US20070178156A1 - Pharmaceutical formulations - Google Patents
Pharmaceutical formulations Download PDFInfo
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- US20070178156A1 US20070178156A1 US10/598,810 US59881005A US2007178156A1 US 20070178156 A1 US20070178156 A1 US 20070178156A1 US 59881005 A US59881005 A US 59881005A US 2007178156 A1 US2007178156 A1 US 2007178156A1
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- klucel
- shell wall
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- capsule
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
-
- 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
- A61K9/4816—Wall or shell material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- 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
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Definitions
- This invention relates to the preparation of injection molded single or multi-component dosage forms using novel pharmaceutically acceptable polymeric blends.
- compositions are known for oral dosing.
- Pharmaceutical capsules are well known, generally being intended for oral dosing.
- Such capsules generally comprise an envelope wall of a pharmaceutically acceptable, e.g. orally ingestible, polymer material such as gelatin, although other materials for capsule walls, e.g. starch and cellulose based polymers are also known.
- Such capsules generally have soft walls made by making a film on a capsule former, which is then allowed to dry.
- Rigid walled capsules made by injection molding are also known, see for example U.S. Pat. No. 4,576,284; U.S. Pat. No. 4,591,475; U.S. Pat. No. 4,655,840; U.S. Pat. No.
- Multi-compartment capsules including those of the type where each compartment has different drug release characteristics, or for example, contains a different drug substance or formulation are also known, for example in U.S. Pat. No. 4,738,724 (Warner-Lambert); U.S. Pat. No. 5,672,359 (University of Kentucky); U.S. Pat. No. 5,443,461 (Alza Corp.); WO 95/16438 (Cortecs Ltd.); WO 90/12567 (Helminthology Inst.); DE-A-3727894, and BE 900950 (Warner Lambert); FR 2524311, and NL 7610038 (Tapanhony Nev.); FR 1,454,013 (Pluripharm); U.S.
- U.S. Pat. No. 3,228,789 (Glassman); and U.S. Pat. No. 3,186,910 (Glassman) among others.
- U.S. Pat. No. 4,738,817 discloses a multicompartment capsule with a similar construction to those of U.S. Pat. No. 3,228,789 and U.S. Pat. No. 3,186,910, made of a water-plasticized gelatin.
- U.S. Pat. No. 4,738,817 ('817) Witter et al., U.S. Pat. No. 4,790,881 ('881), Wittwer et al., and EP 0 092 908, Wittwer, F., all discloses injection molded capsules prepared with gelatin and other excipients.
- Pharmaceutical dosage forms are also known which comprise a matrix of a solid polymer, in which a drug substance is dispersed, embedded or dissolved as a solid solution. Such matrixes may be formed by an injection molding process. This technology is discussed in Cuff G, and Raouf F, Pharmaceutical Technology, June (1998) pages 96-106. Some specific formulations for such dosage forms are disclosed in U.S. Pat. No. 4,678,516; U.S. Pat. No. 4,806,337; U.S. Pat. No. 4,764,378; U.S. Pat. No. 5,004,601; U.S. Pat. No. 5,135,752; U.S. Pat. 5,244,668; U.S. Pat. No. 5,139,790; U.S. Pat.
- US Pat. No. 5,705,189 is directed to a group of co-polymers of methacrylic acid, methyl methacrylate and methyl acrylate, for use as thermoplastic agents in the production of drugs coatings, and capsules. No information is presented on the quality of the capsule formation with respect to warping or other distortions produced by the injection molding process. Nor is shear rate data presented for the viscosity/temperature figures of the emulsions presented therein.
- a pharmaceutical dosage form in which a pharmaceutically acceptable polymeric blend is extruded by hot melt into a suitable dosage form, or is injection molded into suitable dosage forms, which may be multicompartmental, such as in a capsule.
- This pharmaceutical polymeric composition as the dosage form may provide differing physio-chemical characteristics for each segment containing an active agent, such that a convenient dosage form can be optioned which may include a rapid dissolve, immediate, delayed, pulsatile, or modified release which can be produced by simply selecting the appropriate polymer(s) to be molded for each section.
- the present invention provides for novel pharmaceutical compositions, and their use in melt extrusion technologies, and in the making of injection molded capsule shells, linkers, spacers, multicomponent injection molded capsule shells, linkers or spacers, multicomponent pharmaceutical dosage forms, and other aspects as defined in the claims and description of this application.
- Another embodiment of the invention is to provide an alternative and improved pharmaceutical dosage form which provides, inter alia, greater flexibility in the dosage form adapted to a patient's specific administration requirement, using the novel formulations, or compositions, of pharmaceutically acceptable polymers and suitable excipients in said dosage forms.
- Another embodiment of the invention is to provide a process of producing the multicomponent dosage forms comprising the novel pharmaceutically acceptable polymeric blends by injection molding. These multi-component dosage forms are suitable for containing a pharmaceutically acceptable active agent, or agents, for release thereby.
- a melt extrusion composition and an injection molded capsule shell, and/or linker is provided for, with a composition, preferably including Eudragit RL 100 or Eudragit RS 100 or a combination thereof.
- the capsule or linker comprises a solid matrix, and preferably comprises is Eudragit RL 100 present in an amount of about 10 to 80% w/w, and a hydroxypropyl cellulose derivative, or blend of hydroxypropyl celluloses, from about 30 to about 70% w/w.
- composition may optionally further comprises dissolution-modifying excipients present in an amount of about 0% w/w to about 30% w/w; a lubricant present in an amount up to about 30% w/w; a plasticizer present in an amount up to about 10% w/w, and a processing agent present in an amount up to about 10% w/w.
- the pharmaceutical dosage form comprises a plurality of sub-units, each being a drug substance-containing capsule compartment.
- each compartment is physically separated from at least one adjacent compartment, preferably by a wall made of a pharmaceutically acceptable polymer material.
- its wall thickness is in the range of about 0.1-0.8 mm. In another embodiment the wall thickness is in the range of about 0.3-0.8 mm.
- the multi-component dosage form of the invention affords a high degree of versatility in that it can be composed of various combinations of different dosage forms having different release characteristics.
- the sub-units can be a substantially immediate release sub-unit, a sustained release sub-unit, or a pulsed release sub-unit.
- the present invention is directed to novel compositions of a pharmaceutically acceptable polymer and excipients, which polymeric composition may be injection molded into one or more components which can optionally be utilized together, such as in a stacked or multi-component dosage form. It is recognized that the polymeric blends may be injection molded into a single component that may also contain the active agent for oral administration.
- the present invention also relates to the application of a pharmaceutically acceptable film coating over a component comprising the novel pharmaceutically acceptable polymeric blends as described herein.
- the film coating may be a delayed release formulation, or a pH control formulation as are well known in the art.
- One suitable coating is Opradry, and/or Eudragit L30D-55.
- the enteric coatings, represented by application of L30D-55 for instance, may be applied using standard equipment such as a GMP Aerocoater column coater.
- the component weight gain is nominally from about 3% to about 5% w/w.
- the pharmaceutically acceptable polymeric blends herein are designed to provide consistent dissolution profiles.
- a suitable multicomponent dosage form is disclosed in PCT/EP00/07295, filed Jul. 27, 2000, published as WO 01/08666 on Feb. 8, 2001, the contents of which are incorporated by reference herein in its entirety.
- the parts of the dosage form of this invention e.g. a capsule compartment wall, a solid sub-unit, or a closure or linker, comprise a pharmaceutically acceptable polymeric blend (and adhesive material if adhesive welds are formed) which is generally regarded as safe, e.g. for oral ingestion and is capable of being formed into the required shape of a capsule compartment wall, a solid sub-unit, or a closure or linker as described above.
- a preferred method of forming the polymer material into the desired shape is injection molding, which may be a hot or cold runner injection molding process. Suitable injection molding machines for such a process are known.
- the pharmaceutical dosage form may comprises a plurality of capsule compartments each bounded and physically separated from at least one adjacent compartment by a wall made of a pharmaceutically acceptable polymer material, such as described herein, adjacent compartments being connected together in the assembled dosage form, and being retained together by the connection at least prior to administration to a patient, one or more of the compartments containing a drug substance.
- a wall made of a pharmaceutically acceptable polymer material such as described herein
- adjacent compartments being connected together in the assembled dosage form, and being retained together by the connection at least prior to administration to a patient, one or more of the compartments containing a drug substance.
- the assembled dosage form of this first embodiment there are at least two, for example three, such capsule compartments.
- Three or more such compartments may be linearly disposed in the assembled dosage form, e.g. in an arrangement comprising two end compartments at opposite ends of the line, and one or more intermediate compartments.
- one of such two capsule compartments may be made of a material which is a sustained release component, i.e. so that the capsule compartment wall dissolves, bursts or is otherwise breached to release its contents after a time delay, e.g. when the compartment has reached the intestine.
- the other of such two capsule compartments may be made of a material which is an immediate release component, i.e. so that the capsule compartment wall dissolves, bursts or is otherwise breached to release its contents immediately or effectively immediately, e.g. when the compartment is in the mouth or stomach.
- One or more, e.g. all, of the capsule compartments may for example be substantially cylindrical, which term includes shapes which have a circular, oval or oblate circular cross section across the longitudinal axis, and shapes which have parallel or tapering e.g. with side walls which taper conically over at least part of their extent.
- Such substantially cylindrical capsule compartments may be provided with connectable parts at one or both of their longitudinally disposed ends so that the assembled dosage form may also be overall of a substantially cylindrical shape.
- methacrylic acid copolymers such as Eudragit E®g, Eudragit E100® Eudragit® L and/or Eudragit® S
- poly(meth)acrylate copolymers such as Eudragit® 4135F, and 4155F
- ammonium methacrylate copolymers such as Eudragit® RL and/or Eudragit® RS
- the group of poly(meth)acrylate copolymers, such as Eudragit® RS 100 or RL100 are an embodiment of this invention.
- Acrylic and/or methacrylic acid-based polymers which are soluble in intestinal fluids and which can be formed into capsules are for example disclosed in U.S. Pat. No. 5,705,189 (Roehm GmbH) the content of which is incorporated herein by reference in its entirety.
- These poly(meth)acrylate copolymers were extrudable and injection molded into capsule half s wherein the ratio of acrylic and/or methacrylic acid was generally 20% w/w or more of the copolymer (Examples 1-8).
- glycerol monostearate was added on a 1-6% wt base of the polymer as the sole mold-releasing agent.
- the Lehmann patent teaches that unblended polymers alone are not suitable for injection molding, but must be blended with a lubricant to produce a capsule shell therein.
- the polymer Eudragit RL100 is described by the manufacturer, Rohm Pharma, as being a highly permeable pH independent polymer which granules are insoluble in water.
- Eudragit RS 100 is also described as being a pH independent polymeric granule with low permeability, and insoluble in water.
- Eudragit 4135F/4155F dissolves only above pH 7, e.g. in the colon, therefore suitable for use as a sustained or delayed release component
- the polymer Eudragit E100 dissolves in acid and is suitable for use as an immediate release component.
- the RL100 polymer is blended with additional excipients which include, but are not limited to, swelling agents, such as HPMC, HPC, etc.; surfactants, such as SDS or the Pluronic group of agents; pore-forming/chanelling agents, such as lactose or PEG; additional polymers for co-blending such as RS100; and additional buffering agents for adjust of microclimate pH conditions.
- additional excipients include, but are not limited to, swelling agents, such as HPMC, HPC, etc.; surfactants, such as SDS or the Pluronic group of agents; pore-forming/chanelling agents, such as lactose or PEG; additional polymers for co-blending such as RS100; and additional buffering agents for adjust of microclimate pH conditions.
- RL100 is a co-blend of RL100 with the polymer HPC, such as that marketed by Aqualon, a division of Hercules Incorporated, as Klucel®.
- Klucel HPC is produced in various grades, determined by their intended use. Suitable Klucel polymers are Klucel EF, Klucel JH, Klucel LF, and Klucel GF.
- Klucel E has a viscosity in the range of 150-700 (a 300-6-mPas for EF pharm/EXF Phann), and a molecular weight of about 80,000; J has a viscosity of 150-400 and a molecular weight of about 140,000, L has a viscosity in the range of 75-150, and a molecular weight of about 95,000; and G has a viscosity in the range of 75-400, and a molecular weight of about 370,000.
- thermoplastic polymers additive of these thermoplastic polymers to the blend provides for reduced sensitivity to welding conditions, improved tensile properties both pre and post hydration, and a more robust swelling of the polymer at pH of 1 to 6.
- co-blends still require additional excipients as herein described.
- excipient is a lubricant, such as stearyl alcohol.
- the Eudragit RL100 co-blended components have further been found to be stable after prolonged storage conditions.
- the polymeric compositions are first melted in a melt extrusion process, and may also contain additional additives or excipients to assists in melt flow, strength, brittleness, and other molding characteristics, these additional excipients include but are not limited to, plasticizers, absorption enhancers, additional surfactants, flavouring agents, dyes, etc. Therefore, another aspect of the present invention is a pharmaceutical composition for melt extrusion comprising Eudragit RL100 or RS100 and a lubricant, such as stearyl alcohol.
- compositions herein may be molded in varying wall-thickness, it is preferably that capsules or components have a wall-thickness of about 0.3 to about 0.8 mm, suitably 0.5 mm.
- dissolution performance will more appropriately tailor the wall thickness depending upon the release profiles desired. Increases in wall thickness may be necessary to reduce warping of the components, or modification of the additional excipients in addition to this may be necessary.
- the polymer polymethacyrlate, Eudragit RL100 or RS 100 is present in the formulation in an amount of about 10 to about 80% w/w. In another embodiment Eudragit RL100 or RS 100is present in an amount of about 20 to about 50% w/w. In another embodiment Eudragit RL100 or RS 100 is present in an amount of about 20 to 40% w/w.
- the polymeric material(s) may include other substances to modify their properties and to adapt them to various applications, including but not limited to surfactants, absorption enhancers, lubricants, plasticizers, dissolution modifying agents, processing aids, colouring agents, flavouring agents and sweetening agents.
- Incorporation of a surfactant into the formulation may be necessary or desired to lower the viscosity and surface tension of the formulation/blend, however, in higher amounts it may adversely effect the quality of the resulting dosage form.
- the surfactant selection may be guided by HLB values but is not necessarily a useful criterion.
- Pluronic made by BASF, USA has a synonym of POLOXAMER.
- Pluronic F68 for instance has a molecular weight of 8,400.
- Pluronic F127 has a molecular weight of 12,600.
- Pluronics are polyoxypropylene-polyoxyethylene block copolymers.
- a surfactant may also be called an oligomeric surface modifier and includes, but is not limited to: Pluronics® (block copolymers of ethylene oxide and propylene oxide, and are also referred to as polyoxypropylene-polyoxyethylene block copolymers); lecithin, Aerosol OT® (sodium dioctyl sulfosuccinate), sodium lauryl sulfate, Polyoxyl 40® hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, i.e., the polysorbates such as Tween®, such as Tween 20, 60 & 80, the sorbitan fatty acid esters, i.e., sorbitan monolaurate, monooleate, monopalmitate, monostearate, etc.
- Pluronics® block copolymers of ethylene oxide and propylene oxide, and are also referred to as polyoxypropylene-polyoxyethylene block copolymers
- lecithin Aerosol
- Span® or Arlacel® such as Span® or Arlacel®, Emsorb®, Capmul®, or Sorbester®, Triton X-200, polyethylene glycol's, glyceryl monostearate, Vitamin E-TPGS® (d-alpha-tocopheryl polyethylene glycol 1000 succinate), sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate, etc.; and combinations and mixtures thereof.
- the formulation may optionally contain from about 0 to about 10% w/w surfactant(s).
- Suitable surfactants for use herein include, sodium lauryl sulfate, also referred to as sodium dodecyl sulfate (SDS) or a block copolymers of ethylene oxide and propylene oxide, or mixtures thereof.
- SDS sodium dodecyl sulfate
- suitable surfactants are Vitamin E-TPGS®, sodium lauryl sulfate, sucrose fatty acid esters, lecithin, and the Pluronic groups.
- SDS Texapon K-12®
- a block copolymers of ethylene oxide and propylene oxide are present in an amount less than 2% by weight, suitably, less than 1% w/w.
- the polymeric carriers or oligomeric surface modifiers may themselves act as absorption enhancers.
- Suitable absorption enhancers for use herein include but are not limited to, chitosan, lecithin, lectins, sucrose fatty acid esters such as the ones derived from stearic acid, oleic acid, palmitic acid, lauric acid, and Vitamin E-TPGS, and combinations or mixtures thereof.
- these absorption enhancers are present in a range of about 0 to about 20% w/w.
- Plasticizers may be employed to assist in the melting characteristics of the composition.
- Exemplary of plasticizers that may be employed in this invention are triethyl citrate (TEC), triacetin, tributyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS), diethyl phthalate, vinyl pyrrolidone glycol triacetate, polyethylene glycol, polyoxyethylene sorbitan monolaurate, propylene glycol, or castor oil; and combinations or mixtures thereof.
- the polymeric material will determine which plasticizer is suitable for use.
- the plasticizer is present in an amount of about 0 to about 20% w/w. In one embodiment of the invention the plasticizers are present in an amount from about 0 about 5% w/w.
- One embodiment of the present invention is the ability to form an injection molded shell of a Eudragit RL 100 or RS 100 formulation without the addition of a plasticizer such as those noted above.
- Dissolution modifying agents or substances that assist in release modification, alter the erosion and/or swelling characteristics of the capsule shell/linker/component.
- agents such as the known disintegrants represented by “Explotab” (sodium starch glycollate), “Kollidon-CL”, (cross-linked PVP), Kollidon VA 64 (copovidone) commercially available from BASF, Starch 1500, swelling agents such as polyvinyl pyrrolidone (PVP, also know as POVIDONE, USP), manufactured by ISP-Plasdone or BASF-Kollidon, primarily Grades with lower K values (K-15, K-25, but also K-30 to K-90), cellulosic derivatives such as hydroxypropyl methyl cellulose (HPMC), wicking agents such as low molecular weight solutes, e.g. mannitol, lactose, and starch; inorganic salts such as sodium chloride (typically at 5-10%).
- Explotab sodium starch glycoll
- Kollidan VA 64, or copovidone is also known as copolyvidone, copovidonum, copovidone or copovidon, is ratio of two monomers, vinylpyrrolidone and vinyl acetate.
- swellable solids include but are not limited to poly(ethylene)oxide, the cellulosic derivatives, such as ethyl cellulose and cellulose acetate phthalate; hydroxypropylcellulose (HPC), such as the lower molecular weights, e.g., KLUCEL EF and LF grades, and mixtures of the lower molecular weights with higher molecular weight grades such as JF or GF; hydroxypropylmethyl cellulose (HPMC), and other hydroxyalkylcellulose derivatives.
- the swellable solids used as dissolution modifying excipients are in the range of about 10% to about 70% w/w.
- the swelling agents is present in an amount from about 20 to about 65% w/w, suitably about 50% w/w.
- Suitable dissolution modifying excipients include, but are not limited to the class of non-reducing sugars, such as xylitol, or mannitol, present in the range of about 2.5 to about 15% w/w.
- a class of water soluble fillers such as lactose, lactitol, maltitol, sorbitol or alternatively organic acids such as malic acid, citric acid or succinic acid, suitably present in the range of about 5 to about 70% w/w.
- the water soluble fillers may be present from an amount of about 5 to about 20% w/w
- dissolution modifying excipients are the agents generally referred to as disintegrants, such as sodium starch glycolate, croscarmellose sodium NF (Aci-Di-Sol® produced by FMC), copovidone, and crospovidone (cross-linked polyvinyl pyrrolidone); and combinations or mixtures thereof.
- disintegrants such as sodium starch glycolate, croscarmellose sodium NF (Aci-Di-Sol® produced by FMC), copovidone, and crospovidone (cross-linked polyvinyl pyrrolidone); and combinations or mixtures thereof.
- the class of disintegrants are present in the range of about 10 to 40%, more preferably about 20 to 30% w/w. It is recognized that the one of more classes of dissolution modifying excipients may be used alone, or in combination as mixtures with each other, resulting in a range from about 2.5 to about 70% w/w.
- processing aids include strengthening agents, such as talc.
- the processing aids are present from about 0 to about 10% w/w. In another embodiment, the processing aids are present from about 0 to about 5% W/W.
- Suitable mold processing lubricants or glidants for use herein include but are not limited to, stearyl alcohol, stearic acid, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, and fumed silica; and combinations or mixtures thereof.
- the lubricant functions primarily as a flow promoter for the composition.
- One embodiment of the present invention is the use of stearyl alcohol as a suitable lubricant.
- a commercial grade of stearyl alcohol such as Crodacol S95 (Croda Oleochemicals) is used herein.
- the lubricant materials should also be suitable for milling.
- the amount of lubricant present in the formulation is from about 0 to about 30% w/w. In another embodiment the lubricant is present from about 10 to about 25% W/W. In another embodiment, the lubricant is present from about 10 to 15% w/w.
- Stearyl alcohol has been found to act as a mold processing lubricant but and causes no mold distortion, i.e. crumpling of the multidosage compartment shell when the hot soft shell is taken out of the mold.
- Another alternative material useable as a lubricant/flow promoter is lecithin (a natural product).
- lecithin a natural product
- the lubricants for use herein do not introduce any metal ion contamination.
- One embodiment of the present invention is the combination of stearyl alcohol, at least one swellable solid, and the polymer Eudragit RL100.
- the formulation may further comprise a surfactant, such as SDS at 2% w/w or less, or 1% or less.
- the swellable solid may be the polymer hydroxypropylcellulose or a blend of hydroxypropylcellulose.
- the final products of this invention i.e. the capsules, and or components or sub-units may additionally include materials in the polymer materials of which they are made to enhance the ease with which they can be welded together.
- the sub-units may additionally be provided with constructional features and/or include materials in the polymer materials of which they are made to enhance the ease with which they can be joined together, either by simple mechanical joints, or welded together.
- a suitable material for assisting such are opacifier materials such as carbon (e.g. 0.2-0.5%), iron oxides or titanium dioxide (e.g. 0.5-1.0%) which help the polymer to absorb laser energy.
- opacifier materials are generally regarded as safe.
- each of a plurality of sub units may comprise the same or different polymer(s).
- each of a plurality of sub units, e.g. of capsule compartments, solid sub-units, or combinations thereof may comprise the same or different drug substance.
- each sub-unit may contain the same drug substance but release the contents into the gastro-intestinal tract of the patient at a different rate, at different times after administration to the patient or at different places in the patient's gastro-intestinal system.
- each sub-unit may contain a different drug substance, each of which may be released at the same or a different rate or time after administration or place in the patient's gastrointestinal system.
- two or more sub-units may each contain different drug substances, and/or different drug substance formulations, and/or the same drug in different formulations, so that a combination of two or more drug substances or formulations may be administered to a patient.
- the dosage form of this invention enables the assembly together of sub-units which differ in their drug content and/or drug content release characteristics to provide a dosage form tailored to specific administration requirements.
- each of the sub-units and hence of the overall assembled dosage form may be determined by the nature and quantity of the material to be contained therein and the intended mode of administration and intended recipients.
- a dosage form intended for oral administration may be of a shape and size similar to that of known capsules intended for oral administration.
- the dosage form is particularly suitable for presentation as an oral dosage form containing one or more drug substances suitable for oral administration, and appears to be suitable for all types of such drug substance.
- the drug substance(s) contained in any capsule compartment may be present in any suitable form, e.g. as a powder, granules, compact, microcapsules, gel, syrup or liquid provided that the capsule compartment wall material is sufficiently inert to the liquid content of the latter three forms.
- the contents of the compartments, e.g. drug substances may be introduced into the compartments by standard methods such as those used conventionally for filling capsules, such as dosating pins or die filling.
- the sub-units may differ from each other in their drug content release characteristics, and this may be achieved in various ways.
- one or more solid sub-units and/or capsule compartments may be substantially immediate release, i.e. releasing their drug contents substantially immediately upon ingestion or on reaching the stomach. This may for example be achieved by means of the matrix polymer or the capsule compartment wall dissolving, disintegrating or otherwise being breached to release the drug content substantially immediately.
- immediate-release sub-units are preferably provided by being capsule compartments.
- one or more solid sub-units and/or capsule compartments may be sustained-release sub-units.
- one or more solid sub-units and/or capsule compartments may be pulsed-release sub-units for example releasing their drug content at a specific predetermined point in a patient's gastro-intestinal system.
- This may be achieved by the use of polymer materials which dissolve or disperse only at defined pH environments, such as the above mentioned Eudragit® polymers.
- E100 is acid labile.
- one capsule compartment may be effectively immediate release and the other may be sustained, delayed or pulsed release.
- one capsule compartment may be made of polymer materials which cause the capsule compartment to release its drug content in the stomach or upper part of the digestive tract, and the linker (acting as a closure for the second compartment) and the second compartment itself may be made of materials e.g. the above described enteric polymers, which release their drug content only in the intestinal environment.
- Determination of the time or location within the gastro-intestinal tract at which a sub-unit releases its drug substance content may be achieved by for example the nature of the sub-unit material, e.g. a solid sub-unit matrix polymer or a capsule compartment wall material, or in the case of an end compartment which is closed by a closure, by the nature of the closure material.
- the wall of different, e.g. adjacent, compartments may be made of polymers which are different or which otherwise differ in their dissolution or disintegration characteristics so as to endow different compartments with different drug release characteristics.
- the polymer matrix material of different, e.g. adjacent, solid sub-units may be made of polymers which are different or which otherwise differ in their dissolution or disintegration characteristics so as to endow different solid sub-units with different drug release characteristics.
- the matrix, wall or closure material may be a polymer which dissolves or disperses at stomach pH to release the drug substance in the stomach.
- the wall material of different compartments may differ so that different compartments have different release characteristics.
- a solid sub-unit or a capsule compartment may have respectively a matrix or a wall or a closure comprising an enteric polymer which dissolves or disperses at the pH of the small or large intestine to release the drug substance in the intestine.
- enteric polymer which dissolves or disperses at the pH of the small or large intestine to release the drug substance in the intestine.
- Suitable such polymers have been described above, for example, with reference to U.S. Pat. No. 5,705,189.
- the wall material may differ in thickness between compartments so that thicker walled compartments disrupt more slowly than thinner walled compartments.
- the compartment walls or the closure may have areas or points of weakness which preferentially dissolve and may thereby determine the time of onset and/or rate of release of the drug substance content.
- points of weakness may comprise holes, e.g. small holes, e.g. laser-drilled holes in the compartment wall or the closure, these holes being closed and/or covered with a film of a polymer material that dissolves at a predetermined point in the digestive tract, for example an enteric polymer material.
- such points of weakness may comprise thinned parts in a capsule compartment wall formed during the molding operation in which the capsule compartment is formed.
- the sub-units may additionally or alternatively have surface or other constructional features that modify their drug release characteristics.
- solid sub-units may be provided with internal cavities or channels to create a large surface area.
- solid sub-units may be in the form of hollow cylinders, donuts, or toroids, which shapes are known to tend towards first-order dissolution or erosion in liquid media and correspondingly to tend toward first-order release of drug content dispersed therein.
- “Pharmaceutically acceptable agents” includes, but is not limited to, drugs, proteins, peptides, nucleic acids, nutritional agents, as described herein. This term includes therapeutic active agents, bioactive agents, active agents, therapeutic agents, therapeutic proteins, diagnostic agents, or drug(s) as defined herein, and follows the guidelines from the European Union Guide to Good Manufacturing Practice. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease or to affect the structure and function of the body. The substance may also include a diagnostic agent, such as an imaging agent and/or a radioactive labeled compound. Their use may be in a mammal, or may be in a human.
- a diagnostic agent such as an imaging agent and/or a radioactive labeled compound. Their use may be in a mammal, or may be in a human.
- the pharmacological activity may be prophylactic, or for treatment of a disease state.
- the agents herein include both small molecule therapeutics, as well as peptides and proteins.
- the pharmaceutical compositions described herein may optionally comprise one or more pharmaceutically acceptable active agent, bioactive agent, active agent, therapeutic agent, therapeutic protein, diagnostic agent, or drug(s) or ingredients distributed within.
- active agent drug moiety
- drug drug
- Suitable drug substances can be selected from a variety of known classes of drugs including, but not limited to, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillin's), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobactefial agents, antineoplastic agents, imnmunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics
- Preferred drug substances include those intended for oral administration and intravenous administration.
- a description of these classes of drugs and a listing of species within each class can be found in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The Pharmaceutical Press, London, 1989, the disclosure of which is hereby incorporated herein by reference in its entirety.
- the drug substances are commercially available and/or can be prepared by techniques known in the art.
- the polymeric blends can be preferably selected from known pharmaceutical polymers.
- the physico-chemical characteristics of these polymers, as well as the thickness of the ultimate injection molded component, will dictate the design of the dosage form, such as rapid dissolve, immediate release, delayed release, modified release such as sustained release, controlled release, or pulsatile release. etc.
- the polymer blends are made by well-known methods for producing hot melt extrusions in which the selected ingredients are fed into a feed hopper of an extrusion machine. Suitable well known equipment is readily available for producing a hot melt extrusion of the blends herein.
- the polymer Eudragit RL 100 may be extruded into a thin walled component shell (such as those indicated herein), by blending with the excipients as noted herein.
- formulation with a lubricant, and hydroxypropylcellulose, or a coblend of HPC has now been shown to produce a stable, injection molded component which can be reliably reproduced and injected from the mold with reduced, or no warpage of the shell.
- the pharmaceutical formulations include various hydrophilic excipients.
- the hydrophilic excipient is one which does not melt at the extrusion temperature, e.g. the lactose, inorganic salts, HPC, HPMC, such as Pharnacoat 603 (an HPMC with a glass transition temperature 175° C.).
- HPC lactose, inorganic salts
- HPMC HPMC with a glass transition temperature 175° C.
- Pharnacoat 603 an HPMC with a glass transition temperature 175° C.
- these swellable solids are available commercially in a number of grades by molecular weight, for examples 95K, or 80K grades of HPC.
- a change in the molecular weight of HPC for instance, should retain the ability to hydrate the shell, but the hydration rate may be slower, i.e. the rate of expansion will be reduced.
- a lubricant such as stearyl alcohol enhances flow. It is also found that higher proportions of stearyl alcohol increase the flowability so as to enable molding of thinner walls.
- the formulation may optionally include surfactants, and disintegrating agents.
- Example 1 Manufacture of multicomponent pharmaceutical dosage forms with pharmaceutically acceptable polymeric compositions as described herein.
- Example 1 will describe a general process used to mold the various multicomponent capsules and appropriate subunits. Additional pharmaceutical compositions are shown and described below.
- Item number Material % w/w 1.
- Ammonium methacrylate copolymer 25.0 (Eudragit RL100) 2.
- Lactose monohydrate 13.0
- Example processing parameters are as follows: Extruder: Screw speed 150 rpm (range 100-500 rpm) Temperature of zone 1 (feed zone) 50° C. (range 30-75° C.) Temperature of zone 2 95° C. (range 85-130° C.) Temperature of zone 3 100° C. (range 90-135° C.) Temperature of zone 4 110° C. (range 95-140° C.) Temperature of zone 5 115° C. (range 100-145° C.) Temperature of strand die 120° C.
- Ammonium methacrylate copolymer Eudragit RL100
- Input appropriate machine settings and pre-heat the injection molder. Load the hopper with the pellets and mold the multi-components units.
- the resulting shells from these examples are welded together with a linker unit, as previously described herein, having a composition comprising Eudragit 4135F, 10% hypromellose (HPMC)—Pharmacoat 603, Shin-etsu Chemical Company, and 12% Stearyl alcohol using a maximum weld strength. Unless otherwise indicated a standard is weld for RL100 shells is ⁇ 2.50mm, 100% amplitude.
- the shell is of 0.5 mm thickness.
- the welded capsules, where applicable were tested using either a USP2 or a USP3 dissolution apparatus.
- Extrusion/Injection moulding Extrusion—1 kg/hr die temp. 120° C., 150 rpm screw, torque 46%, die pressure 5 bar; Injection Moulding—partially filled 2/4 0.5 mm wall section shells, complete mouldings from other pins; 185 C. probe temp. Additional Shell Observations: many cracked or incompletely moulded shells, and a polymer knit line was present on all shells. There was also a high degree of breakage on welding.
- Extrusion/Injection moulding Extrusion—1.1 kg/hr die temp. 110° C., 200 rpm screw, torque 53%, die pressure 2 bar; Injection Moulding—crack in 1 ⁇ 4 of the 0.5 mm wall section shells, complete mouldings from other pins, 175 C. probe temp.
- Extrusion/Injection moulding Extrusion—1.2 kg/hr die temp. 110° C., 200 rpm screw, torque 35%, die pressure 1 bar; Injection Moulding—satisfactory 0.5 mm wall section shells, Small knit line on some 0.3 mm shells, 180 C. probe temp.
- Dissolution Testing using USP 2 0.5 mm capsules, welded at ⁇ 2.50 mm; a 100% run at 50 rpm in pH 1.2SGF using Disc sinkers demonstrated a variable release times from 58 to 100 minutes.
- a film coat was added of Eudragit L30D-55.
- An Aeromatic Aerocoater was used for applying the coating, with standard procedures, at a 6% film coat by weight gain.
- coated shells have not been tested for their release profile in a USP2 or USP3 dissolution apparatus.
- Extrusion/Injection moulding Extrusion—1.2 kg/hr die temp. 115° C., 200 rpm screw; torque 41%, die pressure 4 bar; Injection Moulding—satisfactory 0.5 mm wall section shells, 185 C. probe temp.
- Dissolution Testing using USP 3 0.5 mm capsule shells with a 1.5% sub coat (A) and a 2.5% enteric coat (B) containing an active ingredient, welded at ⁇ 2.60 mm; a 100% run at 10 dpm in pH 1.2SGF demonstrated a release profile which was very reproducible and had a detachment ranging from 40-55 minutes for 6 samples tested.
- the 0.5 mm shells of this example were film coated with an Opadry clear sub coat.
- the 0.5 mm shells of this example were film coated with Opadry clear sub coat & then over coated with a Eudragit L30D-55 enteric coat.
- the 0.5 mm shells of this example film were coated with an Opadry clear sub coat using an Aeromatic Aerocoater.
- 0.3 mm shells produced using this formulation were film coated with an Opadry clear sub coat then over coated with a Eudragit L30D-55 enteric coat (about 24 hrs between applications).
- Extrusion/Injection moulding Extrusion—1.00 kg/hr die temp. 105° C., 200 rpm screw torque 41%, die pressure 1 bar; Injection Moulding—satisfactory 0.5 mm wall section shells; 180 C. probe temp.
- Extrusion/Injection moulding Extrusion 1.00 kg/hr die temp. 110° C., 200 rpm screw torque 46%, die pressure 1 bar, smooth ‘glassy’ strand. Injection Moulding—0.5 mm; persistent sticking in cavities. A 0.3 mm shell was not attempted.
- Extrusion/Injection moulding Extrusion—0.73 kg/hr die temp. 110° C., 200 rpm screw torque, 41%, die pressure 2 bar; Injection Moulding—satisfactory 0.5 mm shells at 150 C. probe.
- Shells of this example have not been tested for their release profile in a USP2 or USP3 dissolution apparatus.
- Extrusion/Injection moulding Extrusion—1.5 kg/hr; die temperature 120° C., 150 rpm screw; torque 38%.; Injection Moulding—satisfactory 0.5 mm shells at 180° C. probe; occasional sticking in mould.
- Extrusion/Injection moulding Extrusion—1.5 kg/hr; die temnperature of about 120° C., 153 rpm screw; torque 35%.; Injection Moulding—satisfactory 0.5 mm shells at 180° C. probe; Occasional sticking in mould.
- Extrusion 1.0 kg/hr; with a die temperature of about 110° C.; a 200 rpm screw; and torque 35%.
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US10/598,810 US20070178156A1 (en) | 2004-03-12 | 2005-03-11 | Pharmaceutical formulations |
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JP (2) | JP2007528901A (fr) |
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Also Published As
Publication number | Publication date |
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KR101242988B1 (ko) | 2013-03-13 |
KR20130010511A (ko) | 2013-01-28 |
CA2559227A1 (fr) | 2005-09-29 |
WO2005089726A1 (fr) | 2005-09-29 |
RU2011127852A (ru) | 2013-01-20 |
EP1729744A4 (fr) | 2012-10-31 |
RU2447885C2 (ru) | 2012-04-20 |
KR20070002004A (ko) | 2007-01-04 |
RU2006136020A (ru) | 2008-04-20 |
BRPI0508342A (pt) | 2007-07-24 |
AR048033A1 (es) | 2006-03-22 |
JP2012097088A (ja) | 2012-05-24 |
NZ549264A (en) | 2010-07-30 |
TW201240679A (en) | 2012-10-16 |
IL177566A0 (en) | 2006-12-10 |
MA28489B1 (fr) | 2007-03-01 |
AU2005222612C1 (en) | 2011-12-08 |
JP2007528901A (ja) | 2007-10-18 |
EP1729744A1 (fr) | 2006-12-13 |
IL177566A (en) | 2011-03-31 |
CN1953739B (zh) | 2011-12-14 |
PE20060003A1 (es) | 2006-03-01 |
TW200539903A (en) | 2005-12-16 |
US20050249807A1 (en) | 2005-11-10 |
US20120196940A1 (en) | 2012-08-02 |
AU2005222612A1 (en) | 2005-09-29 |
US8147871B2 (en) | 2012-04-03 |
KR20120044365A (ko) | 2012-05-07 |
AU2005222612B2 (en) | 2011-04-21 |
CN1953739A (zh) | 2007-04-25 |
NO20064570L (no) | 2006-10-10 |
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