C). The percent dissolution of ibuprofen was measured at 5 minutes and the data summarized as follows:
Reasonab~ variations, such as those that would ocxur to a skilled artisan, can be made herein without departing from the scope of the invention.
SUBSTITUTE SHEET ( rule 26 )
Using the procedure of Example I, particles of 5096 micronixed IBP and 50°~ milled Poloxamer 188 were made.
Using the testing method described in A, above, dissolution studies were run in pH 8.0 medium. The properties were:
PERCENT
MINUTES DISSOLVED*
g0 101 *Ca~ulated values 10 Examcle III
Ihuorofen Particle Studies In bioavailability tests, particles of the inventive delivery system made in accordance with Example f gave faster times to maximum plasma concentration 15 (T"",~) than times obtained using a commercial IBP tablet (NUPRIN, Bristol-Myers Squibb Co.).
The tests were designed to determine IBP plasma concentrations at various points in time. Enhanced absorption of ibuprofen was seen at earlier time points, with individual subject plasma concentration time profiles given below.
20 T"~ was determined from the concentration data, and was found to be 1.10 hours for the particles and 1.38 hours for the commercial product.
SUBSTTTUTE SHEET ( rule 26 ) Ten healthy male volunteers took part in a single dose, randomized crossover study. Plasma samples were collected pre dose and at 0.25, 0.5, 0.75, 1, 1,25, 1, 5, 1,75, 2, 2.25, 2.5, 3, 4, 6, 8, 10 and 12 hours post-dose.
The following tables show individual subject plasma concentration-time profiles at early time points comparing the fast release delivery system and NUPRIN tablets.
A. NUPRIN B Particles of the Invention Subiect .Q~,."5 hours ~~hours a ' ct 0. h urs 0; 5 hour 1 0 15.4 1 10.4 14.5 2 0 7.31 2 9.24 13 3 0.418 7.31 3 7.64 11.5 4 3.53 9.88 4 5.82 9.28 5 8.74 22.2 5 8.65 14.5 8 0.250 2.34 6 6.09 11.8 7 2.73 5.63 7 6.15 11.8 8 0.29 4.43 8 0.914 6.2 9 3.65 8 9 10.3 20 10 1.78 10.8 10 16:7 19.9 Average 2.1397 9.33 Average 7.9904 13.248 SD 2.735264 5.787295 SD 4.113166 4.290661 el~.l~l Ibuprofen Tablets Tablets were prepared containing 58% of 60:40 ibuprofen:Pluronic F-68 particles; 35% Avicel PH101; 3% croscam~ellose sodium; 2% Cab-o-sil and 2%
Stearic acid. The ingredients were blended in a V-blender and compressed on a Killian T200 rotary tablet press using 8 x 18 mm caplet tooling. ' .
SUBSTITUTE SKEET ( rude 26 ) *rB
Example V
Ibuprofen Tablet Dissolution Studies 200mg ibuprofen tablets containing 60:40 ibuprofenaolubilizer rapid release particle were subjected to dissolution testing using USP Method II, (50 rpm), phosphate buffer (900 rnl, 3?°C) adjusted to pH 5.2. They had the following dissolution profile:
TIME PERCENT
(MINUTES) DISSOLVED
10 For comparison, a dissolution study was run on 200 mg tablets of ADV11l, a commercially available preparation of Whitehall Labs (American Home Products Corp.).
Each tablet is believed to contain: ibuprofen, acetylated monoglyceride, beeswax andlor camauba wax, croscarmellose sodium, iron oxides, lecithin, 15 methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, propylparaben, silicon dioxide, simethicone, sodium benzoate, sodium lauryl sulfate, starch, stearic acid, sucrose, and titanium dioxide. See page 828 of the Physician's Desk Reference for Non-prescription Druqs_, 19th ed. (1998).
Using the same conditions as above, the ADVIL tablets had the following 20 dissolution profile:
*Trade-mark wo ~n~~~ PCTNS98J20266 TIME PERCENT
(MINUTES) DISSOLVED
g0 58 Clearly, the delivery system material containing the ibuprofen in the tablets of the invention dissolved faster than the commercial formulation. Seventy-seven 5 percent (7?%) of the ibuprofen in the particles was dissolved in 5 minutes, compared to 23% dissolution of ADVIL in the same time period.
Example Vf Ilbunrofen Delivery SVStem A 60:40 weight ratio mixture of micronized ibuprofen and Pluronic~ F68 was extruded in a MPV 2015,15 mm twin screw co-rotating Baker Perkins extruder.
During the initial phase of processing, only the Pluronic~ F68 surfactant was fed into the extruder. All four (4) temperature zones, namely bam3l, die, and zone 2 and 3, were set at 73° C. One a smooth extrudate flow was ensured, the 80:40 mixture was fed into the extruder. At this point the temperatures of the various zones were lowered to about 55° C. As the extrusion process continued, samples of the extrudate were collected on Teflon~ coated flat trays at various time intervals from the start of the run. During this time the processing temperatures were dropped from about 55° C to about 42° C.
The extrusion process was run at an average rotational speed of about 31 - _ _ rpm.
SUBSTITUTE SHEET ( rude 26 ) WO 99/17744 PCTlUS98/20266 After completion of these runs, another set of runs was carried out with the same mix but extruded at the higher temperature of 80° C. The processing run con5nued for approximately 15 minutes during which three (3) sample were collected.
The samples collected were misled in a Braun coffiee grinder and sieved through a 40 mesh sieve. These saved samples were then subjected to dissolution toting using USP Method II in phosphate buffer adjusted to pH 5.2 (37° C). The percent dissolution of ibuprofen was measured at 5 minutes and the data summarized as follows:
Reasonab~ variations, such as those that would ocxur to a skilled artisan, can be made herein without departing from the scope of the invention.
SUBSTITUTE SHEET ( rule 26 )
Claims (18)
1. Microparticles useful in making dosage forms having improved dissolution and shorter time to maximum plasma concentration consisting essentially of:
(a) 50% to 80% of one or more analgesic agents, in an undissolved solid particulate form, and (b) 50% to 20% of one or more polymeric solubilizing agents, wherein the ingredient (b) is at least one diblock copolymer containing polyoxyethylene and polyoxypropylene units; the ingredients (a) and (b) are in intimate contact with each other; and the ingredient (a) is generally soluble in a melt of the ingredient (b).
(a) 50% to 80% of one or more analgesic agents, in an undissolved solid particulate form, and (b) 50% to 20% of one or more polymeric solubilizing agents, wherein the ingredient (b) is at least one diblock copolymer containing polyoxyethylene and polyoxypropylene units; the ingredients (a) and (b) are in intimate contact with each other; and the ingredient (a) is generally soluble in a melt of the ingredient (b).
2. The microparticles of claim 1, wherein the analgesic is ibuprofen.
3. The microparticles of claim 2, wherein the ratio of (a) to (b) is 40:60.
4. The microparticles of claim 2, wherein the ratio of (a) to (b) is 50:50.
5. The microparticles of claim 2, wherein the ratio of (a) to (b) is 60:40.
6. A dosage unit comprising the microparticles of claim 1, and one or more pharmaceutically acceptable excipients.
7. The dosage unit of claim 6, wherein the one or more analgesic agents is ibuprofen.
8. The dosage unit of claim 7, wherein the active agent therein is released in 5 minutes or less.
9. The dosage unit of claim 6, which is a rapidly dissolving tablet or capsule.
10. The dosage unit of claim 9, which is a tablet containing ibuprofen and a solublilizer wherein the ratio of ibuprofen to solubilizer is 60:40.
11. The microparticles of claim 1, made by way of liquiflash processing.
12. The microparticles of claim 2, made by way of liquiflash processing.
13. The dosage unit of claim 6, wherein the microparticles are made by way of liquiflash processing.
14. The dosage unit of claim 7, wherein the microparticles are made by way of liquiflash processing.
15. The microparticles of claim 1, wherein the at least one diblock copolymer contains from 60% to 90%
polyoxyethylene units.
polyoxyethylene units.
16. The microparticles of claim 1, wherein the at least one diblock copolymer contains from 70% to 80%
polyoxyethylene units.
polyoxyethylene units.
17. The microparticles of claim 1, wherein at least one of the diblock copolymers is polaxamer 188 (Pluronic*
F68).
*Trade-mark
F68).
*Trade-mark
18. ~The particles of claim 1, wherein one or more of the diblock copolymers is chosen from the group consisting of poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/946,070 | 1997-10-07 | ||
| US08/946,070 US6013280A (en) | 1997-10-07 | 1997-10-07 | Immediate release dosage forms containing microspheres |
| US12916498A | 1998-08-05 | 1998-08-05 | |
| US09/129,164 | 1998-08-05 | ||
| PCT/US1998/020266 WO1999017744A1 (en) | 1997-10-07 | 1998-09-28 | Immediate release drug delivery forms |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2273272A1 CA2273272A1 (en) | 1999-04-15 |
| CA2273272C true CA2273272C (en) | 2004-09-21 |
Family
ID=26827301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002273272A Expired - Fee Related CA2273272C (en) | 1997-10-07 | 1998-09-28 | Immediate release drug delivery forms |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0966269A1 (en) |
| JP (1) | JP2000507991A (en) |
| KR (1) | KR20000069356A (en) |
| AU (1) | AU9587198A (en) |
| BR (1) | BR9806303A (en) |
| CA (1) | CA2273272C (en) |
| WO (1) | WO1999017744A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0182801B1 (en) * | 1991-04-16 | 1999-05-01 | 아만 히데아키 | Method of manufacturing solid dispersion |
| WO2000024380A1 (en) * | 1998-10-27 | 2000-05-04 | Fuisz Technologies Ltd. | Microparticles containing peg and/or peg glyceryl esters |
| IE981008A1 (en) * | 1998-12-02 | 2000-06-14 | Fuisz Internat Ltd | Microparticles Containing Water Insoluble Active Agents |
| AP2002002552A0 (en) | 1999-12-23 | 2002-06-30 | Pfizer Prod Inc | Pharmaceutical compositions providing enhanced drug concentrations. |
| US8980870B2 (en) * | 2002-09-24 | 2015-03-17 | Boehringer Ingelheim International Gmbh | Solid telmisartan pharmaceutical formulations |
| US9149433B2 (en) * | 2004-11-30 | 2015-10-06 | Basf Corporation | Method for formation of micro-prilled polymers |
| EP1897543A1 (en) | 2006-08-30 | 2008-03-12 | Euro-Celtique S.A. | Buprenorphine- wafer for drug substitution therapy |
| US8475832B2 (en) | 2009-08-07 | 2013-07-02 | Rb Pharmaceuticals Limited | Sublingual and buccal film compositions |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1388786A (en) * | 1972-04-03 | 1975-03-26 | Scherer Corp R P | Integral solid gel-lattice dosage form of high-moisture content |
| DE3927113C2 (en) * | 1989-08-17 | 1993-11-25 | Dolorgiet Gmbh & Co Kg | Agent for the treatment of severe pain conditions and process for their preparation |
| CA2095776C (en) * | 1992-05-12 | 2007-07-10 | Richard C. Fuisz | Rapidly dispersable compositions containing polydextrose |
| DK0644755T3 (en) * | 1992-06-10 | 1997-09-22 | Nanosystems Llc | Surface Modified NSAID Nanoparticles |
| US5683720A (en) * | 1994-10-28 | 1997-11-04 | Fuisz Technologies Ltd. | Liquiflash particles and method of making same |
| IE80467B1 (en) * | 1995-07-03 | 1998-07-29 | Elan Corp Plc | Controlled release formulations for poorly soluble drugs |
| CA2231050A1 (en) * | 1995-09-07 | 1997-03-13 | Biovail International Ltd. | System for rendering substantially non-dissoluble bio-affecting agents bio-available |
-
1998
- 1998-09-28 WO PCT/US1998/020266 patent/WO1999017744A1/en not_active Application Discontinuation
- 1998-09-28 JP JP11521930A patent/JP2000507991A/en active Pending
- 1998-09-28 EP EP98949575A patent/EP0966269A1/en not_active Withdrawn
- 1998-09-28 BR BR9806303-0A patent/BR9806303A/en not_active Application Discontinuation
- 1998-09-28 CA CA002273272A patent/CA2273272C/en not_active Expired - Fee Related
- 1998-09-28 KR KR1019997005064A patent/KR20000069356A/en not_active Application Discontinuation
- 1998-09-28 AU AU95871/98A patent/AU9587198A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000507991A (en) | 2000-06-27 |
| CA2273272A1 (en) | 1999-04-15 |
| KR20000069356A (en) | 2000-11-25 |
| EP0966269A1 (en) | 1999-12-29 |
| AU9587198A (en) | 1999-04-27 |
| WO1999017744A1 (en) | 1999-04-15 |
| BR9806303A (en) | 2000-03-14 |
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| EEER | Examination request | ||
| MKLA | Lapsed |