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WO2007002041A2 - Films polymeres charges de medicaments - Google Patents

Films polymeres charges de medicaments Download PDF

Info

Publication number
WO2007002041A2
WO2007002041A2 PCT/US2006/023916 US2006023916W WO2007002041A2 WO 2007002041 A2 WO2007002041 A2 WO 2007002041A2 US 2006023916 W US2006023916 W US 2006023916W WO 2007002041 A2 WO2007002041 A2 WO 2007002041A2
Authority
WO
WIPO (PCT)
Prior art keywords
mixture
film
drug
mixer
extruder
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.)
Ceased
Application number
PCT/US2006/023916
Other languages
English (en)
Other versions
WO2007002041A3 (fr
Inventor
Lawrence Acquarulo
Richard Quigley
Anthony Listro
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.)
Foster Corp
Original Assignee
Foster Corp
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
Application filed by Foster Corp filed Critical Foster Corp
Publication of WO2007002041A2 publication Critical patent/WO2007002041A2/fr
Publication of WO2007002041A3 publication Critical patent/WO2007002041A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to drug filled polymeric films. Such films may be based on an organic alcohol and a cellulosic resin where the films may be filled with an active pharmaceutical ingredient (API) and may be substantially gel-free.
  • API active pharmaceutical ingredient
  • the present invention further relates to a method of preparing such films.
  • gels in thin-walled extrusion products such as film, tubing, and fiber may create unacceptable cosmetic and mechanical defects in the finished product.
  • Gels may be visible in transparent or translucent polymeric products due to differences in refractive index, and may appear as spherical or elliptical bubbles embedded in the polymeric product.
  • These small agglomerations may originate from a variety of sources, such as air entrapment, moisture, contamination, foreign matter, surface agents, inorganic material, additives, degradation, and the polymeric material itself.
  • the polymeric material may cause gels if it contains volatile species, has a high molecular weight, undergoes crosslinking, or consists of unblended or undissolved polymer.
  • Gels are referred to by many different names, such as voids, bubbles, fish eyes, P-gels (formed during polymerization), and E-gels (formed during extrusion). Gels may result when the flow process in an extruder is not streamlined. For example, a screw and die designed with regions of stagnation may contribute to gel formation. Additionally, mixing sections with regions of stagnation may contribute to gel formation, as may equipment that has not been thoroughly cleaned for contaminants and degraded material.
  • the presence of gels may adversely affect the efficacy of the finished product.
  • the presence of gels may impede the even, continuous elution of an active pharmaceutical ingredient (API) from a drag-filled polymeric film.
  • API active pharmaceutical ingredient
  • the present invention is directed towards polymeric films based on an organic alcohol and a cellulosic resin, where the films may be filled with an active pharmaceutical ingredient (API) and are substantially gel-free.
  • the present invention is further directed towards a method of making such films, comprising melt mixing an organic alcohol, and a cellulosic resin in a mixer to form a first mixture.
  • the first mixture may be extruded through a die at the bottom of the mixer and converted into pellets.
  • the pellets may then be fed into a first extruder at a controlled rate in combination with an active pharmaceutical ingredient (API) to form a second mixture.
  • the second mixture may then be converted into pellets, remelted in a second extruder, and formed into a film.
  • the present invention is directed towards another method of making such films, comprising melt mixing an organic alcohol and a cellulosic resin in a mixer to form a first mixture.
  • the first mixture may be fed directly into a first extruder in parallel with an active pharmaceutical ingredient (API) to form a second mixture.
  • API active pharmaceutical ingredient
  • the second mixture may then be converted into pellets, remelted in a second extruder, and formed into a film.
  • the present invention is directed towards a different method of making such films, comprising melt mixing an organic alcohol and a cellulosic resin in a mixer to form a first mixture.
  • the first mixture may be extruded through a die at the bottom of the mixer and converted into pellets.
  • the pellets may then be fed into a first extruder at a controlled rate in combination with an active pharmaceutical ingredient (API) to form a second mixture.
  • API active pharmaceutical ingredient
  • the second mixture may then be directly formed into a film through a film die at the end of the first extruder.
  • the present invention is directed towards a final method of making such films, comprising melt mixing an organic alcohol and a cellulosic resin in a mixer to form a first mixture.
  • the first mixture may be fed directly into a first extruder in parallel with an active pharmaceutical ingredient (API) to form a second mixture.
  • API active pharmaceutical ingredient
  • the second mixture may then be directly formed into a film through a film die at the end of the first extruder.
  • the present invention provides a substantially gel-free polymeric film. Such films may therefore provide for the even, continuous elution of an active pharmaceutical ingredient (API).
  • a gel may be referred to as any small agglomeration of air, moisture, contamination, foreign matter, surface agents, inorganic material, additives, degradation, polymer, volatile species, high molecular weight polymer, crosslinked polymer, unblended or undissolved polymer, or mixture thereof. Gels may further be referred to as any spherical or elliptical bubble of a diameter similar to the thickness of the finished film, which may be present in the finished film.
  • a substantially gel-free film may be one in which all gels larger than about 40 microns in diameter constitute less than about 5.0% of all gels in a finished product.
  • the polymeric film may be characterized as having a maximum average gel size of about 20-25 microns in diameter.
  • the polymeric film may be one in which the maximum size of all gels present may be at or below about 20-25 microns in diameter.
  • a mixer may be used to provide the substantially gel- free film.
  • the mixer may be a helicone mixer, which may be understood to mean a mixer equipped with one or more helical blades in a conical bowl.
  • the mixer may include an inner auger for mixing, lifting, or discharging product by means of a pumping action.
  • a dispersion blade or high shear emulsifier head may be used in place of the inner auger.
  • the helical blades may be independently driven such that the direction and speed of rotation of each blade may be independently adjusted.
  • the blades may rotate in the same direction or counter-rotate.
  • the blades may rotate 1-200 rotations per minute, including all values and increments therebetween. If an inner auger is used, it may spin in either an upwards or downwards rotation.
  • Heat may be provided to the mixer through a jacketed outer vessel by means of electricity or a heat transfer fluid such as steam or oil.
  • the temperature of the mixer may be about 70-165 degrees Celsius, including all values and increments therebetween.
  • a J type thermocouple may be located in the cusp of the vessel wall for monitoring the temperature of the mixture itself. Accordingly, the temperature of the mixture may be regulated to that of the mixing bowl.
  • the mixer may specifically include a 4CV mixer from Design Integrated Technology, Inc.
  • the 4CV mixer is a twin cone reactor that uses intersecting dual helical-conical blades with a 270 degree twist, where the blades intermesh through the conical envelope of the bowl. Such intermeshing mixing action may encourage a high rate of mixture turnover, which may further provide acceptable mix dispersement and efficient heat transfer capability.
  • the 4CV mixer equipped with a 1.5 HP constant vector drive motor, may provide medium shear and may mix high viscosity materials up to 12,000,000 cps.
  • the 4CV mixer allows for mixing of relatively small batches, of about 0.05-0.5 gallons and all values and increments therebetween, with a capacity of about 0.75 gallons.
  • an organic alcohol may be pre-melted in a mixer until completely liquefied.
  • the organic alcohol may be stearyl alcohol.
  • the organic alcohol may be capryl alcohol, pelargonic alcohol, capric alcohol, 1-dodecanol, myristyl alcohol, cetyl alcohol, palmitoleyl alcohol, stearyl alcohol, isostearly alcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol, elaidolinoleyl alcohol, linolenyl alcohol, elaidolinolenyl alcohol, ricinoleyl alcohol, arachidyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, ceryl alcohol, montanyl alcohol, myricyl alcohol, geddyl alcohol, or mixtures thereof.
  • a cellulosic resin may then be introduced into the mixer using a volumetric or loss-in- weight feeder.
  • the cellulosic resin may be hydroxypropyl cellulose.
  • the cellulosic resin may be ethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, or mixtures thereof.
  • the feeder may operate at a controlled rate. Melting and mixing may continue until a substantially uniform, viscous mixture of the two constituents is obtained.
  • the mixture may be substantially free of visible agglomerations. Additional components may be added to the mixture, including but not limited to excipients, additives such as fillers, colorants, flavorants, preservatives, or other materials.
  • An excipient may be any inert substance used as a diluent or vehicle for a drag, such as microcrystalline cellulose.
  • microcrystalline cellulose may be a highly crystalline cellulose obtained by isolating crystalline regions of microfibrils (i.e. bundled linear cellulose chains) by hydrolytic degradation.
  • the active pharmaceutical ingredient (API) may be introduced to the mixture at a later period. Melting and mixing may continue until a substantially uniform, viscous mixture of the two constituents is obtained. The mixture may be substantially free of visible agglomerations. Furthermore, the mixture may be processed from 5 minutes to 120 hours, including all values and increments therebetween.
  • the mixer may have a handwheel actuated slide valve that may be opened to allow the mixture to exit through a die at the bottom of the mixer.
  • the direction of rotation and speed of the auger may be adjusted to force the material out of the die.
  • the die may be a multiple strand die, although other dies may be substituted to permit the formation of other shapes including but not limited to a solid shape or single strand.
  • the molten mixture may be fed onto release paper.
  • the mixture may be cooled using ambient or chilled cooling air or by using chilled casting rolls.
  • the cooling mixture may be transported on a cooling conveyor from the mixer to a pelletizer, where the mixture may be converted into pellets.
  • the pellets thus formed may be fed into an extruder, where the extruder may be but is not limited to a hot melt twin-screw extruder.
  • the extruder may be a 27mm extruder. However, other diameters and other types of extruders, such as a single-screw extruder, may also be used.
  • the extrusion temperature may be about 70-165 degrees Celsius, including all values and increments therebetween.
  • extrusion head pressure may be about 70- 700 kilopascal, including all values and increments therebetween.
  • a feeder such as a loss-in-weight feeder
  • a separate feeder such as a loss-in-weight feeder
  • the separate feeder for feeding the active pharmaceutical ingredient (API) may be located anywhere along the extruder barrel to maximize dispersion of the active pharmaceutical ingredient into the polymeric mixture, while minimizing exposure to shear and heat. It should be appreciated, however, that other methods of feeding the pellets and active pharmaceutical ingredient (API) into the extruder are also contemplated.
  • the first extruder thus contains a second mixture which comprises the first mixture of an organic alcohol and a cellulosic resin, further including an active pharmaceutical ingredient (API).
  • the active pharmaceutical ingredient (API) may be but is not limited to acetaminophen, acetylsalicylic acid, dextromethorphan, diphenylhydramine, ketorolac, caffeine, or mixtures thereof.
  • the final product may have about 0.1-30% by weight of an active pharmaceutical ingredient (API), including all values and increments therebetween.
  • the second mixture may be melted in the extruder and discharged through a die, such as a multiple strand die. Upon exiting the die, the molten mixture may be fed onto release paper.
  • the mixture may be cooled using ambient or chilled cooling air or by using chilled casting rolls.
  • the cooling mixture may be transported on a cooling conveyor from the mixer to a pelletizer, where the mixture may be converted into pellets.
  • the resultant pellets may be blended to obtain a homogeneous mixture.
  • the pellets may then be fed into a second extruder where they may be melted and forced through a die to produce the finished product, which may be in the form of a film.
  • the extruded film may be drawn down into a thinner film by placing it on a hot plate until visibly melted then using a draw down tool.
  • the hot plate may be about 120-160 degrees Celsius, including all values and increments therebetween.
  • the film may be passed through a series of chilled casting rolls.
  • the casting rolls may be about 40 to 70 degrees Celsius, including all values and increments therebetween.
  • the film may be collected on release paper and carried on a cooling conveyor. Further, the film may be coiled for additional processing or packaging.
  • the finished product may be about 0.001-0.010 inches in thickness, including all values and increments therebetween.
  • the first mixture exiting from the mixer may be directly fed into the first extruder.
  • a handwheel actuated slide valve at the bottom of the mixer may be opened and the speed and direction of the augers may be adjusted to force the mixture through a die at the bottom of the mixer and directly into the first extruder.
  • the active pharmaceutical ingredient (API) may then be fed into the first extruder through a separate feeder at an appropriate location. The location may be chosen to maximize uniform melting and mixing while minimizing exposure to heat and shear.
  • This embodiment may eliminate the first reheating and re-melting step, during which those constituents that are sensitive to heat and/or shear may degrade. Further, this embodiment may improve yield due to avoidance of the first pelletization step, during which material maybe lost.
  • the second mixture exiting from the first extruder may be directly formed into a film.
  • the first extruder may be equipped with a film die and a gear pump to facilitate film formation. Once formed, the film may be passed through a series of chilled casting rolls. The casting rolls may be about 40 to 70 degrees Celsius, including all values and increments therebetween.
  • This embodiment may eliminate the step of re-melting and re-extruding the pellets obtained from the second mixture. Accordingly, the active pharmaceutical ingredient (API) may not be subjected to a second heating, melting, and shearing. This may be beneficial because pharmaceutical materials may degrade when subjected to temperatures typically need to melt polymeric materials. Further, this embodiment may improve yield due to avoidance of the second extrusion process, during which material may be lost.
  • API active pharmaceutical ingredient
  • the first mixture exiting from the mixer may be directly fed into the first extruder, and the second mixture exiting from the first extruder may be directly formed into a film.
  • a handwheel actuated slide valve at the bottom of the mixer may be opened and the speed and direction of the augers may be adjusted to force the mixture through a die at the bottom of the mixer and directly into the first extruder.
  • the active pharmaceutical ingredient (API) may then be fed into the first extruder barrel using a separate feeder at an appropriate location. The location may be chosen to maximize uniform melting and mixing while minimizing exposure to heat and shear.
  • the resultant second mixture exiting from the first extruder may be forced through a film die at the end of the first extruder.
  • the film may be collected on release paper, carried on a cooling conveyor, and coiled for additional processing and packaging.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Manufacture Of Macromolecular Shaped Articles (AREA)

Abstract

La présente invention concerne un film polymère chargé d'un médicament sensiblement exempt de gels, et un procédé de préparation de ce film. Un alcool organique et une résine cellulosique peuvent être mélangés par fusion dans un mélangeur hélicône pour obtenir un premier mélange. Un ingrédient pharmaceutique actif peut être combiné au premier mélange de façon à obtenir un second mélange. Ce second mélange peut être poussé dans une filière de film à l'extrémité d'une extrudeuse, le film obtenu pouvant contenir moins de 5,0 % environ de gels ayant un diamètre égal ou supérieur à environ 40 microns.
PCT/US2006/023916 2005-06-21 2006-06-20 Films polymeres charges de medicaments Ceased WO2007002041A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69237305P 2005-06-21 2005-06-21
US60/692,373 2005-06-21

Publications (2)

Publication Number Publication Date
WO2007002041A2 true WO2007002041A2 (fr) 2007-01-04
WO2007002041A3 WO2007002041A3 (fr) 2007-03-08

Family

ID=37595734

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/023916 Ceased WO2007002041A2 (fr) 2005-06-21 2006-06-20 Films polymeres charges de medicaments

Country Status (1)

Country Link
WO (1) WO2007002041A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4780320A (en) * 1986-04-29 1988-10-25 Pharmetrix Corp. Controlled release drug delivery system for the periodontal pocket
US5242910A (en) * 1992-10-13 1993-09-07 The Procter & Gamble Company Sustained release compositions for treating periodontal disease

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8309613B2 (en) 2003-08-28 2012-11-13 Abbvie Inc. Solid pharmaceutical dosage form
US8333990B2 (en) 2003-08-28 2012-12-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8399015B2 (en) 2003-08-28 2013-03-19 Abbvie Inc. Solid pharmaceutical dosage form
US8691878B2 (en) 2003-08-28 2014-04-08 Abbvie Inc. Solid pharmaceutical dosage form

Also Published As

Publication number Publication date
WO2007002041A3 (fr) 2007-03-08

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