US20080274177A1 - Controlled release dosage forms - Google Patents

Controlled release dosage forms Download PDF

Info

Publication number
US20080274177A1
US20080274177A1 US12/169,852 US16985208A US2008274177A1 US 20080274177 A1 US20080274177 A1 US 20080274177A1 US 16985208 A US16985208 A US 16985208A US 2008274177 A1 US2008274177 A1 US 2008274177A1
Authority
US
United States
Prior art keywords
controlled release
dosage form
oral dosage
release oral
weight
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
Application number
US12/169,852
Inventor
Fang Zhou
Paul Maes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Valeant International (Barbados) Srl
Original Assignee
Biovail Laboratories International Srl
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
Priority to US35785102P priority Critical
Priority to US10/370,109 priority patent/US7780987B2/en
Priority to US12/169,852 priority patent/US20080274177A1/en
Application filed by Biovail Laboratories International Srl filed Critical Biovail Laboratories International Srl
Publication of US20080274177A1 publication Critical patent/US20080274177A1/en
Assigned to J.P. MORGAN CHASE BANK, N.A., TORONTO BRANCH, AS ADMINISTRATIVE AGENT reassignment J.P. MORGAN CHASE BANK, N.A., TORONTO BRANCH, AS ADMINISTRATIVE AGENT PATENT AND TRADEMARK SECURITY AGREEMENT Assignors: BIOVAIL LABORATORIES INTERNATIONAL SRL
Assigned to GOLDMAN SACHS LENDING PARTNERS LLC, AS COLLATERAL AGENT reassignment GOLDMAN SACHS LENDING PARTNERS LLC, AS COLLATERAL AGENT SECURITY AGREEMENT Assignors: BIOVAIL INTERNATIONAL LABORATORIES (BARBADOS) SRL, BIOVAIL INTERNATIONAL LABORATORIES SRL
Assigned to BIOVAIL CORPORATION, BIOVAIL LABORATORIES INTERNATIONAL SRL reassignment BIOVAIL CORPORATION RELEASE OF SECURITY AGREEMENT Assignors: JPMORGAN CHASE BANK, N.A., TORONTO BRANCH
Assigned to BIOVAIL INTERNATIONAL LABORATORIES (BARBADOS) SRL, BIOVAIL INTERNATIONAL LABORATORIES SRL reassignment BIOVAIL INTERNATIONAL LABORATORIES (BARBADOS) SRL PATENT SECURITY RELEASE AGREEMENT Assignors: GOLDMAN SACHS LENDING PARTNERS LLC
Assigned to VALEANT INTERNATIONAL (BARBADOS) SRL reassignment VALEANT INTERNATIONAL (BARBADOS) SRL CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: BIOVAIL LABORATORIES INTERNATIONAL SRL
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27765948&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20080274177(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Assigned to GOLDMAN SACHS LENDING PARTNERS LLC, AS COLLATERAL AGENT reassignment GOLDMAN SACHS LENDING PARTNERS LLC, AS COLLATERAL AGENT SECURITY AGREEMENT Assignors: BIOVALE LABORATORIES INTERNATIONAL (BARBADOS) SRL, A BARBADOS INTERNATIONAL SOCIETY WITH RESTRICTED LIABILITY, VALEANT INTERNATIONAL (BARBADOS) SRL, A BARBADOS INTERNATIONAL SOCIETY WITH RESTRICTED LIABILITY
Assigned to VALEANT INTERNATIONAL BERMUDA reassignment VALEANT INTERNATIONAL BERMUDA CHANGE IN NAME AND COUNTRY OF INCORPORATION Assignors: VALEANT INTERNATIONAL (BARBADOS) SRL
Assigned to BARCLAYS BANK PLC, AS SUCCESSOR AGENT reassignment BARCLAYS BANK PLC, AS SUCCESSOR AGENT NOTICE OF SUCCESSION OF AGENCY Assignors: GOLDMAN SACHS LENDING PARTNERS, LLC
Application status is Abandoned legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846Poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/155Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/2853Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

The invention provides stable controlled release monolithic coating compositions for use in coating pharmaceutical oral dosage forms comprising a polyglycol having a melting point greater than 55° C. and an aqueous dispersion of a neutral ester copolymer lacking functional groups.

Description

    RELATED APPLICATIONS
  • This application claims priority from U.S. provisional patent application No. 60/357,851 filed Feb. 21, 2002.
  • FIELD OF THE INVENTION
  • This invention relates to a novel monolithic film coating for obtaining controlled release of drugs from oral dosage forms.
  • BACKGROUND
  • The manner in which chemicals or drugs are administered has gained increasing attention in the past two decades. Normally, a chemical is administered in a high dose at a given time only to have to repeat that dose several hours or days later. This is not economical and sometimes results in damaging side effects. As a consequence, increasing attention has been focused on methods of giving drugs continually for prolonged time periods and in a controlled fashion. Controlled or sustained release dosage forms provide a therapeutic dose of the drug soon after administration, and then gradually release the drug over an extended period of time. The primary method of accomplishing this controlled release has been through incorporating the drugs within polymers or to surround or encapsulate a core comprising the drug with a polymer coat. Depending on the type and amount of drug, as well as the type and amount of polymer and other pharmaceutically acceptable excipients the desired controlled release profile can be obtained.
  • The majority of polymers used to develop coatings for controlled release dosage forms are hydrophobic and can be applied either dry, from a solution, or suspension. As most of these polymers are poorly soluble in water, they are usually applied by dissolving the polymer in an organic solvent and then sprayed onto the drug core and evaporating off the solvent. The use of organic solvents, however, is considered problematic for several reasons. The most obvious reason relates to the safety hazards associated with the use of organic solvents. Organic solvents in general are highly flammable and carcinogenic. Further, organic solvents are expensive and the storage, disposal and use of organic solvents raise environmental concerns. Accordingly, it would be desirable to prepare aqueous suspensions or solutions of controlled release coatings comprising hydrophobic polymers suitable for coating a wide variety of drug cores.
  • Eudragit® NE30D, which contains 30% solids, is one of the first aqueous polymeric dispersions used for coating pharmaceutical dosage forms. Eudragit® NE30D has many advantages over other polymers for use as a film former for obtaining a controlled release drug profile and is thus ideally suited for controlled or sustained release drug formulations. The polymer forms a soft, flexible film at room temperature without any plasticizer. Also, no reactions or absorptive effects are observed when the polymer comes in direct contact with a therapeutically active agent. It is prepared by emulsion polymerization and consists of neutral copolymers of ethyl acrylate-methyl methacylate esters that are insoluble over the entire physiological pH range but will still swell in water and give permeable membranes. The permeability is independent of pH and is thus suitable for the development of pH-independent modified-release oral dosage forms, provided that the solubility of the drug is also pH-independent.
  • One of the most significant differences between aqueous polymeric solutions and dispersions is the role water plays during film formation. In solutions, water is a solvent and drying is accompanied by an excessive increase in viscosity, which in turn suppresses the rate of evaporation. Excess energy is therefore required to drive off the water. In contrast, in polymeric dispersions such as Eudragit® NE30D, water is only a dispersion medium and does not solvate the polymers. Consequently, less heat is needed to evaporate the water. Fast water evaporation coupled with the high solids content of the dispersion significantly reduces processing time. These properties are especially critical when dealing with highly water-soluble or moisture sensitive therapeutically active agents.
  • The pigment binding capacity of Eudragit® NE30D is very high, so that up to ˜2-3 parts by weight of additives can be incorporated into 1 part by weight of dry polymer without affecting the film properties. The polymer is also compatible with a wide variety of pharmaceutical excipients.
  • Plasticizers are generally added to coating formulations to modify the physical properties i.e., the glass transition temperature (Tg) of the polymer to make it more usable. The Tg is the temperature at which an amorphous polymer (or the amorphous regions in a partially crystalline polymer) changes from a hard and relatively brittle condition to a viscous or rubbery condition. Plasticizers function by decreasing the Tg of the polymer so that under ambient conditions the films are softer, more pliable and often stronger, and thus better able to resist mechanical stress. Eudragit® NE30D, however, has a low Tg and accordingly does not require the use of plasticizers. In fact, addition of plasticizers can be detrimental as it can increase the viscosity of the Eudragit® NE30D formulation and negate one of the distinct advantages of the dispersion over the polymeric solution. Incorporation of plasticizers into Eudragit® NE30D formulations can also increase the tackiness of the coat and complicate the coating process (Ghebre-Sellassie and Nesbit. Application of Eudragit E30D in Controlled-Release Coatings in Aqueous Polymeric Coatings for Pharmaceutical Forms, J. McGinity Ed., 1989, Marcel Dekker, Inc., pp 247-266).
  • Due to its low Tg, Eudragit® NE30D is sensitive to excessive drying conditions or exposure to high temperatures. Ghebre-Sellassie and Nesbit (Application of Eudragit E30D in Controlled-Release Coatings in Aqueous Polymeric Coatings for Pharmaceutical Forms, J. McGinity Ed., 1989, Marcel Dekker, Inc., pp 247-266) state that excessive drying of Eudragit® NE30D coats can be detrimental as such conditions do not allow the coating formulation to spread out evenly and promote particle deformation and coalescence. Also, during the coating process, the product temperature should be kept at around 26° C. If the product temperature is very high, the coating material becomes tacky owing to the low Tg of Eudragit® NE30D, which leads to agglomeration of the coated product. Ghebre-Sellassie and Nesbit also emphasize that Eudragit® NE30D coated products should not be stored at temperatures above 40° C., as stability tests conducted at elevated temperatures may not correlate with the long-term behavior of Eudragit® NE30D coated products at room temperature.
  • Attempts have been made in the prior art to design microporous aqueous polymer coatings suitable for use on drug cores to obtain controlled or sustained release profiles using the Eudragits, and in particular Eudragit® NE30D. U.S. Pat. No. 5,529,791 for example, teaches controlled release dosage forms of Diltiazem in which the Diltiazem drug core is surrounded by a water-soluble and/or dispersible film forming polymer or copolymer constituting the microporous membrane. The polymers or copolymers taught include the polyacrylates and polymethacrylates of the Eudragit type, such as Eudragit NE30D, L30D, and RS30 D, ethylcelluloses, hydroxypropyl cellulose and hydroxypropylmethylcellulose and their derivatives. In addition to the polymer or copolymer, the microporous membrane contains, preferably, talc and/or magnesium stearate as a lubricant, polyvinylpyrrolidone as a plasticizer, titanium dioxide as a pigment, Tween 80 as an emulsifier, and silicone oil as an antifoaming agent. Other plasticizers taught include triacetin, dibutylpthalate, dibutylsebacate, citric acid esters, polyethyleneglycols, and polypropyleneglycols. The Eudragit® NE30D coated beads were cured for 16 hours at 50° C. (Example 3) or for 15 hours at 45° C., 5-10° C. beyond the recommended temperature for Eudragit® NE30D. Further, long-term stabilization data was not presented for the coated products, and accordingly, it is not known what effect the elevated temperature had, if any, on the stability of the controlled release dosage form of Diltiazem.
  • U.S. Pat. No. 5,286,493 is directed to stabilized controlled release formulations having an aqueous acrylic polymer coating. The '493 patent also teaches the use of controlled release coatings covering a solid dosage form. The coating is derived from aqueous dispersions of an acrylic resin, which provides a substantially stable release pattern of a drug from the dosage form. The acrylic resins taught are the ammonio methacrylate co-polymers as for example Eudragit® RL30D, RS30D and combinations thereof. The acrylic coatings include an effective amount of a suitable plasticizing agent. The stable Eudragit® RL30D and/or RS30D coated products are cured at temperatures above the Tg of the acrylic polymers. The '493 patent does not teach the use of Eudragit® NE30D.
  • U.S. Pat. No. 5,478,573 teaches delayed, sustained-release propranolol pharmaceutical preparations purportedly achieved by surrounding a water-soluble drug core with a hydratable diffusion barrier which delays drug release by for about 2-10 hours. The hydratable diffusion barrier is said to comprise a film-forming polymer such as acrylic resin or ethyl cellulose or mixtures thereof and an additive which con trolls the rate of hydration and permeability of the diffusion barrier. The preferred insoluble film-forming polymers are aqueous dispersions of fully esterified acrylic resins such as Eudragit® NE30D. The additives controlling the rate of hydration and permeability of the diffusion barrier are preferably selected from the group consisting of fully esterified acryclic resins containing quaternary amine side chains, anionic surfactants, lubricants, plasticizers, inert water soluble materials and mixtures thereof. The '573 patent teaches that the drug beads coated with the aqueous polymeric dispersion are dried at 35° C. to 60° C. for 8 hours to 5 days. No data is presented on the long-term stability of the products.
  • Another controlled release pharmaceutical dosage form using an aqueous acrylic polymer dispersion is taught in U.S. Pat. No. 5,871,776. The controlled release profile is obtained, however, using multiple layers of films. The outermost layer is comprised of the aqueous acrylic polymer dispersion. The preferred acrylic polymer is Eudragit® NE30D. The coatings may also contain other pharmaceutically acceptable excipients such as fillers, anti-adherents, pharmaceutically acceptable pigments and lubricants/glidants. The coated drug pellets are cured at a temperature in the range of from about 30° C. to about 50° C., preferably from about 35° C. to about 45° C. and most preferably about 40° C. for a period of about 5 to about 10 days, an preferably about 7 days. The inventors surprisingly found that in contrast to the preferred short curing times taught in the prior art, long curing times help stabilize the release of the drug from the coated pellets after long storage periods.
  • International Patent Publication No. WO 02/058677 describes a film coating composition comprising an aqueous acrylic polymer dispersion, a surfactant, and sodium stearyl fumarate. The acrylic polymer dispersion is preferably Eudragit® NE30D. There does not appear to be any teaching as to the curing temperature and furthermore no data is presented with regard to long-term stability of the coated product.
  • In summary, it would seem that although the prior art teaches the use of aqueous acrylic dispersion coatings of Eudragit® NE30D, in most part, the prior art does not seem to have overcome long term stability problems of products coated with aqueous Eudragit® NE30D dispersions. Where the products have been found to be stable, the length of curing is very long and this is inefficient to the manufacturing process and also raises problems with storage of scale-up product. Accordingly, and given the advantages and versatility of Eudragit® NE30D, it would desirable that a stable controlled or sustained release coat be developed with short curing times to enhance process times. It is therefore an object of this invention to develop such a product.
  • SUMMARY OF THE INVENTION
  • This invention is related to a novel monolithic stable controlled release coating for use in coating oral pharmaceutical dosage forms.
  • In one aspect, the coating comprises an aqueous dispersion of a neutral ester copolymer without any functional groups; a poly glycol having a melting point greater than 55° C., and one or more pharmaceutically acceptable excipients; wherein said coating composition is coated onto said oral pharmaceutical dosage forms and cured at a temperature at least equal to or greater than the melting point of the poly glycol.
  • In another aspect, the invention provides a controlled release dosage form comprising a core, wherein the core comprises an effective amount of at least one therapeutically active agent, and one or more first pharmaceutically acceptable excipients, and a stable controlled release monolithic coating composition for coating said core, said coating comprising an aqueous dispersion of a neutral ester copolymer without any functional groups; a poly glycol having a melting point greater than 55° C., and one or more pharmaceutically acceptable excipients; wherein said coating composition is coated onto said oral pharmaceutical dosage forms and cured at a temperature at least equal to or greater than the melting point of the poly glycol.
  • In one embodiment, the neutral ester copolymer without any functional groups is selected from the group consisting of Eudragit® NE30D and Eudragit® NE40D. Preferably, the neutral ester copolymer without any functional groups is Eudragit® NE30D. The neutral ester copolymer without any functional groups is present in an amount from about 1% to about 35% by weight of the coating composition.
  • In one embodiment, the poly glycol is selected from the group consisting of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000 and polyethylene glycol 20000. The poly glycol is present in an amount from about 0.1% to about 10% by weight of the coat composition. Preferably, the poly glycol is polyethylene glycol 8000.
  • The addition of pharmaceutically acceptable excipients to the coating composition is contemplated and can include anti-tacking agents, emulsifying agents, hydrophilic agents, anti-foaming agents, flavourants, colorants, sweeteners and any combination thereof. The preferred ant-tacking agent is talc, the preferred hydrophilic agent is hydroxypropyl methylcellulose, the preferred ant-foaming agent is simethicone, the preferred emulsifying agent is polyoxyethylene sorbitan mono-oleate, and the preferred colorant is titanium dioxide.
  • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention is directed to novel aqueous dispersions of neutral ester copolymers without any functional groups suitable for use as coatings for controlled or sustained release drug dosage forms. The coating formulation is quite versatile in that it can be used to coat a variety of drug cores and can be easily manipulated to obtain the desired drug release profile. In another embodiment, the invention consists of a controlled release pharmaceutical composition, in one embodiment, a tablet, comprising at least one form of a therapeutically active agent, wherein the pharmaceutical composition comprises a core and a stable controlled release coating of the invention.
  • I. Cores
  • The core comprises an effective amount of a therapeutically active agent and at least one pharmaceutically acceptable excipient, in one embodiment a lubricant, a binder and/or filler, and optionally a glidants as well as other pharmaceutically acceptable excipients.
  • A wide variety of therapeutically active agents is contemplated. These include but are not limited to anti-tussives, anti-histamines, decongestants, alkaloids, mineral supplements, vitamins, antacids, ion exchange resins, anti-cholesterolemics, anti-lipid agents, anti-arrhythmics, anti-pyretics, analgesics, appetite suppressants, anti-depressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, opioid agonists, cerebral dilators, peripheral vasodilators, anti-biotics, anti-virals, psycho-tropics, anti-manics, stimulants, gastrointestinal agents, sedatives, anti-diarrheal agents, anti-anginal drugs, vasodilators, anti-hypertensive drugs, vasoconstrictors, migraine treatments, anti-infectives, tranquilizers, anti-psychotics, anti-tumor drugs, anticoagulants, antithrombic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and anti-thyroid agents, diuretics, anti-spasmodics, uterine relaxants, mineral and nutritionaql additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, H2-antagonists, anti-uricemic drugs. Mixtures are operable depending on the type of drugs. The skilled artisan will know, based on his technical knowledge, which drug combinations are acceptable. The therapeutically active agent(s) are present in an amount from about 5% to about 99% by weight of the cores. The amount present is highly dependent on the agent(s), the desired controlled release profile, and the strength of the desired dosage form. Different forms of the therapeutically active agent are also contemplated. One form of the therapeutically active agent may be the individually optically active enantiomers of the therapeutically active agent. Pharmaceutically acceptable salts, as for example pharmaceutically acceptable addition salts, of the therapeutically active agent(s) are also suitable. Suitable pharmaceutically acceptable addition salts may be the hydrochloride salt, the hydrobromide salt, the hydroiodide salt, the saccharinate salt etc.
  • Glidants improve the flowability of the excipient powder by reducing intraparticulate friction. This is especially important during tablet production at high production speeds and during direct compaction. Examples of glidants include but are not limited to starch, talc, lactose, stearates (such as for example magnesium stearate), dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, Cabosil™, colloidal silica (Syloid™) and silicon dioxide aerogels. Glidants, if present, range in amounts from greater than about 0% to about 20%, with amounts of about 0.1% to about 5% being typical.
  • Lubricants ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. High friction during tabletting can cause a series of problems, including inadequate tablet quality (capping or even fragmentation of tablets during ejection, and vertical scratches on tablet edges) and may even stop production. Lubricants are thus included in almost all tablet formulations. Such lubricants include but are not limited to adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sodium chloride, sterotex, polyoxyethylene, glyceryl monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, light mineral oil and the like may be employed, with sodium stearyl fumarate being preferred. Waxy fatty acid esters, such as glyceryl behenate, sold as “Compritol™” products, can be used. Other useful commercial lubricants include “Stear-O-Wet™” and “Myvatex™ TL”. Mixtures are operable. Lubricants are used in amounts typically ranging from greater than about 0% to about 10%, with about 0.01% to about 5.0% by weight of the tablet preferred.
  • It is well known in the art that besides reducing friction, lubricants may cause undesirable changes in the properties of a tablet. The presence of a lubricant in the excipient powder is thought to interfere in a deleterious way with the bonding between the particles during compaction and thus reduce tablet strength. Because many lubricants are hydrophobic, tablet disintegration and dissolution are often retarded by the addition of a lubricant. Such negative effects are strongly related to the amount of lubricant present. Other considerations known in the art include the manner in which a lubricant is mixed, the total mixing time and the mixing intensity. In order to avoid these negative effects, hydrophilic substances may be substituted for the hydrophobic lubricants. Examples include, but are not limited to, surface-active agents and polyethylene glycol. A combination of hydrophilic and hydrophobic substances can also be used.
  • Anti-adherents reduce adhesion between the excipient powder mixture and the punch faces and thus prevent particles sticking to the punches, a phenomenon know in the art as “sticking” or “picking”, and is affected by the moisture content of the powder. One example of antiadherent is microcrystalline cellulose. Many lubricants such as magnesium stearate have also antiadherent properties. However, other substances with limited ability to reduce friction can also act as antiadherents. Such substances include for example talc and starch. Mixtures are operable. Antiadherents, if present, range from about 0% to about 20% by weight of the tablet depending on the antiadherent being used.
  • Sorbents are substances that are capable of sorbing some quantities of fluids in an apparently dry state. Thus, oils or oil-drug solutions can be incorporated into a powder mixture, which is granulated and compacted into tablets. Other examples of sorbing substances include microcrystalline cellulose and silica.
  • Diluents or fillers are added to increase the bulk weight of the blend resulting in a practical size for compression. The ideal diluent or filler should fulfill a series of requirements, such as: be chemically inert, be non-hygroscopic, be biocompatible, possess good biopharmaceutical properties (e.g. water soluble or hydrophilic), good technical properties (such as compactibility and dilution capacity), have an acceptable taste and be cheap. As a single substance cannot fulfill all these requirements, different substances have gained use as diluents or fillers in tablets.
  • Lactose is a common filler in tablets. It possesses a series of good filler properties, e.g. dissolves readily in water, has a pleasant taste, is non-hygroscopic and fairly non-reactive and shows good compactibility. Other sugars or sugar alcohols, such as glucose, sucrose, sorbitol and mannitol, have been used as alternative fillers to lactose, primarily in lozenges or chewable tablets because of their pleasant taste. Mannitol has a negative heat of solution and imparts a cooling sensation when sucked or chewed.
  • Apart from sugars, perhaps the most widely used fillers are celluloses in powder forms of different types. Celluloses are biocompatible, chemically inert, and have good tablet forming and disintegrating properties. They are therefore used also as dry binders and disintegrants in tablets. They are compatible with many drugs but, owing to their hygroscopicity, may be incompatible with drugs prone to hydrolyse in the solid state. The most common type of cellulose powder used in tablet formulation is microcrystalline cellulose.
  • Another important example of a diluent or filler is dibasic and tribasic calcium phosphate, which is insoluble in water and non-hygroscopic but is hydrophilic, i.e. easily wetted by water. Other examples of diluents include but are not limited to di- and tri-basic starch, calcium carbonate, calcium sulfate, and modified starches. Many diluents are marketed in “direct compression” form, which adds other desirable properties, such as flow and binding. There are no typical ranges used for the diluents, as targeted dose and size of a tablet are variables that influence the amount of diluent that should be used.
  • Binders (also sometimes called adhesives) are added to ensure that tablets can be formed with the required mechanical strength. Binders can be added in different ways: (1) As a dry powder, which is mixed with other ingredients before wet agglomeration; (2) As a solution, which is used as agglomeration liquid during wet agglomeration. Such binders are often referred to as “solution binders”, and (3) As a dry powder, which is mixed with the other ingredients before compaction (slugging or tabletting). Such binders are often referred to as “dry binders”. Common traditional solution binders are starch, sucrose, and gelatin. More commonly used binders with improved adhesive properties, are polymers such as polyvinylpyrrolidone and cellulose derivates such as for example hydropropyl methylcellulose. Examples of dry binders include microcrystalline cellulose and crosslinked polyvinylpyrrolidone. Other examples of binders include but are not limited to pregelatinized starches, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone and polyvinylalcohols. Binders, if present, range in amounts from about greater than about 0% to about 25% depending on the binder used.
  • The manufacturing process of the core can be as follows. The at least one therapeutically active agent is first granulated with the at least one binder, in one embodiment a granulator, but not necessarily a fluidized bed granulator. The at least one binder is first dissolved or dispersed in a suitable solvent, in one embodiment water. The solution or suspension of the at least one binder is then sprayed onto the at least one therapeutically active agent in a granulator, in one embodiment a fluidized bed granulator. For example, fluidized bed granulators manufactured by Glatt (Germany) or Aeromatic (Switzerland) can be used for this operation. An alternative process can be to use a conventional or high shear mixer for granulation. If necessary, the at least one therapeutically active agent can be mixed with a filler, prior to the granulation step. Granules once dried can be mixed with the other pharmaceutically acceptable excipients, especially with the at least one lubricant, but also with at least one glidant and any other pharmaceutically acceptable excipient suitable to improve processing. The mixture of granules (in one embodiment with the at least one lubricant), and optionally at least one glidant is pressed into tablets. Alternatively, the at least one therapeutically active agent and the at least one lubricant can be mixed in a granulator, in one embodiment a fluidized bed granulator, and heated to the melting point of the at least one lubricant to form granules. This mixture can then be mixed with at least one suitable filler and compressed into tablets. Also, it is possible to mix the at least one therapeutically active agent and the at least one lubricant (in one embodiment polyvinyl alcohol) in a granulator, in one embodiment a fluidized bed granulator, and then to press the resulting granules into tablets. Tablets can be obtained by standard techniques, in one embodiment on a (rotary) press (for example Manesty Betapress®) fitted with suitable punches. The resulting tablets are hereinafter referred as tablet cores.
  • The tablet cores are then coated with the semi-permeable coating designed to achieve a controlled release of the at least one therapeutically active agent.
  • II. Coating Formulation
  • Particularly useful neutral ester copolymers without any functional groups constituting the coat of the invention described herein are Eudragit® NE30D, Eudragit® NE40D (Röhm America LLC). The preferred polymer is Eudragit NE30D and is present in an amount of from about 1% to about 35% by weight of the coat depending on the therapeutically active agent used and the controlled release profile desired. Hydrophilic agents may also be included in the coat to promote wetting of the coat when in contact with gastrointestinal fluids. Such hydrophilic agents include hydrophilic water soluble polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and combinations thereof. HPMC is the preferred hydrophilic water soluble polymer. If hydrophilic agents are to be included in the coat composition the agents should be present in an amount from about 0.1% to about 10% by weight of the coating composition, preferably from about 0.1% to about 5% by weight of the coating composition and most preferably from about 0.1% to about 3% by weight of the coating composition.
  • The coat formulation also comprises a poly gycol with a melting point of greater than 55° C. The poly glycol is selected from the group consisting of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, and polyethylene glycol 20000. The preferred poly glycol is polyethylene glycol 8000. The poly glycol is present in an amount of from about 0.1% to about 5% by weight of the coat. Other suitable polyglycol derivatives having a melting point at least of 55 deg C. can be, but are not limited to, Poloxamer 188, Poloxamer 338, Poloxamer 407, Polyethylene Oxides, Polyoxyethylene Alkyl Ethers, and Polyoxyethylene Stearates.
  • In addition to the copolymers and the poly glycol, the coating formulation comprises other pharmaceutically acceptable excipients. The excipients can include but are not limited to anti-tacking agents, emulsifying agents, antifoaming agents, flavourants, colourants, etc. It is known in the art that depending on the intended main function, excipients can affect the properties of the coat in a series of ways, and many substances used in coat formulations can thus be described as multifunctional. A skilled worker will know, based on his technical knowledge, which pharmaceutically acceptable excipients are suitable for the desired controlled release coating composition.
  • The tackiness of polymeric films is important for the coating of solid dosage forms and for the subsequent curing step (post coating thermal treatment). During coating with either cellulosic or acrylic polymers, an unwanted, and sometimes irreversible agglomeration of several granules or beads or, in the worst case, of the complete batch, can occur, especially at higher product processing temperatures. Accordingly, the addition of anti-tacking agents to coating formulations is desirable. The anti-tacking agents which can be used include but are not limited to adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, glyceryl monostearate, talc, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and the like may be employed. Talc is the preferred anti-tacking agent. Talc may also function as a wetting agent. Mixtures of the anti-tacking agents are operable. The amount of anti-tacking agent in the coating composition is preferably in the range from about 1% to about 15% by weight of the coating dispersion and more preferably from about 1% to about 7% by weight of the coating dispersion.
  • The anti-foaming agents, which may be included in the coating composition of the invention include silicon oil or simethicone, with simethicone being the preferred anti-foaming agent. The anti-foaming agent, if present, is present in an amount up to about 0.5% by weight of the coat composition and preferably from about 0.1% to about 0.4% by weight of the coating composition.
  • The inclusion of an emulsifying agent or agents (also called emulsifiers or emulgents) is necessary to facilitate actual emulsification during manufacture of the coat, and also to ensure emulsion stability during the shelf-life of the product. Emulsifying agents useful for the coat composition of the invention include, but are not limited to naturally occurring materials and their semi synthetic derivatives, such as the polysaccharides, as well as glycerol esters, cellulose ethers, sorbitan esters and polysorbates. Mixtures are operable. The preferred emulsifying agent is Polysorbate 80 (polyoxyethylene sorbitan mono-oleate) (Tween 80). The emulsifying agent or agents are present in an amount up to about 0.5% by weight of the coat composition and preferably from about 0.1% to about 0.3% by weight of the coat composition.
  • Any permitted colourants in a film coat formula are invariably water-insoluble colors (pigments). Pigments have certain advantages over water-soluble colors in that they tend to be more chemically stable towards light, provide better opacity and covering power, and optimize the impermeability of a given film to water vapor. Examples of suitable colorants include, but are not limited to iron oxide pigments, titanium dioxide, and aluminum Lakes. Mixtures are operable. The preferred pigment is titanium dioxide. The pigment or colorant is present in an amount of from about 0.1% to about 10% by weight of the coat composition, preferably from about 0.1% to about 5% by weight of the coat composition and most preferably from about 0.1% to about 2% by weight of the coat composition.
  • The coating may be applied onto a core comprising an effective amount of the therapeutically active agent by a process, which involves the atomization (spraying) of the coating solution or suspension onto a bed of the tablet cores. Some examples of equipment suitable for film coating include: Accela Cota (Manesty Machines, Liverpool, UK), Hi-Coater (Freund Company, Japan), Driacoater (Driam Metallprodukt GmbH, Germany), HTF/150 (GS, Italy), and IDA (Dumoulin, France). Examples of units that function on a fluidized-bed principle include: Aeromatic (Fielder, Switzerland and UK) and Glatt AG (Switzerland). The preferred and most widely used apparatus is the Accela Cota.
  • The coating fluid is delivered to the coating apparatus from a peristaltic pump at the desired rate and sprayed onto the rotating or fluidizing tablet cores. The tablet cores are pre-warmed to about 30° C. During the coating process, the product temperature range is maintained between about 25° C. and 35° C. by adjusting the flow rate of the inlet and outlet air, temperature of the inlet air and spray rate. A single layer of coat is applied and once spraying is complete, the coated tablet cores are dried between about 30° C. to about 40° C. for about 3-5 minutes at a low pan speed and low air flow. The pan was readjusted to jog speed, and drying continued for 12-15 minutes.
  • The coated tablet cores are placed onto a tray and cured (post coating thermal treatment) in an electrical or steam oven at a temperature above the temperature of the melting point of the polyethylene glycol or derivative thereof. The curing temperature is preferably greater than the melting point of the polyethylene glycol or derivative thereof. The curing time is preferably about 2 to about 7 hours. The cured coated tablets are subsequently cooled to room temperature.
  • The findings disclosed herein are particularly surprising in light of the prior art teachings with regard to Eudragit® NE30D. As mentioned above, Eudragit® NE30D has a low Tg and the use of plasticizers, such as polyethylene glycol or its derivatives, is not recommended. In fact, as mentioned above, the prior art teaches that the addition of plasticizers can be detrimental to Eudragit® NE30D. Surprisingly, however, applicants have found that addition of polyethylene glycol or its derivatives in the amounts described herein and curing the coated tablets at above the melting temperature of the polyethylene glycol provided for a controlled release of the therapeutically active agent. Moreover, the coated tablet cores were found to be stable over time. The desired dissolution profile obtained provides a controllable lag time such as in an S-shaped Weibull profile. This is a surprising result and is not taught in the prior art. The controlled lag time and the desired dissolution profile can be accomplished by a single coating.
  • As will be seen from the non-limiting examples described below, the coating of the invention is quite versatile. The length and time for the delay is controlled by rate of hydration and the thickness of the coat. The drug release rate subsequent to the delay is determined by the thickness and permeability of the hydrated coat. Thus, it is possible to regulate the rate of hydration and permeability of the coat so that the desired controlled-release drug profile can be achieved. There is no preferred coat thickness, as this will depend on the drug being used in the core and also the controlled release profile desired. Other parameters in combination with the thickness of the coat include varying the concentrations of some of the ingredients of the stable coat composition of the invention described and/or varying the curing temperature and length of curing the coated tablet cores. The skilled artisan will know which parameters or combination of parameters to change for a desired controlled release profile.
  • The following non-limiting examples illustrate the invention:
  • EXAMPLE 1 Metformin HCl Tablets 1.1 Tablet Core Preparation
  • The following formulation was prepared for Metformin HCl 500 mg strength tablets:
  • Ingredients % w/w
    Metformin HCl 95.70
    Silicon Dioxide* 0.50
    Polyvinyl alcohol (PVA)** 1.80
    Atomized Glyceryl 2.00
    Behenate***
    Total 100.00
    *Aerosil 200.
    **The PVA is prepared as a 4% solution (w/w) in purified water. The purified water is not considered as part of the theoretical batch size since it is evaporated during drying of the core in the fluid bed granulator.
    ***Compritol 888 ATO
  • All of the metformin and silicon dioxide was transferred to a V-blender and blended for about 10 min. The blended material was then discharged into a fluid bed granulator and granulation was carried out in the presence of the PVA solution under the following process parameters:
  • Granulation Temperature (° C.) 35-45
    Air Volume (m/s) 0.5-3.0
    Atomization Air Pressure 0.5-2.0
    (Bar)
    Fluid Spray Rate (g/min)  3-11
    Drying Temperature (° C.) 45-55

    The LOD % of the granules after drying was NMT 3% as determined by moisture balance.
  • After drying, the granules were sized by passing the granules through a 0.71 mm screen. The screened granules were then transferred to a V-blender and blended with the remainder of the lactose and all of the atomized glyceryl behenate for about 10 min. Finally, the magnesium stearate was added and blending was carried out for about 5-10 more minutes.
  • The dissolution profile of the compressed tablet cores was determined under the following conditions:
  • Medium: 900 ml water
  • Method: USP Type II Apparatus, 50 rpm at 37° C.
  • The tablet cores are immediate release. The release of metformin HCl from the tablet cores was found to be about 100% in about 30 min.
  • 1.2 Core Coating
  • The following three coating formulations were prepared:
  • Coating
    MA Coating MB Coating MC
    Ingredients (%) (%) (%)
    Eudragit NE30D 25.33 26.97 27.03
    Talc 400 6.84 5.30 5.32
    HPMC 606 5.98 2.47 2.25
    PEG 8000 2.14 2.25 2.25
    Titanium dioxide 1.71 1.35 1.35
    Somethicone 0.39 0.31 0.31
    Tween 80 0.34 0.23 0.23
    Purified Water 57.27 61.12 61.26
    Total 100.00 100.00 100.00
  • The metformin tablet cores were then coated with either one of the coating formulations. The coating process was carried out in a Glatt GPCG-1 apparatus equipped with a coating chamber without a Wuster column. The mesh size of the bottom screen was 200 μm and the size of the spray nozzle was 1 mm.
  • The coating formulation was prepared as follows:
  • Materials
    Component A Eudragit NE30D
    Water
    Component B HPMC 606
    Water
    Component C Simethicone
    (DOW CORNING ®)
    Water
    Component D Tween 80
    Water
    Component E Component D + C
    Component F Talc
    PEG 8000 (MT)
    Titanium dioxide
    Water
    Final coating Dispersion G
    (A + B + C + D + E + F)
  • 1.2.1 Preparation of Component A
  • Water is transferred to a stainless steel container of a Silverson high-shear mixer and the mixer turned on at continuous low speed to produce a sufficient mixer. All of the Eudragit NE 30D dispersion is added to the water and mixed for about 10 min using a Caframo Mixer.
  • 1.2.2 Preparation of Component B
  • All of the Pharmacoat 606 is added to 65±5° C. water and mixed for about 5 min using a silverson high shear mixer at a low speed.
  • 1.2.3 Preparation of Component C
  • All of the simethicone is placed in a 100 ml beaker to which 50 g of water is added and mixed to uniformity.
  • 1.2.4 Preparation of Component D
  • All of the Tween 80 is transferred to a 100 ml beaker to which 50 g of water is added and mixed until all the Tween 80 is dissolved.
  • 1.2.5 Preparation of Component E
  • Dispersion E is prepared by uniformly mixing component D and component C.
  • 1.2.6 Preparation of Component F
  • Water is transferred to a stainless steel container of a Silverson high-shear mixer and the mixer turned on at continuous low speed to produce a sufficient vortex. The PEG is added gradually to the vortex and mixed until the all of the PEG is dissolved. Components B and E are next added and mixing is continued for 5 min. All of the talc and titanium dioxide is added and mixed for another 15 min.
  • 1.2.7 Preparation Final Coating Dispersion G
  • Component F is slowly added component A while stirring.
  • The processing parameters for coating the tablet cores were as follows:
  • Coating Temperature (° C.) 30-32
    Air Volume (m/s) 4.0-6.5
    Atomization Air Pressure (Bar) 1.3-2.3
    Coating Fluid Spray Rate 3-6
    (g/min)
    Drying Temperature (° C.)** 30-35
    **Coated tablets were dried for about 3 min.
  • After application of the coating the tablets were cured in an oven at 62±2° C. for about 2 hours. This temperature is above the melting temperature of the polyethylene glycol 8000.
  • The metformin tablet cores were next coated with either one of the coating formulations MA, MB, or MC to a weight gain of either 14% or 16% w/w by weight of the tablet core and cured in an oven at between about 60° C. to about 75° C. for between about 2 hours to about 15 hours.
  • Dissolution tests of the coated tablet cores was carried out under the following dissolution conditions:
  • Medium: 900 ml water.
  • Method: USP Type II Apparatus, 50 rpm at 37° C.
  • The results are presented in Table 1 as a % release into the medium of the total metformin HCl in the tablet:
  • TABLE 1
    Tablet cores coated Tablet cores coated Tablet cores coated
    with coating with coating with coating
    Time formulation MA to formulation MB to formulation MC to
    (h) 16% weight gain 14% weight gain 14% weight gain
    0 0 0 0
    1 21.15 11.26 7.04
    2 50.35 24.4 16.59
    3 73.8 38.12 26.69
    4 89.73 52.75 38.02
    5 98.65 66.73 50.56
    6 102.24 79.25 63.31
    7 103.55 88.78 74.98
    8 95.41 84.71
    9 99.42 91.92
    10 101.76 96.47
    11 103.05 99.45
    12 103.86 101.21
  • A study was done to determine the effect of curing temperature and length of curing on drug dissolution. The curing temperature was set at 65° C. for 1, 2 and 5 hours. The effect on the dissolution of the drug at a curing temperature of 75° C. for about 2 hours was also determined. Dissolution tests of the coated tablets under the different curing temperatures and lengths of time were carried under the following dissolution conditions:
  • Medium: 900 ml water.
  • Method: USP Type II Apparatus, 50 rpm at 37° C.
  • The results are presented in Table 2 as a % release into the medium of the total metformin HCl in the tablet:
  • TABLE 2
    Time MB (65° MB MB (65° MB
    (h) C.-60 min) (65° C.-120 min) C.-300 min) (75° C.-120 min)
    0 0 0 0 0
    1 9.98 8.08 7 6.47
    2 23.73 18.65 17.14 15.76
    3 40.53 29.8 27.62 25.67
    4 61.77 42.52 39.8 36.6
    5 81.77 56.48 53.84 48.63
    6 92.51 71.32 67.67 60.74
    7 80.94 79.85 72.57
    8 86.35 88.24 82.13
    9 90.36 92.96 88.28
    10 92.69 95.47 91.68
    11 94.87 97.57 94.02
    12 96.14 98.39 95.67
    13 97.37 99.23 96.93
    14 98.21 99.69 97.56
    15 98.71 99.97 98.33
    16 99.47 100.37 98.83
  • A study was done to determine the effect of curing temperature and time on drug dissolution. The curing temperature was set at 55° C. for 5 and 16 hours. The effect on the dissolution of the drug at a curing temperature of 70° C. for about 2 hours was also determined. Dissolution tests of the coated tablets under the different curing temperatures and lengths of time were carried under the following dissolution conditions:
  • Medium: 900 ml water.
  • Method: USP Type II Apparatus, 50 rpm at 37° C.
  • The results are presented in Table 3 as a % release into the medium of the total metformin HCl in the tablet:
  • TABLE 3
    Time Tablet MC
    (h) Cores (55° C.-5 hr) MC (55° C.-16 hr) MC (70° C.-2 hr)
    0 0 0 0 0
    1 103.92 13.08 11.86 7.04
    2 37.54 32.76 16.59
    3 54.51 54.39 26.69
    4 67.48 67.85 38.02
    5 78.38 78.89 50.56
    6 87.14 88.15 63.31
    7 93.31 93.43 74.98
    8 96.5 96.12 84.71
    9 98.11 97.55 91.92
    10 99.11 98.36 96.47
    11 99.51 98.82 99.45
    12 99.91 99.13 101.21
  • The influence of the coat on different dissolution media relative to water was determined as follows:
  • Media: water, 0.1N HCl (pH1.2)+Citramide, or pH5.8 phosphate buffer+Citramide.
  • Method: USP Type II Apparatus, 50 rpm at 37° C.
  • The results are presented in Table 4 as a % release into the medium of the total metformin HCl in the tablet:
  • TABLE 4
    MC MB MC MC MB MB
    Time (h) water water pH 5.8 + Citramide pH 1.2 + Citramide pH 5.8 + Citramide pH 1.2 + Citramide
    0 0 0 0 0 0 0
    1 7.04 11.26 5.62 5.74 8.61 8.98
    2 16.59 24.4 13.28 13.39 19.69 20.58
    3 26.69 38.12 20.99 20.83 31.23 31.96
    4 38.02 52.75 29.47 28.94 43.42 43.46
    5 50.56 66.73 38.99 37.84 56.09 54.97
    6 63.31 79.25 49.47 47.76 68.35 66.08
    7 74.98 88.78 60.68 58.06 78.89 76.22
    8 84.71 95.41 72.25 68.75 86.79 84.81
    9 91.92 99.42 81.02 77.34 92.06 89.75
    10 96.47 101.76 86.63 83.99 95.01 92.56
    11 99.45 103.05 90.01 87.32 96.72 94.64
    12 101.21 103.86 92.45 90.03 97.77 95.52
    13 102.36 104.25 94.27 92.21 98.49 96.58
    14 103.38 95.51 93.2 98.97 96.79
    15 104.06 96.61 94.45 99.34 97.45
    16 104.77 97.46 95.47 99.6 97.74
  • The stability of the tablet coated with formulation MD coated to 16% weight gain stored at 40° C./75% relative humidity (RH) was determined at periodic intervals over a 12 month period by determining the dissolution of the metformin under the following conditions:
  • Media: 900 ml water
  • Method: USP Type II Apparatus, 50 rpm at 37° C. The dissolution data is presented in Table 5 as a % release into the medium of the total metformin HCl in the tablet:
  • TABLE 5
    Time (h) 0 Month 1 Month 2 Month 3 Month 6 Month 12 Month
    1 7 5.3 7.3 8.3 3.3 9.7
    2 16.6 13.8 16.9 19.1 13.4 21.4
    4 38 35 39.7 46.8 38 49.7
    8 84.7 79 87.3 98.1 89.4 92.9
    12 101.2 90.4 99.4 106.8 102.8 99.9
  • A comparative study was conducted to determine the bioavailability following administration of a single dose metformin tablet (Tables 6 and 7) or multiple-dose metformin tablet (Table 8) of the invention
  • TABLE 6
    Metformin HCl
    Metformin HCl 500 mg ER Glucophage
    500 mg ER Tablets, q.d. 500 mg,
    Tablets, q.d. (Lot #07(C)/00 500 b.i.d. (Lot #
    Time (Hrs) (Lot # 00F167) XL-HT)) C8J247A)
    0 0.00 ± 0.00 12.68 ± 39.85 2.51 ± 9.71
    2  7.37 ± 15.46 53.96 ± 31.93 73.39 ± 59.00
    4 343.92 ± 146.45 164.46 ± 65.57  200.20 ± 114.59
    5 476.22 ± 151.89 176.46 ± 80.87  485.69 ± 188.37
    6 390.96 ± 129.93 146.23 ± 65.48  630.49 ± 161.58
    7 325.99 ± 104.84 116.62 ± 59.84  707.85 ± 215.67
    8 284.59 ± 104.39 97.20 ± 51.97 651.46 ± 183.34
    9 242.05 ± 95.88  85.26 ± 47.76 466.04 ± 128.06
    10 204.51 ± 86.24  77.24 ± 43.17 259.19 ± 78.14 
    12 127.37 ± 62.84  49.53 ± 28.71 158.77 ± 42.42 
    16 60.11 ± 37.32 21.02 ± 19.97 55.69 ± 16.58
    20 40.52 ± 30.87 15.63 ± 16.54 25.93 ± 19.96
    24 19.64 ± 23.26  9.49 ± 14.00  6.01 ± 12.75
  • TABLE 7
    Metformin HCl
    Metformin HCl 500 mg ER
    500 mg ER Tablets, q.d. Glucophage 500 mg,
    Tablets, q.d. (Lot #07(C)/00 500 b.i.d. (Lot #
    (Lot # 00F167) XL-HT)) C8J247A)
    SUBJECT Cmax AUC0-t Tmax Cmax AUC0-t Tmax Cmax AUC0-t Tmax
     1 423.94 3203.04 5.0 296.51 1589.86 5.0 901.58 5608.64 3.0
     2 357.51 4267.79 10.0
     3 318.39 1602.89 5.0 216.55 1842.90 5.0 447.61 2971.16 5.0
     4 489.60 2784.57 4.0 127.03 1447.85 4.0 510.26 3504.43 4.0
     5 592.40 3864.41 5.0 166.35 1484.23 5.0 735.54 5394.77 4.0
     6 414.96 2295.36 5.0 175.21 1285.79 5.0 686.09 4258.03 4.0
     7 419.53 3619.34 5.0 191.15 1415.17 5.0 520.19 3435.10 3.0
     8 227.86 1548.93 5.0 203.87 1373.32 4.0 806.18 5076.93 3.0
     9 664.24 4366.66 5.0 187.89 1779.67 5.0 697.26 4994.51 2.0
    10 583.18 3398.15 5.0 144.69 978.64 5.0 1002.36 6098.66 4.0
    11 566.79 5048.15 6.0 173.95 1771.12 6.0 641.14 4709.57 5.0
    12 573.18 3370.02 5.0 42.10 236.63 4.0 654.03 4208.54 4.0
    13 302.20 2559.23 5.0 192.13 2090.60 5.0 586.54 4177.75 4.0
    14 158.98 1152.05 4.0 1090.92 6671.03 5.0
    16 625.70 4278.32 5.0 152.38 930.85 0.0 808.43 4882.53 4.0
    19 640.76 3353.70 4.0 123.43 496.15 5.0 578.89 3108.53 2.0
    20 768.94 4284.70 5.0 396.18 2689.22 5.0 1125.20 6308.03 4.0
    Mean 498.1 3365.33 5.3 184.3 1410.25 4.5 737.0 4713.01 3.8
    SD 151.9 1006.86 1.3 77.4 594.66 1.3 205.5 1133.00 0.9
    CV (%) 30.5 29.92 25.6 42.0 42.17 29.3 27.9 24.04 24.8
    GeoMean 474.1 3199.36 5.1 168.4 1247.38 4.8 711.4 4581.55 3.6
    Min 227.86 1548.93 4.00 42.10 236.63 0.00 447.61 2971.16 2.00
    Max 768.94 5048.15 10.00 396.18 2689.22 6.00 1125.20 6671.03 5.00
  • TABLE 8
    Metformin HCl
    Metformin HCl 500 mg ER
    500 mg ER Tablets, q.d. Glucophage 500 mg,
    Tablets, q.d. (Lot #07(C)/00 500 b.i.d. (Lot #
    (Lot # 00F167) XL-HT)) C8J247A)
    SUBJECT Cmax AUC0-t Tmax Cmax AUC0-t Tmax Cmax AUC0-t Tmax
     1 945.40 6232.57 5.0 872.61 5177.02 5.0 886.47 12899.68 3.0
     3 722.90 8312.65 5.0 475.83 4403.99 5.0 628.12 10229.16 15.0
     4 540.79 4332.49 4.0 155.28 1538.15 4.0 580.82 7692.77 3.0
     5 1562.92 10130.87 5.0 401.35 3980.27 5.0 968.26 12011.86 3.0
     6 770.21 5346.86 6.0 425.47 3514.28 4.0 821.17 10603.35 3.0
     7 560.34 4490.96 5.0 409.97 3884.59 5.0 721.95 10518.02 4.0
     8 1105.38 8133.56 5.0 442.39 4111.28 5.0 757.45 11971.60 4.0
     9 727.04 4863.71 5.0 541.01 5228.69 5.0 977.96 12244.88 4.0
    10 1150.00 7974.91 5.0 694.61 4673.33 5.0 1123.79 14656.81 4.0
    11 983.35 6791.08 5.0 594.71 5228.49 6.0 817.43 10463.89 5.0
    12 961.04 6548.23 5.0 454.24 4037.80 5.0 856.27 11769.61 4.0
    13 963.88 8612.93 6.0 430.68 4788.57 5.0 734.24 12074.02 4.0
    14 615.73 5939.67 5.0
    16 990.87 5890.99 5.0 359.87 3273.11 5.0 567.54 7890.22 3.0
    19 835.28 4797.61 4.0 368.31 2801.78 4.0 893.94 11735.13 4.0
    20 3835.55 11037.19 6.0 774.96 6522.10 5.0 970.78 15109.04 6.0
    Mean 1110.3 6899.77 5.1 501.1 4318.94 4.9 820.4 11458.00 4.6
    SD 795.1 2072.53 0.6 176.3 1222.75 0.5 158.5 2042.45 3.0
    CV (%) 71.6 30.04 11.7 35.2 28.31 10.3 19.3 17.83 65.1
    GeoMean 973.3 6620.63 5.0 469.2 4119.36 4.8 805.7 11278.47 4.1
    Min 540.79 4332.49 4.00 155.28 1538.15 4.00 567.54 7692.77 3.00
    Max 3835.55 11037.19 6.00 872.61 6522.10 6.00 1123.79 15109.04 15.00
  • EXAMPLE 2 Bupropion HCl Tablets 2.1 Tablet Core Preparation
  • The following formulation was prepared for Bupropion HCl 300 mg and 150 mg strength tablets:
  • Ingredients % w/w
    Bupropion HCl 93.75
    Polyvinyl alcohol (PVA)* 3.31
    Atomized Glyceryl Behenate** 2.94
    Total 100.00
    **The PVA is prepared as a 4.6% solution (w/w) in purified water. The purified water is not considered as part of the theoretical batch size since it is evaporated during drying of the core in the fluid bed granulator.
    ***Compritol 888 ATO
  • The tablet cores were prepared as described above for oxycodone
  • HCl. The granules were compressed into either 320 mg tablets (for 300 mg strength tablets) or 160 mg tablets (for 150 mg strength tablets). The dissolution profile of the compressed tablets was determined under the following conditions:
  • Medium: 900 ml water
  • Method: USP Type II Apparatus, 50 rpm at 37° C.
  • The release of bupropion HCl from the tablet cores was found to be about 100% in about 30 minutes.
  • 2.2 Core Coating
  • The following four coating formulations were prepared for the bupropion HCl 300 mg strength tablet cores:
  • Ingredients BA (% w/w) BB (% w/w) BC (% w/w) BD (% w/w) BE (% w/w)
    Eudrgit NE 30D (Liquid) 26.82 26.82 26.82 26.82 26.82
    Talc 400 4.83 4.02 3.62 4.43 4.02
    Titanium Dioxide 0.81 0.81 0.81 0.81 0.81
    HPMC 2.01 2.82 3.22 2.41 2.82
    PEG 8000 2.01 2.01 2.01 2.01 2.01
    Simethicone 0.2 0.2 0.2 0.2 0.2
    Tween 80 0.1 0.1 0.1 0.1 0.1
    Purified water 63.22 63.22 63.22 63.22 63.22
    Total 100.00 100.00 100.00 100.00 100.00
  • The following two coating formulations were prepared for the bupropion HCl 150 mg strength tablet cores:
  • Ingredients BF (w/w %) BG (% w/w)
    Eudrgit NE 30D (Liquid) 26.82 26.82
    Talc 400 4.02 3.62
    Titanium Dioxide 0.81 0.81
    HPMC 606 2.82 3.22
    PEG 8000 2.01 2.01
    Somethicone 0.2 0.2
    Tween 80 0.1 0.1
    Purified water 63.22 63.22
    Total 100.00 100.00
  • The bupropion HCl 300 mg core tablets were coated with either one of the coat formulations BA-BE to 15% weight gain as described for the metformin HCl core tablets. Coated tablet cores were cured at 62±2° C. Dissolution tests of the coated tablet cores was carried out under the following dissolution conditions:
  • Medium: 900 ml 0.1N HCl or water
  • Method: USP Type I Apparatus, 75 rpm at 37° C.
  • The results are presented in Table 9 and 10 as a % release into 0.1 N HCl and water respectively of the total bupropion HCl in the 300 mg tablet:
  • TABLE 9
    Time (h) BB BC BD BE
    0 0 0 0 0
    1 2.6 4.18 1.73 2.2
    2 5.9 9.03 4.23 4.58
    3 9 14.3 6.44 6.62
    4 12 19.89 8.43 10.25
    5 15.5 27.23 10.44 12.93
    6 19.3 33.14 12.6 16.65
    7 23.7 40.45 14.9 20.43
    8 28.5 46.81 17.32 24.39
    9 33.7 52.46 20.04 29.24
    10 39.1 59.59 23 34.72
    11 44.5 64.57 26.3 38.98
    12 49.9 69.7 29.84 44.62
    13 55 74.6 33.66 47.26
    14 59.9 78.17 37.69 51.94
    15 64.5 81.99 41.85 56.03
    16 69 85.05 46.37 60.72
    17 88.58 50.72 63.61
    18 91.14 54.7 67.4
    19 92.25 58.4 70.4
    20 93.62 62.1 73.93
    21 94.86 65.6 76.55
    22 95.72 68.9 77.86
    23 96.25 72.1 79.97
    24 96.69 75.1 82.32
  • TABLE 10
    Time (h) BA BB BC BD BE
    0 0 0 0 0 0
    1 1 1.97 4.62 1.6 2.4
    2 2.5 4.65 8.73 3.6 5.1
    3 3.8 7.3 12.7 5.3 7.3
    4 4.8 9.93 17.09 6.8 9.3
    5 5.8 12.73 21.96 8.2 11.4
    6 6.7 16 27.37 9.6 13.5
    7 7.6 19.3 33.18 11 15.8
    8 8.5 22.5 39.22 12.5 18.3
    9 9.4 26 45.16 14 21
    10 10.3 29.1 50.78 15.7 23.9
    11 11.2 33.2 56.13 17.5 27.15
    12 12.3 36.7 61.09 19.5 30.52
    13 13.4 40.7 65.72 21.7 34.11
    14 14.6 44.5 69.95 24.2 37.89
    15 15.8 47.8 73.76 26.8 41.58
    16 17.2 51.5 77.15 29.8 45.27
    17 54.9 80.1 33.3 48.91
    18 58.6 82.65 37.1 52.59
    19 61.7 84.75 40.7 56.06
    20 64.7 86.51 45.6 59.35
    21 68.2 87.97 50.1 62.5
    22 71.4 89.15 53.8 65.67
    23 74.3 90.12 57.3 68.49
    24 77 90.96 60.4 71.1
  • The 150 mg tablet cores were coated with formulations BF and BG to 15% and 25% weight gain respectively and dissolution tests were performed on these tablets under the following conditions:
  • Media: 900 ml 0.1N HCl
  • Method: USP Type I Apparatus, 75 rpm at 37° C.
  • The dissolution data is presented in Table 11 as a % release into the medium of the total bupropion HCl:
  • TABLE 11
    BG (25% BF (15%
    weight weight
    Time (h) gain) gain)
    0 0 0
    1 1.61 2.89
    2 5.75 6.9
    3 9.89 10.83
    4 14.3 15.3
    5 19.3 20.38
    6 24.58 25.98
    7 29.97 31.91
    8 35.18 37.86
    9 40.18 43.79
    10 44.87 49.29
    11 49.33 54.64
    12 53.55 59.58
    13 57.49 64.28
    14 61.33 68.63
    15 64.87 72.65
    16 68.24 76.34
    17 71.41 79.71
    18 74.32 82.7
    19 77.05 85.31
    20 79.55 87.52
    21 81.84 89.38
    22 83.92 90.97
    23 85.64 92.34
    24 87.31 93.47
  • The stability of the tablet coated with formulation BG supplemented with 0.65% titanium dioxide and 0.12% synthetic iron oxide pigment. The tablet was coated to 20% weight gain stored at 40° C./75% relative humidity (RH) was determined at periodic intervals over a 3 month period by determining the dissolution of the bupropion under the following conditions:
  • Media: 900 ml 0.1N HCl
  • Method: USP Type I Apparatus, 75 rpm at 37° C.
  • The dissolution data is presented in Table 12 as a % release into the medium of the total bupropion HCl in the tablet:
  • TABLE 12
    Time (h) 0 Month 1 Month 3 Month
    2 6.0 6.2 6.4
    4 14.4 15.3 15.7
    8 36.6 41.0 42.1
    16 72.8 82.6 84.2
    24 92.3 99.4 93.6
  • A comparative study was conducted to determine the bioavailability following administration of a single dose bupropion tablet (Tables 13 and 14) the invention
  • TABLE 13
    Bupropion HCl Bupropion HCl 150
    150 mg ER mg ER Bupropion
    Tablets. (Lot # Tablets. (Lot # HCl XL
    Bup-Bio (AQ) Bup-Bio (AQ) Tablets, 150 mg.
    Time (Hrs) 02C-02/150-NE) 03A-02/150-S) (Lot # 02A063)
    0 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00
    0.5 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00
    1 0.14 ± 0.51 0.00 ± 0.00 0.00 ± 0.00
    1.5 1.37 ± 1.55 0.00 ± 0.00 0.00 ± 0.00
    2 4.27 ± 2.25 0.00 ± 0.00 0.81 ± 1.64
    2.5 7.14 ± 2.76 0.43 ± 0.60 3.25 ± 3.40
    3 9.55 ± 3.57 1.15 ± 0.96 11.56 ± 10.81
    3.5 11.49 ± 4.68  2.35 ± 1.72 22.75 ± 16.54
    4 12.12 ± 4.91  3.26 ± 2.25 30.24 ± 18.87
    4.5 13.35 ± 5.35  5.37 ± 4.20 39.88 ± 23.52
    5 17.35 ± 6.80  7.27 ± 3.59 53.42 ± 20.15
    5.5 17.40 ± 6.69  8.53 ± 3.34 60.76 ± 19.45
    6 16.07 ± 5.48  9.40 ± 3.82 62.08 ± 18.83
    8 13.00 ± 5.34  8.98 ± 4.17 46.47 ± 16.36
    10 22.40 ± 10.48 16.39 ± 20.64 44.23 ± 15.86
    12 34.46 ± 13.26 18.57 ± 13.43 35.14 ± 15.55
    16 28.01 ± 9.36  27.36 ± 15.05 20.40 ± 6.96 
    24 17.87 ± 8.27  19.81 ± 8.32  10.11 ± 3.58 
    36 6.76 ± 3.93 8.51 ± 7.13 4.94 ± 1.58
    48 3.51 ± 1.36 4.01 ± 2.26 3.41 ± 1.66
    72 1.35 ± 0.88 1.65 ± 0.83 1.21 ± 0.90
    96 0.19 ± 0.46 0.35 ± 0.55 0.21 ± 0.51
    120 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00
  • TABLE 14
    Bupropion HCl Bupropion HCl 150 mg
    150 mg ER Tablets. ER Tablets. (Lot Bupropion HCl XL
    (Lot # Bup-Bio (AQ) # Bup-Bio (AQ) Tablets, 150 mg.
    02C-02/150-NE) 03A-02/150-S) (Lot # 02A063)
    SUBJECT AUC CMAX TMAX AUC CMAX TMAX AUC CMAX TMAX
     1 783.88 27.72 24.0 637.03 36.23 12.0 654.49 74.73 5.5
     2 366.41 28.05 12.0 550.51 30.78 16.0 534.11 53.70 6.0
     3 1179.19 52.75 16.0 1223.27 86.66 10.0 1223.86 91.77 6.0
     4 789.01 44.01 12.0 167.84 17.49 4.5 954.87 106.52 5.5
     5 730.90 44.92 10.0 518.11 29.30 16.0 881.67 62.52 6.0
     7 577.62 27.97 16.0 577.76 24.60 24.0 677.27 54.21 10.0
     8 1095.68 32.75 24.0 1094.55 32.36 24.0 1098.80 75.11 10.0
     9 494.33 23.05 12.0 495.00 17.49 16.0 440.79 43.58 5.5
    10 1000.63 35.30 16.0 911.09 35.40 24.0 1093.05 70.28 5.5
    12 837.22 32.33 12.0 877.09 23.13 36.0 747.36 50.07 5.0
    13 855.14 46.38 12.0 911.36 58.44 16.0 836.02 69.49 6.0
    14 806.11 55.63 12.0 572.52 21.93 16.0 1050.24 85.35 8.0
    15 612.93 27.04 16.0 717.12 36.47 16.0 613.25 72.73 5.5
    16 654.03 57.51 12.0 699.39 23.97 16.0 1082.74 71.07 6.0
    Mean 770.22 38.24 14.71 710.90 33.87 17.61 849.18 70.08 6.46
    Std. Dev 224.61 11.70 4.41 272.38 18.43 7.55 243.23 17.02 1.65
    CV (%) 29.16 30.58 29.97 38.32 54.41 42.85 28.64 24.29 25.47
    GeoMean 737.74 36.63 14.20 650.74 30.60 16.00 814.20 68.19 6.30
    Min 366.41 23.05 10.00 167.84 17.49 4.50 440.79 43.58 5.00
    Max 1179.19 57.51 24.00 1223.27 86.66 36.00 1223.86 106.52 10.00
  • EXAMPLE 3 Tramadol HCl tablets
  • 3.1 Tablet Core Preparation
  • The following formulation was prepared for tramadol HCl 40 mg or 80 mg strength tablets:
  • Ingredients % w/w % w/w
    Tramadol HCl 40.0 80.0
    Silicon Dioxide* 0.4 0.4
    Polyvinyl alcohol (PVA)** 1.1 0.9
    Lactose Anhydrous DT 56.5 16.69
    Atomized Glyceryl Behenate*** 2.00 2.00
    Total 100.00 100.00
    *Aerosil 200.
    **The PVA is prepared as a 3.8% solution (w/w) in purified water. The purified water is not considered as part of the theoretical batch size since it is evaporated during drying of the core in the fluid bed granulator.
    ***Compritol 888 ATO
  • All of the ingredients were transferred into a V-blender and processed as described above for metformin HCl. The granules were subsequently compressed into tablets.
  • The dissolution profile of the compressed tablet cores was determined under following conditions:
  • Medium: 900 ml water
  • Method: USP Type II Apparatus, 75 rpm at 37° C.
  • The tablet cores are immediate release. The release of tramadol HCl from the tablet cores was found to be 100% in about 30 min.
  • 3.2 Core Coating
  • The following four coat formulations were prepared:
  • TA TB TC TD
    Ingredients (% w/w) (% w/w) (% w/w) (% w/w)
    Eudrgit NE 38.5 33.3 27.74 28.82
    30D (Liquid)
    Talc 400 4.7 4.21 4.14 4.32
    Titanium Dioxide 1.6 1.35 1.2 1.24
    HPMC 606 1.4 1.35 1.02 1.05
    PEG 8000 0 1.18 0 0.43
    Simethicone 0.32 0.25 0.2 0.21
    Tween 80 0.24 0.2 0.12 0.12
    Purified water 53.24 58.16 65.58 63.81
    Total 100 100 100 100
  • The coating procedure was carried out as described above for metformin HCl tablet cores. Coated tablet cores were cured at 62±° C. for about 2 hours.
  • The tramadol tablet cores were coated with either one of the coating formulations TA, TB, TC, and TD. The coating was applied to a weight gain of approximately 8% to about 18%. Curing temperatures ranged from about 60° C. to about 65° C. and curing times were for either 3 or 4 hours. Dissolution tests were carried out as follows:
  • Medium: 900 ml 0.1N HCl (pH 1.2)
  • Method: USP Type I Apparatus, 75 rpm at 37° C.
  • The dissolution data is presented in Table 15 as a % release into the medium of the total tramadol HCl:
  • TABLE 15
    TC (8% weight TB (13% weight TA (18% weight
    TD (8% weight gain, gain, cured at gain, cured at gain, cured at
    Time (h) cured at 65° C. for 3 hrs) 60° C. for 3 hrs) 60° C. for 4 hrs) 60° C. for 3 hrs)
    0 0 0 0 0
    1 1.15 1.64 0.29 1.31
    2 3.05 5.16 0.44 1.94
    3 5.48 10.83 0.89 2.5
    4 8.32 21.09 1.73 3.23
    5 11.26 37.21 2.89 3.92
    6 15.07 51.97 4.1 4.93
    7 20 65.54 5.32 5.94
    8 25.01 76.21 6.55 6.97
    9 30.96 83.67 7.92 8.24
    10 36.99 90.23 9.22 9.65
    11 43.48 94.47 10.58 12.1
    12 49.4 97.8 12.07 17.08
    13 55.33 100.02 13.55 21.78
    14 60.97 101.6 15.25 31.93
    15 66.43 102.66 17.02 38.89
    16 71.33 103.39 19.12 44.12
    17 76.25 103.92 21.3 48.31
    18 80.54 23.76 52.18
    19 84.05 26.36 55.78
    20 87.18 28.93 58.96
    21 89.85 31.48 61.62
    22 91.87 64.63
    23 93.65 66.97
    24 95.2 69.54
  • Tablets coated with formulation TC were cured at either 60° C. for 3 hrs or for 22 hrs or at 70° C. for 3 hrs. Dissolution tests were conducted as follows:
  • Media: 900 ml 0.1N HCl
  • Method: USP Type I Apparatus, 75 rpm at 37° C. The dissolution data is presented in Table 16 as a % release into the medium of the total tramadol HCl:
  • TABLE 16
    TC cured at TC cured at TC cured at
    Time (h) 60° C. for 22 hrs 70° C. for3 hrs. 60° C. for 3 hrs
    0 0 0 0
    1 1.4032 1.3888 1.64
    2 3.9566 3.8022 5.16
    3 7.9378 7.3746 10.83
    4 13.631 12.784 21.09
    5 21.956 20.607 37.21
    6 32.55 31.338 51.97
    7 44.124 42.846 65.54
    8 54.9 53.873 76.21
    9 64.3 63.568 83.67
    10 73 71.219 90.23
    11 79.5 77.418 94.47
    12 84 82.787 97.8
    13 88.5 86.683 100.02
    14 91.5 89.748 101.6
    15 94 92.209 102.66
    16 96 94.006 103.39
    17 97.7 95.484 103.92
    18 98.9 96.959
    19 100 97.853
    20 100.6 98.695
    21 101.4 99.294
    22 101.9
    23 102.4
    24 102.6
  • The 80 mg tramadol tablet core was coated to about 8% weight gain with formulation TD and cured at about 65° C. for about 3 hours. Dissolution tests on the tablets was conducted under the following conditions:
  • Media: 900 ml, 0.1N HCl, pH 5.8 phosphate buffer or pH 6.8 phosphate buffer.
  • Method: USP Type I Apparatus, 75 rpm at 37° C.
  • The dissolution data is presented in Table 17 as a % release into the medium of the total tramadol HCl:
  • TABLE 17
    Time (h) TD-pH1.2 TD-pH5.8 TD-pH6.8
    0 0 0 0
    1 0.58 0.5 0.44
    2 1.49 1.96 1.61
    3 2.66 3.81 2.84
    4 4.12 6.2 4.58
    5 6.18 7.79 6.99
    6 9.34 12.6 11.16
    7 14.43 18.73 19.19
    8 22.98 28.78 32.31
    9 34.85 42.14 48.55
    10 49.13 55.48 62.39
    11 62.65 65.45 71.68
    12 73.37 72.39 78.03
    13 81.08 77.11 82.39
    14 85.36 80.71 85.52
    15 88.37 83.36 87.77
    16 90.66 85.54 89.72
    17 92.34 87.33 91.14
    18 93.79 88.83 92.42
    19 94.92 89.9 93.44
    20 95.74 91.04 94.3
    21 96.36 91.72 95.08
    22 96.97 92.63 95.65
    23 97.51 93.11 96.25
    24 97.94 93.68 96.78

Claims (46)

1-40. (canceled)
41. A controlled release oral dosage form comprising:
a) a core, wherein said core comprises:
i) an effective amount of at least one therapeutically active agent, and
ii) at least one first pharmaceutically acceptable excipient, and
b) a stable controlled release monolithic coating surrounding the core, wherein the stable controlled release monolithic coating is formed by a process comprising
coating the core with a coating composition to form a coated core, and
curing the coated core to form the stable controlled release monolithic coating,
wherein the coating composition comprises
i) an aqueous dispersion of a neutral ester copolymer without any functional groups;
ii) a poly glycol having a melting point of at least 55° C., and
iii) at least one second pharmaceutically acceptable excipient;
wherein the curing is conducted at a temperature at least equal to or greater than the melting point of the poly glycol, and
wherein the stable controlled release monolithic coating hydrates when placed into water.
42. The controlled release oral dosage form of claim 41, wherein the aqueous dispersion of neutral ester copolymer without any functional groups is selected from the group consisting of a 30% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate, a 40% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate, and combinations thereof.
43. The controlled release oral dosage form of claim 42, wherein the aqueous dispersion of neutral ester copolymer without any functional groups comprises a 30% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate.
44. The controlled release oral dosage form of claim 42, wherein the aqueous dispersion of neutral ester copolymer without any functional groups comprises a 40% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate.
45. The controlled release oral dosage form of claim 41, wherein the neutral ester copolymer without any functional groups is present in an amount of from about 1% to about 35% by weight of the coating composition.
46. The controlled release oral dosage form of claim 45, wherein the neutral ester copolymer without any functional groups is present in an amount of from about 1% to about 25% by weight of the coating composition.
47. The controlled release oral dosage form of claim 46, wherein the neutral ester copolymer without any functional groups is present in an amount of from about 1% to about 7% of the coating composition.
48. The controlled release oral dosage form of claim 41, wherein the poly glycol is selected from the group consisting of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000, Poloxamer 188, Poloxamer 338, Poloxamer 407, polyethylene oxides, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, and combinations thereof.
49. The controlled release oral dosage form of claim 41, wherein the poly glycol is selected from the group consisting of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000 and any combination thereof.
50. The controlled release oral dosage form of claim 49, wherein the polyethylene glycol comprises polyethylene glycol 8000.
51. The controlled release oral dosage form of claim 41, wherein the poly glycol is present in an amount of from about 0.1% to about 10% by weight of the coating composition.
52. The controlled release oral dosage form of claim 41, wherein the poly glycol is present in an amount of from about 0.1% to about 5% by weight of the coating composition.
53. The controlled release oral dosage form of claim 52, wherein the poly glycol is present in an amount of from about 0.1% to about 3% by weight of the coating composition.
54. The controlled release oral dosage form of claim 53, wherein said poly glycol is present in an amount of from about 0.1% to about 0.5% by weight of the coating composition.
55. The controlled release oral dosage form of claim 41, wherein the at least one second pharmaceutically acceptable excipient is selected from the group consisting of an anti-tacking agent, an emulsifying agent, a hydrophilic agent, an antifoaming agent, a flavorant, a colorant, a sweetener and any combination thereof.
56. The controlled release oral dosage form of claim 55, comprising the anti-tacking agent, wherein the anti-tacking agent is selected from the group consisting of adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, glyceryl monostearate, talc, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate and any combination thereof.
57. The controlled release oral dosage form of claim 56, wherein the anti-tacking agent is talc.
58. The controlled release oral dosage form of claim 56, wherein the anti-tacking agent is present in an amount of from about 1% to about 15% by weight of the coating composition.
59. The controlled release oral dosage form of claim 58, wherein the anti-tacking agent is present in an amount of from about 1% to about 7% by weight of the coating composition.
60. The controlled release oral dosage form of claim 55, comprising the hydrophilic agent, wherein said hydrophilic agent is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose and any combination thereof.
61. The controlled release oral dosage form of claim 60, wherein the hydrophilic agent comprises hydroxypropyl methylcellulose.
62. The controlled release oral dosage form of claim 60, wherein the hydrophilic agent is present in an amount from about 0.1% to about 10% by weight of the coating composition.
63. The controlled release oral dosage form of claim 62, wherein said hydrophilic agent is present in an amount from about 0.1% to about 6% by weight of the coating composition.
64. The controlled release oral dosage form of claim 63, wherein the hydrophilic agent is present in an amount from about 0.1% to about 3% by weight of the coating composition.
65. The controlled release oral dosage form of claim 55, comprising the anti-foaming agent, wherein said anti-foaming agent is selected from the group consisting of silicon oil, simethicone and any combination thereof.
66. The controlled release oral dosage form of claim 65, wherein the anti-foaming agent comprises simethicone.
67. The controlled release oral dosage form of claim 65, wherein the anti-foaming agent is present in an amount up to about 0.5% by weight of the coating composition.
68. The controlled release oral dosage form of claim 67, wherein the anti-foaming agent is present in an amount from about 0.1% to about 0.4% by weight of the coating composition.
69. The controlled release oral dosage form of claim 55, comprising the emulsifying agent, wherein said emulsifying agent is selected from the group consisting of a polysaccharide, a glycerol ester, a cellulose ether, a sorbitan ester, a polysorbate and any combination thereof.
70. The controlled release oral dosage form of claim 69, wherein the emulsifying agent comprises the polysorbate, and wherein said polysorbate is polyoxyethylene sorbitan mono-oleate.
71. The controlled release oral dosage form of claim 70, wherein the polyoxyethylene sorbitan mono-oleate is present in an amount of up to about 0.5% by weight of the coating composition.
72. The controlled release oral dosage form of claim 71, wherein the polyoxyethylene sorbitan mono-oleate is present in an amount of from about 0.1% to about 0.3% by weight of the coating composition.
73. The controlled release oral dosage form of claim 55, comprising the colorant, wherein said colorant is selected from the group consisting of iron oxide pigments, titanium dioxide, aluminum lakes and any combination thereof.
74. The controlled release oral dosage form of claim 73, wherein the colorant comprises titanium dioxide.
75. The controlled release oral dosage form of claim 73, wherein the colorant is present in an amount of from about 0.1% to about 10% by weight of the coating composition.
76. The controlled release oral dosage form of claim 73, wherein the colorant is present in an amount of from about 0.1% to about 5% by weight of the coating composition.
77. The controlled release oral dosage form of claim 76, wherein the colorant is present in an amount of from about 0.1% to about 2% by weight of the coating composition.
78. The controlled release oral dosage form of claim 41, wherein the controlled release oral dosage form is selected from the group consisting of a tablet and a capsule.
79. The controlled release oral dosage form of claim 41, wherein the at least one therapeutically active agent comprises metformin, a pharmaceutically acceptable salt thereof, or a combination thereof.
80. The controlled release oral dosage form of claim 41, wherein the at least one first pharmaceutically acceptable excipient is selected from the group consisting of a glidant, a lubricant, an anti-adherent, a sorbent, a diluent, a filler, a binder, and combinations thereof.
81. A controlled release oral dosage form comprising:
a) a core, wherein said core comprises:
i) an effective amount of metformin hydrochloride, and
ii) one or more first pharmaceutically acceptable excipients, and
b) a stable controlled release monolithic coating surrounding the core, wherein the stable controlled release monolithic coating is formed by a process comprising:
coating the core with a coating composition to form a coated core, and
curing the coated core to form the stable controlled release monolithic coating,
wherein the coating composition comprises
i) an ethyl acrylate and methyl methacrylate copolymer dispersion;
ii) a poly glycol comprising at least one of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000, and a mixture thereof;
iii) one or more second pharmaceutically acceptable excipients; and
wherein the curing is conducted at a temperature at least equal to or greater than the melting point of the poly glycol, and
wherein the stable controlled release coating hydrates when placed into water.
82. The controlled release oral dosage form of claim 81, wherein the effective amount of metformin hydrochloride is from about 5% to about 99% by weight of the core.
83. A controlled release oral dosage form comprising:
a) a core, wherein said core comprises:
i) an effective amount of at least one therapeutically active agent, and
ii) at least one first pharmaceutically acceptable excipient, and
b) a stable controlled release monolithic coating surrounding the core,
wherein said coating comprises
i) a neutral ester copolymer without any functional groups;
ii) a poly glycol having a melting point of at least 55° C., and
iii) at least one second pharmaceutically acceptable excipient;
wherein the stable controlled release monolithic coating hydrates when placed into water.
84. The controlled release oral dosage form of claim 83, wherein the neutral ester copolymer without any functional groups is selected from the group consisting of a 30% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate, a 40% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate, and combinations thereof.
85. The controlled release oral dosage form of claim 83, wherein the poly glycol is selected from the group consisting of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000 and any combination thereof.
US12/169,852 2002-02-21 2008-07-09 Controlled release dosage forms Abandoned US20080274177A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US35785102P true 2002-02-21 2002-02-21
US10/370,109 US7780987B2 (en) 2002-02-21 2003-02-21 Controlled release dosage forms
US12/169,852 US20080274177A1 (en) 2002-02-21 2008-07-09 Controlled release dosage forms

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12/169,852 US20080274177A1 (en) 2002-02-21 2008-07-09 Controlled release dosage forms
US13/892,657 US20130245154A1 (en) 2002-02-21 2013-05-13 Controlled release dosage forms
US14/262,622 US20150030675A1 (en) 2002-02-21 2014-04-25 Controlled Release Dosage Forms

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/370,109 Continuation US7780987B2 (en) 2002-02-21 2003-02-21 Controlled release dosage forms

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/892,657 Continuation US20130245154A1 (en) 2002-02-21 2013-05-13 Controlled release dosage forms

Publications (1)

Publication Number Publication Date
US20080274177A1 true US20080274177A1 (en) 2008-11-06

Family

ID=27765948

Family Applications (4)

Application Number Title Priority Date Filing Date
US10/370,109 Active 2025-03-23 US7780987B2 (en) 2002-02-21 2003-02-21 Controlled release dosage forms
US12/169,852 Abandoned US20080274177A1 (en) 2002-02-21 2008-07-09 Controlled release dosage forms
US13/892,657 Abandoned US20130245154A1 (en) 2002-02-21 2013-05-13 Controlled release dosage forms
US14/262,622 Abandoned US20150030675A1 (en) 2002-02-21 2014-04-25 Controlled Release Dosage Forms

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/370,109 Active 2025-03-23 US7780987B2 (en) 2002-02-21 2003-02-21 Controlled release dosage forms

Family Applications After (2)

Application Number Title Priority Date Filing Date
US13/892,657 Abandoned US20130245154A1 (en) 2002-02-21 2013-05-13 Controlled release dosage forms
US14/262,622 Abandoned US20150030675A1 (en) 2002-02-21 2014-04-25 Controlled Release Dosage Forms

Country Status (14)

Country Link
US (4) US7780987B2 (en)
EP (2) EP1476139B1 (en)
JP (3) JP4704685B2 (en)
AT (1) AT536173T (en)
AU (2) AU2003211145B2 (en)
CA (2) CA2476201C (en)
CY (1) CY1112517T1 (en)
DK (1) DK1476138T3 (en)
ES (2) ES2377729T3 (en)
MX (2) MXPA04008100A (en)
NO (1) NO20043913L (en)
NZ (2) NZ535456A (en)
PT (1) PT1476138E (en)
WO (2) WO2003072089A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110159045A1 (en) * 2008-08-29 2011-06-30 Macgregor Alexander Method of treating dysglycemia and glucose excursions

Families Citing this family (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8128957B1 (en) * 2002-02-21 2012-03-06 Valeant International (Barbados) Srl Modified release compositions of at least one form of tramadol
US8323692B2 (en) * 2002-02-21 2012-12-04 Valeant International Bermuda Controlled release dosage forms
AT536173T (en) * 2002-02-21 2011-12-15 Biovail Lab Int Srl Modified release formulations of at least one form of tramadol
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7413749B2 (en) * 2003-03-11 2008-08-19 Purdue Pharma L.P. Titration dosing regimen for controlled release tramadol
EP1905435A3 (en) * 2003-03-11 2008-05-14 Euro-Celtique S.A. Titration dosing regimen for controlled release tramadol
DE60330909D1 (en) * 2003-08-08 2010-02-25 Biovail Lab Int Srl Modified release tablet of bupropion hydrochloride
US7206632B2 (en) 2003-10-02 2007-04-17 Medtronic, Inc. Patient sensory response evaluation for neuromodulation efficacy rating
US20050074469A1 (en) * 2003-10-03 2005-04-07 Charles Signorino Stable lipophilic emulsions for acrylic coating and method of making
US20060172006A1 (en) * 2003-10-10 2006-08-03 Vincent Lenaerts Sustained-release tramadol formulations with 24-hour clinical efficacy
US20050084531A1 (en) * 2003-10-16 2005-04-21 Jatin Desai Tablet with aqueous-based sustained release coating
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg A process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
US8586085B2 (en) 2004-11-08 2013-11-19 Biokey, Inc. Methods and formulations for making pharmaceutical compositions containing bupropion
US20060099261A1 (en) * 2004-11-08 2006-05-11 Biokey, Inc. Methods and formulations for making controlled release oral dosage form
US20060099262A1 (en) * 2004-11-08 2006-05-11 Biokey, Inc. Methods and formulations for making controlled release oral dosage form
US20080096979A1 (en) * 2004-11-08 2008-04-24 Rubicon Research Pvt. Ltd. Aqueous Pharmaceutical Coating
US7884136B2 (en) 2005-06-27 2011-02-08 Biovail Laboratories International S.R.L. Modified-release formulations of a bupropion salt
RU2008104638A (en) * 2005-07-07 2009-08-20 Фарнэм Компаниз, Инк. (Us) The pharmaceutical compositions are well soluble in water medicaments that ensure their slow release
US8778395B2 (en) * 2005-08-11 2014-07-15 Andrx Labs, Llc Diltiazem controlled release formulation and method of manufacture
US7829120B2 (en) 2005-09-09 2010-11-09 Labopharm Inc. Trazodone composition for once a day administration
WO2007063946A1 (en) * 2005-11-30 2007-06-07 Fujifilm Ri Pharma Co., Ltd. Diagnostic and remedy for disease caused by amyloid aggregation and/or deposition
ES2279715B1 (en) * 2005-12-26 2008-06-01 Laboratorios Lesvi, S.L. oral formulation of olanzapine.
PE02352011A1 (en) 2006-05-04 2011-04-14 Boehringer Ingelheim Int pharmaceutical combinations comprising metformin and linagliptin
CA2810522A1 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Polymorphs
US20070264335A1 (en) * 2006-05-09 2007-11-15 Sherman Bernard C Modified release tablets comprising tramadol
CZ300698B6 (en) * 2006-06-16 2009-07-22 Zentiva, A. S. Metformin-containing tablet
WO2008008801A2 (en) * 2006-07-11 2008-01-17 Mcneil Nutritionals, Llc Solid oral dosage vitamin and mineral compositions
US8703191B2 (en) * 2006-07-25 2014-04-22 Intelgenx Corp. Controlled-release pharmaceutical tablets
US7674479B2 (en) 2006-07-25 2010-03-09 Intelgenx Corp. Sustained-release bupropion and bupropion/mecamylamine tablets
SA2709B1 (en) 2006-08-25 2011-07-20 بيورديو فارما إل. بي. Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic
AR071175A1 (en) 2008-04-03 2010-06-02 Boehringer Ingelheim Int pharmaceutical composition comprising an inhibitor of dipeptidyl peptidase-4 (DPP4) and a companion drug
AR071375A1 (en) * 2008-04-22 2010-06-16 Solvay Pharm Gmbh Formulations for pharmaceutical active ingredients poor permeability, preparation process and product
KR20190016601A (en) 2008-08-06 2019-02-18 베링거 인겔하임 인터내셔날 게엠베하 Treatment for diabetes in patients inappropriate for metformin therapy
KR20170136017A (en) 2009-11-27 2017-12-08 베링거 인겔하임 인터내셔날 게엠베하 Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
US20110136815A1 (en) * 2009-12-08 2011-06-09 Horst Zerbe Solid oral film dosage forms and methods for making same
JP2013515783A (en) * 2009-12-29 2013-05-09 インパックス ラボラトリーズ,インコーポレーテッド Gastroretentive solid oral dosage forms using swellable hydrophilic polymer
EA201201508A1 (en) 2010-05-05 2013-05-30 Бёрингер Ингельхайм Интернациональ Гмбх combination therapy
AR085689A1 (en) 2011-03-07 2013-10-23 Boehringer Ingelheim Int pharmaceutical compositions of metformin, linagliptin and SGLT-2 inhibitor
JP5876150B2 (en) 2011-07-15 2016-03-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Substituted quinazoline, use of these these preparation and pharmaceutical compositions
US9555001B2 (en) * 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
EP2849755A1 (en) 2012-05-14 2015-03-25 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
EP3110449A1 (en) 2014-02-28 2017-01-04 Boehringer Ingelheim International GmbH Medical use of a dpp-4 inhibitor
CA2955229A1 (en) 2014-07-17 2016-01-21 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
CA3022202A1 (en) 2016-06-10 2017-12-14 Boehringer Ingelheim International Gmbh Combinations of linagliptin and metformin

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4800087A (en) * 1986-11-24 1989-01-24 Mehta Atul M Taste-masked pharmaceutical compositions
US5055306A (en) * 1987-10-22 1991-10-08 Aps Research Limited Sustained-release formulations
US5204121A (en) * 1989-02-11 1993-04-20 Bayer Aktiengesellschaft Medicaments having controlled release of the active compound
US5292522A (en) * 1989-06-20 1994-03-08 Rohm Gmbh Aqueous film coating agent for solid medicaments
US5639476A (en) * 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5672359A (en) * 1993-07-21 1997-09-30 The University Of Kentucky Research Foundation Multicompartment hard capsule with control release properties
US5733575A (en) * 1994-10-07 1998-03-31 Bpsi Holdings, Inc. Enteric film coating compositions, method of coating therewith, and coated forms
US6022554A (en) * 1997-12-15 2000-02-08 American Home Products Corporation Polymeric microporous film coated subcutaneous implant
US6183779B1 (en) * 1999-03-22 2001-02-06 Pharmascience Inc. Stabilized pharmaceutical composition of a nonsteroidal anti-inflammatory agent and a prostaglandin
US6254887B1 (en) * 1993-05-10 2001-07-03 Euro-Celtique S.A. Controlled release tramadol
US20030143270A1 (en) * 2001-04-11 2003-07-31 Galephar Pharmaceutical Research, Inc. Extended release composition containing Tramadol
US20040037883A1 (en) * 2002-02-21 2004-02-26 Fang Zhou Controlled release dosage forms
US20040161461A1 (en) * 2001-12-04 2004-08-19 Pawan Seth Extended release pharmaceutical tablet of metformin
US20070027213A1 (en) * 2005-06-27 2007-02-01 Biovail Laboratories International S.R.L. Modified release formulations of a bupropion salt
US20080075774A1 (en) * 2005-06-27 2008-03-27 Bioavail Laboratories International S.R.L. Bupropion hydrobromide and therapeutic applications

Family Cites Families (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3097144A (en) * 1960-10-14 1963-07-09 Upjohn Co Heat-cured, polymeric, medicinal dosage film coatings containing a polyvinylpyrrolidone copolymer, polyethenoid acid, and polyethylene glycol
JPS63215620A (en) * 1987-03-03 1988-09-08 Nippon Soda Co Ltd Sustained release preparation
GB8707416D0 (en) * 1987-03-27 1987-04-29 Wellcome Found Pharmaceutical formulations
JP2700662B2 (en) * 1988-06-22 1998-01-21 大正製薬株式会社 Coated preparation
EP0524180B1 (en) 1990-04-11 1995-04-26 The Upjohn Company Taste masking of ibuprofen by fluid bed coating
US5288505A (en) 1991-06-26 1994-02-22 Galephar P.R., Inc., Ltd. Extended release form of diltiazem
US5376384A (en) * 1992-12-23 1994-12-27 Kinaform Technology, Inc. Delayed, sustained-release pharmaceutical preparation
US5458888A (en) 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
US5871776A (en) 1995-01-31 1999-02-16 Mehta; Atul M. Controlled-release nifedipine
DE19615812A1 (en) 1996-04-20 1997-10-23 Boehringer Mannheim Gmbh Pharmaceutical composition for oral application containing diphosphonic acids
DE19630035A1 (en) * 1996-07-25 1998-01-29 Asta Medica Ag Tramadol multiple unit formulations
AU5310898A (en) 1996-12-20 1998-07-17 Dumex-Alpharma A/S Release-controlled coated tablets
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
US5788987A (en) 1997-01-29 1998-08-04 Poli Industria Chimica Spa Methods for treating early morning pathologies
WO1999001111A1 (en) * 1997-07-02 1999-01-14 Euro-Celtique, S.A. Stabilized sustained release tramadol formulations
US6056977A (en) * 1997-10-15 2000-05-02 Edward Mendell Co., Inc. Once-a-day controlled release sulfonylurea formulation
AT261935T (en) * 1997-12-08 2004-04-15 Squibb Bristol Myers Co salts New metformin and procedural
US6245357B1 (en) * 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US6156342A (en) 1998-05-26 2000-12-05 Andex Pharmaceuticals, Inc. Controlled release oral dosage form
DE19826517B4 (en) 1998-06-15 2006-03-23 Baxter Healthcare S.A. A process for the preparation of film-coated tablets with cyclophosphamide as active ingredient and prepared therefrom cyclophosphamide film-coated tablet
PT974356E (en) * 1998-07-15 2004-02-27 Merck Sante Sas Tablets comprising a combination of metformin and glibenclamide
EP1098635B1 (en) 1998-07-17 2004-06-02 Bristol-Myers Squibb Company Enteric coated pharmaceutical tablet containing didanosine
US20030153607A1 (en) 1998-11-12 2003-08-14 Smithkline Beecham P.L.C. Novel composition and use
DE19901686A1 (en) * 1999-01-18 2000-07-20 Gruenenthal Gmbh Retarded tramadol with a storage-stable release profile and methods for their preparation
IN191482B (en) 1999-03-19 2003-12-06 Ranbaxy Lab Ltd A process for the preparation of a novel pharmaceutical coating composition
DE19940740A1 (en) * 1999-08-31 2001-03-01 Gruenenthal Gmbh pharmaceutical salts
BR0013825A (en) * 1999-08-31 2002-07-23 Gruenenthal Chemie tramadol presentation forms
SK287684B6 (en) 1999-12-20 2011-06-06 Schering Corporation Sustained release solid oral pharmaceutical dosage composition
US6419956B1 (en) 1999-12-30 2002-07-16 Ancile Pharmaceuticals Odor-masking coating for a pharmaceutical preparation
CA2396782A1 (en) 2000-02-04 2001-08-09 Depomed, Inc. Shell-and-core dosage form approaching zero-order drug release
US6627223B2 (en) * 2000-02-11 2003-09-30 Eurand Pharmaceuticals Ltd. Timed pulsatile drug delivery systems
US6676966B1 (en) 2000-05-09 2004-01-13 Intellipharmaceutics Corp. Extended release metformin hydrochloride formulations
IN192159B (en) 2000-05-15 2004-02-28 Ranbaxy Lab Ltd Process for the preparation of an aqueous coating for the controlled release of an active ingredient
US6620439B1 (en) * 2000-10-03 2003-09-16 Atul M. Mehta Chrono delivery formulations and method of use thereof
US6866866B1 (en) 2000-11-03 2005-03-15 Andrx Labs, Llc Controlled release metformin compositions
US6749867B2 (en) 2000-11-29 2004-06-15 Joseph R. Robinson Delivery system for omeprazole and its salts
SE0100200D0 (en) 2001-01-24 2001-01-24 Astrazeneca Ab New film coating
ITMI20010220A1 (en) 2001-02-05 2002-08-05 Valpharma Sa Multiparticulate formulations for oral administration of lithium salts suitable for a daily administration
NZ527930A (en) 2001-03-16 2005-11-25 Andrx Pharmaceuticals Llc Controlled release sulfonylurea formulation
JP5138856B2 (en) * 2001-06-20 2013-02-06 武田薬品工業株式会社 The method of manufacturing tablets
US20040126428A1 (en) 2001-11-02 2004-07-01 Lyn Hughes Pharmaceutical formulation including a resinate and an aversive agent
EP1429724B1 (en) 2001-09-28 2013-11-06 McNeil-PPC, Inc. Dosage form containing a confectionery composition
US6723348B2 (en) 2001-11-16 2004-04-20 Ethypharm Orodispersible tablets containing fexofenadine
US6667054B2 (en) 2001-12-05 2003-12-23 Bernard Charles Sherman Metformin hydrochloride tablets
TWI252111B (en) 2001-12-14 2006-04-01 Solvay Pharm Gmbh Matrix film tablet with controlled release of a natural mixture of conjugated estrogens
RU2323717C2 (en) 2001-12-19 2008-05-10 Астразенека Аб Novel film coating
WO2003055475A1 (en) 2002-01-03 2003-07-10 Lek Pharmaceutical And Chemical Company D.D. Controlled release pharmaceutical formulation containing venlafaxine
JP2003290319A (en) * 2002-01-30 2003-10-14 Kikusui Seisakusho Ltd Device for manufacturing tablet
AU2003225102A1 (en) 2002-04-23 2003-11-10 Bristol-Myers Squibb Company Modified-release vasopeptidase inhibitor formulation, combinations and method
US6902746B2 (en) 2002-07-03 2005-06-07 Yung Shin Pharmaceutical Industrial Co., Ltd. Oral pharmaceutical compositions containing non-steroidal anti-inflammatory drugs and method for preparing the same
SE0202353D0 (en) 2002-08-01 2002-08-01 Astrazeneca Ab New film coating
US7429619B2 (en) 2002-08-02 2008-09-30 Mcneil Consumer Healthcare Polyacrylic film forming compositions
US7985422B2 (en) 2002-08-05 2011-07-26 Torrent Pharmaceuticals Limited Dosage form
US8216609B2 (en) 2002-08-05 2012-07-10 Torrent Pharmaceuticals Limited Modified release composition of highly soluble drugs
US7018658B2 (en) 2002-11-14 2006-03-28 Synthon Bv Pharmaceutical pellets comprising tamsulosin
DE10260919A1 (en) 2002-12-20 2004-07-01 Röhm GmbH & Co. KG A process for preparing coated dosage forms and food supplements with a concentration gradient in the coating
US20040185097A1 (en) 2003-01-31 2004-09-23 Glenmark Pharmaceuticals Ltd. Controlled release modifying complex and pharmaceutical compositions thereof
US20050048118A1 (en) 2003-07-25 2005-03-03 Joan Cucala Escoi Modified release venlafaxine hydrochloride tablets
US20050025829A1 (en) 2003-07-29 2005-02-03 Kim Cherng-Ju Controlled drug release tablets
US20050123596A1 (en) 2003-09-23 2005-06-09 Kohane Daniel S. pH-triggered microparticles
EP1523981A1 (en) 2003-10-13 2005-04-20 Wyeth Extended release formulations of venlafaxine
US20050084531A1 (en) 2003-10-16 2005-04-21 Jatin Desai Tablet with aqueous-based sustained release coating

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4800087A (en) * 1986-11-24 1989-01-24 Mehta Atul M Taste-masked pharmaceutical compositions
US5055306A (en) * 1987-10-22 1991-10-08 Aps Research Limited Sustained-release formulations
US5204121A (en) * 1989-02-11 1993-04-20 Bayer Aktiengesellschaft Medicaments having controlled release of the active compound
US5292522A (en) * 1989-06-20 1994-03-08 Rohm Gmbh Aqueous film coating agent for solid medicaments
US5639476A (en) * 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US6254887B1 (en) * 1993-05-10 2001-07-03 Euro-Celtique S.A. Controlled release tramadol
US5672359A (en) * 1993-07-21 1997-09-30 The University Of Kentucky Research Foundation Multicompartment hard capsule with control release properties
US5733575A (en) * 1994-10-07 1998-03-31 Bpsi Holdings, Inc. Enteric film coating compositions, method of coating therewith, and coated forms
US6022554A (en) * 1997-12-15 2000-02-08 American Home Products Corporation Polymeric microporous film coated subcutaneous implant
US6183779B1 (en) * 1999-03-22 2001-02-06 Pharmascience Inc. Stabilized pharmaceutical composition of a nonsteroidal anti-inflammatory agent and a prostaglandin
US20030143270A1 (en) * 2001-04-11 2003-07-31 Galephar Pharmaceutical Research, Inc. Extended release composition containing Tramadol
US20040161461A1 (en) * 2001-12-04 2004-08-19 Pawan Seth Extended release pharmaceutical tablet of metformin
US20040037883A1 (en) * 2002-02-21 2004-02-26 Fang Zhou Controlled release dosage forms
US7780987B2 (en) * 2002-02-21 2010-08-24 Biovail Laboratories International Srl Controlled release dosage forms
US20070027213A1 (en) * 2005-06-27 2007-02-01 Biovail Laboratories International S.R.L. Modified release formulations of a bupropion salt
US20080075774A1 (en) * 2005-06-27 2008-03-27 Bioavail Laboratories International S.R.L. Bupropion hydrobromide and therapeutic applications

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110159045A1 (en) * 2008-08-29 2011-06-30 Macgregor Alexander Method of treating dysglycemia and glucose excursions
US9061061B2 (en) 2008-08-29 2015-06-23 Orx Pharmaceutical Corporation Method of treating dysglycemia and glucose excursions

Also Published As

Publication number Publication date
ES2627842T3 (en) 2017-07-31
CA2476201A1 (en) 2003-09-04
EP1476139A1 (en) 2004-11-17
MXPA04008164A (en) 2005-05-17
JP4704685B2 (en) 2011-06-15
PT1476138E (en) 2012-02-14
EP1476139A4 (en) 2007-12-26
US7780987B2 (en) 2010-08-24
AT536173T (en) 2011-12-15
AU2003211146A1 (en) 2003-09-09
JP2005526043A (en) 2005-09-02
EP1476138B8 (en) 2012-03-07
CA2476201C (en) 2009-09-01
WO2003072025A3 (en) 2003-11-06
NZ535456A (en) 2006-08-31
NZ535455A (en) 2009-08-28
EP1476138A2 (en) 2004-11-17
SI1476138T1 (en) 2012-07-31
WO2003072089A1 (en) 2003-09-04
EP1476139B1 (en) 2017-05-17
JP2010155864A (en) 2010-07-15
US20150030675A1 (en) 2015-01-29
EP1476138A4 (en) 2008-05-07
US20130245154A1 (en) 2013-09-19
ES2377729T3 (en) 2012-03-30
CA2476496A1 (en) 2003-09-04
AU2003211145B2 (en) 2007-07-12
US20040037883A1 (en) 2004-02-26
MXPA04008100A (en) 2005-06-17
DK1476138T3 (en) 2012-02-20
JP2005526047A (en) 2005-09-02
CA2476496C (en) 2009-12-15
JP5069395B2 (en) 2012-11-07
CY1112517T1 (en) 2015-12-09
NO20043913L (en) 2004-11-16
AU2003211146B2 (en) 2007-07-19
EP1476138B1 (en) 2011-12-07
AU2003211145A1 (en) 2003-09-09
WO2003072025A2 (en) 2003-09-04

Similar Documents

Publication Publication Date Title
US8784888B2 (en) Controlled release and taste masking oral pharmaceutical composition
US7906141B2 (en) Sustained-release, oral pharmaceutical forms of formulation
US6156342A (en) Controlled release oral dosage form
US6033686A (en) Controlled release tablet of bupropion hydrochloride
US5273760A (en) Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
EP1496870B1 (en) Dosage form and method for producing the same
US5411745A (en) Powder-layered morphine sulfate formulations
JP5827952B2 (en) Pharmaceutical composition having a sustained and immediate simultaneously
US6316031B1 (en) Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
EP0553392B1 (en) Stabilized controlled release formulations having acrylic polymer coating
US6270805B1 (en) Two pellet controlled release formulation for water soluble drugs which contains an alkaline metal stearate
US20060204587A1 (en) Use of film coating as taste-masking coating of oral dosage forms
US20050042290A1 (en) Controlled release pharmaceutical formulation containing venlafaxine
US6893661B1 (en) Controlled release formulations using intelligent polymers
US20110045074A1 (en) Matrix type sustained-release preparation containing basic drug or salt thereof and, method for manufacturing the same
US20050042277A1 (en) Pharmaceutical compositions having a swellable coating
US6350471B1 (en) Tablet comprising a delayed release coating
US20060193911A1 (en) Controlled release venlafaxine formulations
JP4790415B2 (en) Pharmaceutical compositions
US20030133982A1 (en) Zero-order sustained release dosage forms and method of making same
KR101575679B1 (en) Controlled release oral dosage formulation comprising a core and at least one barrier layer
US20140242063A1 (en) Pharmaceutical compositions
US20040137156A1 (en) Coated solid dosage form and method for preparing same
US6110494A (en) Cisapride mini-tablet formulations
US6143327A (en) Delayed release coated tablet of bupropion hydrochloride

Legal Events

Date Code Title Description
AS Assignment

Owner name: J.P. MORGAN CHASE BANK, N.A., TORONTO BRANCH, AS A

Free format text: PATENT AND TRADEMARK SECURITY AGREEMENT;ASSIGNOR:BIOVAIL LABORATORIES INTERNATIONAL SRL;REEL/FRAME:022813/0195

Effective date: 20090609

AS Assignment

Owner name: GOLDMAN SACHS LENDING PARTNERS LLC, AS COLLATERAL

Free format text: SECURITY AGREEMENT;ASSIGNORS:BIOVAIL INTERNATIONAL LABORATORIES SRL;BIOVAIL INTERNATIONAL LABORATORIES (BARBADOS) SRL;REEL/FRAME:025084/0022

Effective date: 20100928

AS Assignment

Owner name: BIOVAIL CORPORATION, CANADA

Free format text: RELEASE OF SECURITY AGREEMENT;ASSIGNOR:JPMORGAN CHASE BANK, N.A., TORONTO BRANCH;REEL/FRAME:025095/0479

Effective date: 20100928

Owner name: BIOVAIL LABORATORIES INTERNATIONAL SRL, CANADA

Free format text: RELEASE OF SECURITY AGREEMENT;ASSIGNOR:JPMORGAN CHASE BANK, N.A., TORONTO BRANCH;REEL/FRAME:025095/0479

Effective date: 20100928

AS Assignment

Owner name: BIOVAIL INTERNATIONAL LABORATORIES SRL, BARBADOS

Free format text: PATENT SECURITY RELEASE AGREEMENT;ASSIGNOR:GOLDMAN SACHS LENDING PARTNERS LLC;REEL/FRAME:025950/0073

Effective date: 20110308

Owner name: BIOVAIL INTERNATIONAL LABORATORIES (BARBADOS) SRL,

Free format text: PATENT SECURITY RELEASE AGREEMENT;ASSIGNOR:GOLDMAN SACHS LENDING PARTNERS LLC;REEL/FRAME:025950/0073

Effective date: 20110308

AS Assignment

Owner name: VALEANT INTERNATIONAL (BARBADOS) SRL, BARBADOS

Free format text: CHANGE OF NAME;ASSIGNOR:BIOVAIL LABORATORIES INTERNATIONAL SRL;REEL/FRAME:026404/0095

Effective date: 20110308

AS Assignment

Owner name: GOLDMAN SACHS LENDING PARTNERS LLC, AS COLLATERAL

Free format text: SECURITY AGREEMENT;ASSIGNORS:VALEANT INTERNATIONAL (BARBADOS) SRL, A BARBADOS INTERNATIONAL SOCIETYWITH RESTRICTED LIABILITY;BIOVALE LABORATORIES INTERNATIONAL (BARBADOS) SRL, A BARBADOS INTERNATIONAL SOCIETY WITH RESTRICTED LIABILITY;REEL/FRAME:026605/0801

Effective date: 20110629

AS Assignment

Owner name: VALEANT INTERNATIONAL BERMUDA, BERMUDA

Free format text: CHANGE IN NAME AND COUNTRY OF INCORPORATION;ASSIGNOR:VALEANT INTERNATIONAL (BARBADOS) SRL;REEL/FRAME:028757/0052

Effective date: 20120703

AS Assignment

Owner name: BARCLAYS BANK PLC, AS SUCCESSOR AGENT, NEW YORK

Free format text: NOTICE OF SUCCESSION OF AGENCY;ASSIGNOR:GOLDMAN SACHS LENDING PARTNERS, LLC;REEL/FRAME:034749/0689

Effective date: 20150108