The present invention relates to a controlled release pellet of metoprolol and its pharmaceutically acceptable salts that uses a water soluble or a water swellable inert starting seed or core.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention solves the problems associated with the use of a water-soluble and/or water swellable cores for metoprolol controlled release pellets. The controlled release pellets are prepared by coating a drug layer or layers onto a water soluble or water swellable inert starting seed or core then applying over the drug layer a polymeric coating that controls the release of the drug. Said pellets are then formed into an extended release tablet or capsule for oral administration.

The controlled release pellets of the present invention are comprised of: a) a water soluble or water swellable inert core; b) a drug layer comprising metoprolol or a pharmaceutically acceptable salt thereof applied to the inert core; and c) a controlled release coating surrounding the drug layer.

The pellets can be mixed with conventional tabletting excipients and compressed into a tablet or loaded into a capsule for oral administration.

The present invention also relates to a method of producing the pellets or beads.

Additionally, the present invention relates to the formation of a tablet using the controlled release pellets with and without additional active release pellets. The active release pellets being formed in the same method as the controlled release pellets, but without the controlled release coating.

In a preferred embodiment of the present invention an aqueous solvent system is used instead of an organic solvent system to apply the drug layer to the inert core. This process is also more environmentally friendly due to the lack of conventional organic solvents such as methylene chloride.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, the inert core is a water soluble or water swellable core. The inert core must be of sufficient density and strength to enable it to undergo coating in a fluidized bed process. The inert cores of the present invention should have a diameter less than 30 mesh and preferably less than 40 mesh. In a preferred embodiment the inert cores should have a diameter ranging from about 30 to 200 mesh, preferably 40 to 120 mesh and most preferred 60 to 80 mesh.

Suitable water-soluble cores are sugar seeds or non-pareils that are well known in the art. Examples of water swellable cores are microcrystalline cellulose spheres commercially available from FMC Corporation under the trade name CELPHERE.RTM..

The pharmaceutically active ingredient or drug that is applied to the inert core is metoprolol or its pharmaceutically acceptable salts, such as, succinate, fumarate, tartrate, citrate, pamoate, mandelate or others that are described in U.S. Pat. Nos. 4,281,654; 4,303,637; 4,957,745; 5,001,161 and 5,081,154 which are incorporated herein by reference. The metoprolol or its pharmaceutically acceptable salts may be in its racemic form or a pure enantiomer, such as, the s-enantiomer of the benzoate or sorbate salt. In one of the embodiments of the present invention it is preferred that the metoprolol used is micronized, so the average particle size is less than 100 microns, and preferably less than 50 microns, and most preferably not less than 25 microns.

In order for the drug to be applied to the inert core, a binding agent may be necessary. The binding agent employed in the active pellet can be any type of binding agent commonly known in the art. Examples of some of the preferred binding agents are polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylate, ethylcellulose, or mixtures of the foregoing. In the preferred embodiment of the present invention, the binding agent is a water soluble or rapidly dispersible material, such as hydroxypropyl methylcellulose, or polyvinyl pyrrolidone.

The drug is applied to the inert core by any conventional techniques known in the industry, such as, pan coating, roto-granulation or fluidized bed coating. During such coating operations the drug is dispersed or dissolved in an organic or aqueous solvent, which may also contain other conventional excipients, such as the above mentioned binding agent. In a preferred embodiment, an aqueous solvent is employed. When the aqueous solvent is used, it may be necessary to include a surfactant in the solvent in order to keep the drug and other excipients suspended or dispersed.

If a surfactant is employed, it can be any type of surfactant commonly known in the art such as a fatty acid, a chelating agent, a bile salt or mixtures thereof. Examples of some preferred surfactants are fatty acids such as capric acid, oleic acid and their monoglycerides, especially alkyl sulfates, such as sodium lauryl sulfate, sodium dodecyl sulfate and polysorbate 80; chelating agents such as citric acid and phytic acid. The preferred surfactant used herein is polysorbate 80.

In a preferred embodiment of the present invention, the drug layer comprises the following ingredients -- see Original Patent.

Once the drug layer is applied to the inert core, a controlled release coat is applied to the drug layer. The controlled release coat is applied so that it prevents or retards the release of the drug from the pellet. The controlled release coat is preferably comprised of a polymeric film forming polymer and may optionally contain conventional processing aids such as emulsifiers, plasticizers, surfactants, lubricants or channeling agents.

The film forming polymers suitable for use in the controlled release coating are water insoluble polymers such as, ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, triacetate, cellulose acetate phathalate, cellulose tricetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), chitin, chitosan, poly(anhydrides), poly(lactic acid), ploy(glycolic acid), poly(ortho esters), poly(lactide co-glycollide), poly(hydroxy butyrate) or polyurethane or a mixture thereof.

As used herein the term water insoluble polymer includes polymers that are slightly permeable to water. A suitable polymer which is slightly permeable to water is a polymer sold under the trade name Eudragit.RTM. RS. Eudragit.RTM. Polymers are polymeric lacquer substances based on arcylates and methylarcylates.

The controlled release coating may be built up applying a plurality of coats of polymer solution or suspension to the drug core as hereinafter described. The membrane solution or suspension contains the polymer(s) dissolved or suspended, respectively, in a suitable aqueous or organic solvent or mixture of solvents, optionally in the presence of a conventional excipient.

The controlled release coating solution or suspension may be applied to the active cores in a conventional coating pan as indicated or, alternatively, using an automated system such as a CF granulator, for example a FREUND CF.RTM. granulator, a GLATT.RTM. fluidized bed processor, a modified ACCELA-COTA.RTM. or other suitably automated bead coating equipment.

Suitable emulsifiers that can be used in the present invention are may include, but are not limited to, phospholipids, polysorbate, propylene glycol, poloxamer, glyceryl monostearate, other pharmaceutical emulsifiers and/or mixtures thereof.

Suitable surfactants that may optionally be used in the present invention are sodium lauryl sulfate, sodium taurocholate or a polysorbate.

The controlled release coating may optionally include a plasticizing agent. Plasticizers are used to increase the resiliency of the finished product from cracking and fracturing. Suitable plasticizing agents include polyethylene glycol, propylene glycol, glycerol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil, poloxamers and varying percentages of acetylated monoglycerides.

Suitable lubricants possess anti-sticking or anti-tacking properties. Suitable lubricants used in preparing solid dosage forms may include talc, stearic acid, magnesium stearate, glyceryl monostearate, sodium stearyl fumerate, hydrogenated oils, polyethylene glycols and sodium stearate. A particularly preferred lubricant is talc.

A channeling agent is an excipient that is incorporated into the controlled release coating and functions to increase the volume of fluid imbibed into the core. It creates channels, preferably tortuous channels that enable gastric and intestinal fluid to enter the core and allow the active compound to leave the core. The channeling agent can be a water soluble material or an enteric material. Some examples of the preferred materials that are useful as channeling agents are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, cellulose acetate butyrate, methacrylic acid copolymers, zein and mixtures thereof. The preferred channeling agent is Eudragit.RTM. S100, a methacrylic acid copolymer commercially available from Rohm Pharma Gmbh.

The channeling agent may also be a water soluble drug. If the channeling agent is a drug, such as metoprolol, the present dosage form has the added advantage of providing an immediate release of active component.

In a preferred embodiment of the present invention, the controlled release coating comprises the following ingredients -- see Original Patent.

Once the controlled release coat is applied to the active cores, a plurality of the pellets may be compressed into a tablet or filled into a gelatin capsule, HPMCP capsule, HPMC capsule and/or pullulan capsule. The tablet forming processes preferably involves the mixing of the controlled release pellets with a disintegrant, a lubricant (or plasticizer) and a surfactant. The mixture is then compressed with a cushioning agent into a tablet and optionally coated with a color, esthetic or polishing coat. Suitable cushioning agents include, but are not limited to glyceryl monostearate, various grades of microcrystalline cellulose, lactose and mixtures thereof.

The controlled release pellets prepared in accordance with the present invention should exhibit the following dissolution profile (see Original Patent) when tested in a USP Type 2 apparatus, at 75 rpm, 37.degree. C. and in a phosphate buffer medium with a pH of 7.5.

Disintegrants used in the tabletting process are added to assist in the break down of the tablet. Suitable disintegrants are crospovidone XL-10, microcrystalline cellulose pH-102, microcrystalline cellulose pH-200, sodium starch glycolate and the like. The preferred disintegrant in the present invention is a mixture of crospovidone XL-10, microcrystalline cellulose pH-102 and microcrystalline cellulose pH-200.

Microcrystalline cellulose is added to improve the tabletting properties and assist in disintegration of the tablet in vitro. This in turn, assists in the release of the active pellets in the body. In a preferred embodiment, microcrystalline cellulose is used as a filler and cushioning agent. A cushioning agent is an excipient which facilitates compression of pellets into a tablet or capsule, and helps protect coated pellets from severe compaction forces and surface cracking.

Lubricants are used in the tabletting process to prevent the mixture of components from sticking to the equipment during the tabletting. The lubricant also aids the ejection of the tablet from the dies, and additionally may help improve powder flow. Suitable lubricants are described above. The preferred lubricant in this step of the present invention is glyceryl monostearate. Additionally, lubricants provide cushioning properties.

In a preferred embodiment of the present invention, the tablet comprises the following ingredients -- see Original Patent.

If an immediate release dose of the active ingredients is desired for the final dosage form, the tablet or capsule may further comprise a therapeutically effective amount of the drug which can be mixed into the tablet excipient or with the controlled release pellets prior to encapsulation. In a preferred embodiment, the immediate release amount of the drug is provided by adding active drug pellets or pellets which have not been coated with the controlled release coating to the controlled release pellets prior to encapsulation or tabletting. In a more preferred embodiment of the present invention, a tablet will have the following composition -- see Original Patent.

A tablet or capsule containing the controlled release pellets prepared in accordance with the present invention and an immediate release form of metoprolol should exhibit the following dissolution profile (see Original Patent) when tested in a USP Type 2 apparatus at 75 rpm, 37.degree. C. and in a phosphate buffer medium with a pH of 7.5

The tablet or capsule containing the controlled release pellets prepared in accordance with the present invention and containing an immediate release amount of the metoprolol should obtain its peak plasma level within about 3 to 8 hours, preferably about 4.5 hours to about 7.5 hours and have a C.sub.max of less than 300 ng/ml, preferably less than 275 ng/ml, and most preferably between 200 ng/ml and 275 ng/ml.
 

Claim 1 of 37 Claims

1. A controlled release pellet consisting essentially of: a) an inert core that is water swellable; b) a drug layer applied to the inert core comprising: i) metoprolol succinate; ii) a binder; and iii) optionally a surfactant; c) a controlled release coating surrounding the drug layer comprising: i) 75-90% of a water insoluble film forming polymer selected from the group consisting of cellulose acetate, cellulose acetate butyrate, ethyl cellulose, hydroxypropyl cellulose acetate, hydroxypropyl methyl phthalate and cellulose acetate phthalate or mixtures thereof.

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