Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to a new film coating. More specifically the present invention relates to a new film coating for the achievement of modified release from pharmaceutical formulations such as tablets, pellets, etc., wherein the film coating may be applied in a substantially aqueous environment. Furthermore, the invention provides a process for the preparation of such a film coating.
• Oral administration of a drug is the most convenient for the patient.
• Oral formulations must also meet the requirements of safety and simplicity.
• different approaches are taken during its formulation to obtain a suitable drug delivery profile. For example, a sparingly soluble drug which is given once a day requires a different type of formulation than an easily soluble drug which is taken several times a day.
• ER dosage forms (i) the matrix system where the drug is mixed with the matrix material (often a polymer or a wax) and (ii) the drug reservoir system where the drug is formulated into a core (tablet or pellets) surrounded by a polymeric film.
• the film coating is then a release rate-controlling barrier determined by many factors including its dissolution rate, its permeability, the solubility of the substance, etc.
• Latex particles in water as the dispersion medium have been known for almost half a century. These particles are polymeric colloidal particles in the 10 to 100 nm range and have been utilized as film formers in different applications. If the polymer particle has a sufficiently low glass transition temperature (Tg) when the water is evaporated, the particles can coalesce to form a film.
• Tg glass transition temperature
• Eudragit® NE 30D which contains approximately 28.5 % w/w particles of the copolymer poly(ethylacrylate - co-methylmethacrylate), and 1.5 % w/w of the non-ionic tenside Nonoxynol 100 (a polyoxyethylated nonylphenol) as a stabiliser.
• the advantages of this copolymer are that no plasticizer is needed for film formation, the copolymer has a low film forming temperature and the high flexibility of dried films. The last property is especially useful when preparing tablets.
• an anti-sticking agent has to be added to the dispersion, as reported by Petereit and Weisbrod 1995, due to the tacky property of the pellets during coating.
• Several such agents are available e.g., talc, silica, magnesium stearate and glyceryl mono stearate (GMS).
• GMS glyceryl mono stearate
• PS80 Polysorbate 80
• Instabilities of coated dosage (water based) forms are mainly based on physical interaction caused, most likely, by improper formulations of coating suspension (i.e., plasticizers, surfactants, or pigments), or the film coating process ( Petereit et al, Eur. J pharmaceutics and Biopharmaceutics 47, (1999) 15-25). Residual moisture, probably enclosed in the core and, migrating over time, may increase the permeability of coatings due to plasticizing effects.
• AAPS Pharmasci 2001 3(2) 1-11 by Lin et al discloses that the endogenous surfactant of NE30D, nonoxynol 100, crystallizes in films of NE30D. The importance of compensating for this tendency for crystallization is discussed.
• US 5,478,573 discloses that mixtures of different dispersions are prepared and stabilized with the surface active agent sodium lauryl sulfate. Also disclosed is a coating comprising magnesium stearate dispersed in water and added to a mixture of the two dispersions NE30D and AquacoatTM.
• US 4,784,858 discloses that the anti-tacking agent talc is added together with a surfactant (Tween 80) to Eudragit E30D.
• WO 02058677 discloses coating formulations comprising sodium stearyl fumarate (PRUV®).
• the purpose of the present invention is to provide a new film coating system that does not have the above mentioned problems. Improved properties of the new film coating system are, for example, non-stickiness, high mechanical strength, reproducibility during processing, and stability of the film coating during storage.
• the invention features a film coating composition, a film coating, a formulation including a pharmaceutically core comprising a pharmaceutically active agent (e.g., metoprolol) and a film coat.
• a pharmaceutically active agent e.g., metoprolol
• the invention further includes a process of making the coating and a process to prepare a formulation having the coating of the invention.
• the present invention provides a film coating which, has the unexpected property of having a stable release profile following storage. Specifically, the present invention features a pharmaceutical composition which surprisingly has a low amount of surface active agent. Accordingly, the invention provides a film coating composition suitable for use in coating pharmaceutical formulations comprising a dispersion which comprises:
• GMS glyceryl monostearate
• the invention provides a film coat covering a pharmaceutical core wherein the core includes a pharmacologically active ingredient and optionally one or more pharmaceutically acceptable excipients.
• the film coat includes an:
• the acrylic polymer can be an ethyl acrylate and/or methyl methacrylate copolymer
• the anti-sticking agent can be glyceryl mono stearate (GMS)
• the surface active agent can be nonoxynol 100.
• the film coat has a thickness in the range of 1 to 100 micrometres, preferably in the range of 5 to 50 micrometres and more preferably in the range of 10 to 30 micrometres
• the pharmacologically active ingredient can be provided in a plurality of beads, optionally containing one or more pharmaceutically acceptable excipients, wherein each of the beads is coated with a film coat as defined above.
• Such film coated beads may be provided in sachets or formulated as a capsule, for example a hard gelatin capsule, or compressed to form tablets using known methods with the optional addition of other pharmaceutically acceptable additives.
• Coated beads to be compressed into a tablet are obtained by conventional techniques known to those skilled in the art. Also, during this process suitable other agents can be added.
• suitable fillers e.g., microcrystalline cellulose, talc, sodium stearyl fumarate, etc.
• suitable fillers e.g., microcrystalline cellulose, talc, sodium stearyl fumarate, etc.
• acceptable compression characteristics of the formulation e.g., hardness of the tablet.
• the beads may contain an insoluble core onto which the active ingredient has been deposited, for example, by spraying.
• Suitable materials for the inert core are silicon dioxide, glass or plastic resin particles.
• Suitable types of plastic material are pharmaceutically acceptable plastics such as polypropylene or polyethylene preferably polypropylene.
• Such insoluble cores have a size diameter in the range of 0.01-2mm, 0 preferably in the range of 0.05-0.5mm and more preferably in the range of 0. l-0.3mm.
• the ductility of the film can be in a range of 500-20000 J/m 3 ' In another embodiment the ductility is in the range of 2500-20000 J/m 3 . In yet another embodiment the ductility is in the range of 10000-20000 J/m 3 . 5
• the invention provides a pharmaceutical formulation which includes a) a pharmaceutical core comprising a pharmacologically active ingredient and optionally one or more pharmaceutically acceptable excipients, and b) a film coat comprising: 0 i) an acrylic polymer, which is Eudragit NE30D ii) an anti-sticking agent, which is glyceryl monostearate (GMS) iii) a surface active agent wherein the surface active agent is in the amount less than 5.4 % by weight of the weight of the film coat, wherein the film coat has been deposited from a ater-containing liquid and does not 5 contain a vinyl acetate polymer.
• a pharmaceutical formulation which includes a) a pharmaceutical core comprising a pharmacologically active ingredient and optionally one or more pharmaceutically acceptable excipients, and b) a film coat comprising: 0 i) an acrylic polymer, which is Eudragit NE30D ii) an anti-sticking agent, which is glyceryl monoste
• the pharmacologically active ingredient can be provided in a plurality of beads, optionally containing one or more pharmaceutically acceptable excipients, wherein each of the beads is coated with a film coat as defined above.
• Such film coated beads may be provided in o sachets or formulated as a capsule, for example a hard gelatin capsule, or compressed to form tablets using known methods with the optional addition of other pharmaceutically acceptable additives.
• Coated beads to be compressed into a tablet are obtained by conventional techniques known to those skilled in the art. Also, during this process suitable other agents can be added.
• suitable fillers e.g., microcrystalline cellulose, talc, etc.
• suitable fillers e.g., microcrystalline cellulose, talc, etc.
• the beads have a diameter in the range of 0.01-2mm, preferably in the range of 0.05-1.0mm and more preferably in the range of 0.1 -0.7mm.
• the beads may contain an insoluble core onto which the active ingredient has been deposited, for example, by spraying.
• Suitable materials for the inert core are silicon dioxide, glass or plastic resin particles.
• Suitable types of plastic material are pharmaceutically acceptable plastics such as polypropylene or polyethylene preferably polypropylene.
• Such insoluble cores have a size diameter in the range of 0.01-2mm, preferably in the range of 0.05-0.5mm and more preferably in the range of 0. l-0.3mm.
• the ductility of the film can be in a range of 500-20000 J/m 3 ' In another embodiment the ductility is in the range of 2500-20000 J/m 3 . In yet another embodiment the ductility is in the range of 10000-20000 J/m 3 .
• the present invention provides a modified release formulation wherein the pharmacologically active ingredient is released over a long period of time, for example longer than 3 hours in comparison to an immediate release tablet e.g., up to 24 hours, in comparison to an immediate release tablet.
• the pharmacologically active ingredient is released from the formulation over 10 to 24 hours, for example over 18 to 22 hours.
• the pharmacologically active ingredient has activity in the treatment of cardiovascular diseases.
• the pharmacologically active ingredient is a beta- blocking adrenergic agent such as metoprolol or a pharmaceutically acceptable salt thereof.
• the invention provides a modified release metoprolol formulation including: a) a metoprolol core comprising metoprolol or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients; and b) a film coat as defined above.
• the core comprising metoprolol or a pharmaceutically acceptable salt thereof includes a plurality of beads which comprise metoprolol or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients wherein each of the beads is coated with a film-coat as defined above.
• the beads Preferably, the beads have an inert core as described previously.
• Suitable pharmaceutically acceptable salts of metoprolol include the tartrate, succinate, fumarate or benzoate salts and especially the succinate salt.
• the S-enantiomer of metoprolol or a salt thereof, particularly the benzoate salt or the sorbate salt, may also be used.
• Eudragit NE30D is an ethyl acrylate/ methyl methacrylate copolymer in which the ethyl acrylate concentration is about 67mol%.
• the film coating of the present invention could be made with low amounts of surface active agents and that such a coating exhibited stability over time.
• the surface active agent surfactant
• the amount of surface active agent used in a film coating dispersion is in the amount less than 1.3 %, e.g., 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1%, by weight of the dispersion.
• the surface active agent is in a range from 0.001-1.0 % by weight of the dispersion.
• the surface active agent is in a range from 0.01-0.8% by weight of the dispersion.
• the surface active agent is in a range from 0.1-0.5% by weight of the dispersion.
• the amount of surface active agent present in the film coat is less than 5.4% by weight of the weight of the film coat, e.g., less than 5.0, 4.5, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.5, 0.1, 0.01, or 0.001% by weight of the weight of the film coat.
• the surface active agent in the film coat is in a range from 0.01-5.0 % by weight of the weight of the film coat.
• the surface active agent is in a range from 0.1- 4.0% by weight of the weight of the film coat.
• the surface active agent is in a range from 1.0-3.0% by weight of the weight of the film coat
• the amount of surface active agent present in the dispersion is less than 5.6%, eig., less than 5.0, 4.5, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.5, 0.1, 0.01, or 0.001%, based on the dry weight of the film coating components.
• Suitable surface active agents ⁇ stabilizers include: a nonionic surfactant, like sorbitan esters (Span series); polysorbates (Tween series); polyoxyethylated glycol monoethers (like the Brij series); polyoxyethylated alkyl phenols (like the Triton series or the Igepal series); alkyl glucosides (e.g., dodecylmaltoside); sugar fatty acid esters (e.g., sucrose laurate); saponins; etc: or mixtures thereof;
• a nonionic surfactant like sorbitan esters (Span series); polysorbates (Tween series); polyoxyethylated glycol monoethers (like the Brij series); polyoxyethylated alkyl phenols (like the Triton series or the Igepal series); alkyl glucosides (e.g., dodecylmaltoside); sugar fatty acid esters (e.g., sucrose laur
• ampholytic surfactants like betaines
• anionic surfactants like sulphated fatty alcohols eg sodium dodecylsulphate SDS; sulphated polyoxyethylated alcohols; others like dioctyl sulphosuccinate; bile salts (e.g., dihydroxy bile salts like sodium deoxycholate, trihydroxy bile salts like sodium glycocholate, etc); fusidates (e.g., sodium dihydrofusidate); etc cationic surfactants, like ammonium compounds;
• sulphated fatty alcohols eg sodium dodecylsulphate SDS
• sulphated polyoxyethylated alcohols others like dioctyl sulphosuccinate
• bile salts e.g., dihydroxy bile salts like sodium deoxycholate, trihydroxy bile salts like sodium glycocholate, etc
• fusidates e.g., sodium dihydrofusidate
• soaps fatty acids, and lipids and their salts, like alkanoic acids; (e.g., octanoic acid, oleic acid); monoglycerides (eg monolein), phospholipids which are neutral or positively or negatively charged (eg dialkyl phosphatidylcholine, dialkyl phosphatidylserine, etc).
• alkanoic acids e.g., octanoic acid, oleic acid
• monoglycerides eg monolein
• phospholipids which are neutral or positively or negatively charged
• the surface active agent is a nonionic surfactant. Most preferably the surface active agent is nonoxynol 100.
• excipients can be included in the formulation by methods known to those skilled in the art, such as lubricants, plasticizers, etc.
• the water-containing liquid comprises water and a water miscible organic liquid for example lower alkanols e.g. ethanol, propanol or isopropanol. From a safety point of view it is preferred that the proportion of the organic is kept to a minimum but small amounts are tolerable for example in the range of 0 to 20 % by volume.
• the liquid is water.
• the film-coating composition is particularly suitable for use as an aqueous film-coating composition wherein the film-coat is applied using water as the liquid.
• This process is particularly advantageous as it negates the need to use environmentally unacceptable organic solvents, some of which also present processing problems due to their inflammablility, while also eliminating many of the problems experienced with aqueous coatings described above.
• the present invention provides processes for the preparation of the film- coating composition. Therefore, there is provided a process for the preparation of a film- coating composition comprising mixing together the acrylic polymer dispersion, vinyl acetate polymer dispersion, the stabilizer and the liquid at a temperature in the range of 10 to 100°C. In one embodiment of the process the acrylic polymer dispersion, the stabilizer, the surface active agent and the liquid, are mixed at room temperature.
• Suitably mixing is achieved by methods such as stirring or shaking but other methods of homogenization known to those skilled in the art may be used.
• the present invention provides a process for film coating a pharmaceutical core wherein a film coating composition as defined above is applied to a core.
• a film coating composition as defined above is applied to a core.
• the film coating composition is applied by spraying for example in a fluidised bed with top spray or bottom spray techniques.
• Other coating methods used are coating in standard coating pans with perforated pans, Accela-cota, immersion swords, Glatt, or immersion tubes as described in "Theory and Practice in Industrial Pharmacy” edited by Lachman , published by Lea and Feabiger 1986 3 rd edition.
• the invention provides a process to prepare a film coat as defined above comprising removing the liquid from a film coating composition as defined above.
• the liquid is removed by evaporation for example by spray drying for example in a fluidised bed.
• the invention provides a process to prepare a formulation as defined above comprising coating a pharmaceutical core as defined above with a film coating composition as defined above.
• the invention provides a process to prepare a formulation in which the pharmacologically active ingredient is provided as a plurality of beads as defined above comprising coating the plurality of beads with a film-coating composition as defined above.
• Example 1 Preparation of coated metoprolol succinate pellets from NE30D/GMS/PS80. The preparation contains:
• the mixture of 5g GMS, lg Polysorbate 80 and 190g water was heated to 60-63°C while stirring. After 30 minutes (min) of homogenizing, the mixture was cooled initially by adding 25 g cold water and then further cooled in a cold-water bath until the temperature was below 35°C. The solution was then slowly poured into the NE30D dispersion while gently stirring. Stirring was continued until the start of coating.
• the coating was performed in a small-scale coater. Coating was performed by pouring 400g of metoprolol succinate pellets (size fraction 0.40-0.63 mm, with inert silicon dioxide cores) into the coater and the solution sprayed on to it. The coated pellets where cured afterwards in a 60°C heat cabinet for one (1) hour.
• the coating yield was 92%.
• the drug content for the pellets after coating 630mg/g pellets.
• the coated pellets where then analysed regarding drug content and release profile. Dissolution tests were conducted in USP 23 paddle apparatus equipped with flow -through cells ( at 37°C, 100 rpm, 500ml sodium phosphate buffer solution, pH 6,8). The release from the coated pellets and tablets was measured online using an UV- spectrophotometer ( Lambda 2, Perkin-Elmer) at 274nm. The amount of drug release was calculated on the determined drug content. Table 1
• the mixture of 3g GMS and 150g water was heated to 60-63°C while stirring. After 30 minutes the mixture was cooled initially by adding 25g cold water and then further cooled in a cold-water bath until the temperature was below 35°C. The solution was then slowly poured into the NE30D dispersion while gently stirring. Stirring was continued until the start of coating.
• the coating was performed in a small-scale coater. Coating was performed by pouring 350g of metoprolol succinate pellets(size fraction 0.40-0.63 mm, with inert silicon dioxide cores) into the coater and the solution sprayed on to it. The pellets where cured afterwards in a 60°C heat cabinet for 6 min. The coating yield was 90%. The drag content for the pellets after coating: 659mg/g pellets.
• coated pellets were then stored in a climate cabin at different temperatures and humidity for one and two weeks.
• the coated pellets where then analysed regarding drug content and release profile.
• Dissolution tests were conducted in USP 23 paddle apparatus equipped with flow -through cells (at 37°C, 100 rpm, 500ml sodium phosphate buffer solution, pH 6.8).
• the release from the coated pellets and tablets was measured online using an UV- spectrophotometer (Lambda 2, Perkin-Elmer) at 274nm. The amount of drag release was calculated on the determined drag content.
• Example 3 Tablets made from the coated pellets of Example 2 Preparation of 950 tablets
• the coated pellets where compressed into tablets by conventional techniques. During this process other agents where added, fillers Avicel and Sodium stearyl fumarate (Pruv®) to give acceptable compression characteristics of the formulation, e g hardness and weight.
• Fillers Avicel and Sodium stearyl fumarate (Pruv®) to give acceptable compression characteristics of the formulation, e g hardness and weight.
• Tablets of pellets were compacted in a rotary tablet machine (six (6) punch press, Korch PH 106, Germany).
• the press was equipped with concave-faced punches with a diameter of 10mm.
• the force used was approximately 4 KN.
• the hardness of the tablets were approx. 142 N (mean value of ten measurements). After the tablets have been sorted out by weight, they were put in the same cabin as the coated pellets from Example 2, and samples were taken after one and four weeks. See Table 3.
• the release profile of the tablets was then analysed. .
• Each value is a mean value of two analysis.

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• 2002
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• 2003
  • 2003-07-28 AU AU2003281837A patent/AU2003281837A1/en not_active Abandoned
  • 2003-07-28 US US10/523,553 patent/US20050238719A1/en not_active Abandoned
  • 2003-07-28 JP JP2004525527A patent/JP2005538117A/ja active Pending
  • 2003-07-28 EP EP03740845A patent/EP1572165A1/en not_active Withdrawn
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