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EP1305011A1 - Compositions et films pour fabrication de gelules - Google Patents

Compositions et films pour fabrication de gelules

Info

Publication number
EP1305011A1
EP1305011A1 EP01928586A EP01928586A EP1305011A1 EP 1305011 A1 EP1305011 A1 EP 1305011A1 EP 01928586 A EP01928586 A EP 01928586A EP 01928586 A EP01928586 A EP 01928586A EP 1305011 A1 EP1305011 A1 EP 1305011A1
Authority
EP
European Patent Office
Prior art keywords
weight
film
poly
water
polymer component
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.)
Withdrawn
Application number
EP01928586A
Other languages
German (de)
English (en)
Inventor
Haiyong Haung
Robert Schmitt
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.)
Union Carbide Chemicals and Plastics Technology LLC
Original Assignee
Union Carbide Chemicals and Plastics Technology LLC
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 Union Carbide Chemicals and Plastics Technology LLC filed Critical Union Carbide Chemicals and Plastics Technology LLC
Publication of EP1305011A1 publication Critical patent/EP1305011A1/fr
Withdrawn legal-status Critical Current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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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

Definitions

  • the present invention relates to alkylene oxide polymer containing compositions which can be formed into flexible films having properties suitable for replacement of gelatin containing films in the manufacture of soft or hard shell capsules.
  • the present invention further relates to processes for forming such alkylene oxide containing polymer films and the use of such films in the manufacture of soft shell capsules on conventional encapsulation equipment such as a rotary die machine.
  • gelatin containing compositions are commonly used in the manufacture of capsules, particularly soft capsules for the delivery of a variety of liquid or solid ingredients in pharmaceutical, agricultural and other applications. Such films are generally strong and tough and have processing properties which make them suitable for use in the manufacture of capsules.
  • gelatin is a protein material produced by hydrolysis of collagen from animal bones and connective tissues. Since gelatin is derived from animal sources, there are often inconsistencies in product quality from batch to batch. The physical and chemical properties of gelatin are a function of the source of the collagen, the method of rendering and refining the crude feed stock, and the chemical nature of impurities and additives which may be present.
  • WO 99/40156 discloses manufacturing capsules from compositions containing a mixture of different molecular weight poly(alkylene oxide) polymers in which water is used to compatibilize the mixture of polymers. None of these prior art efforts have resulted in films having all of the physical and mechanical properties required to successfully replace gelatin films in the commercial manufacture of capsules. Summary of the Invention
  • thin flexible films made from compositions containing poly(alkylene oxide) polymers which can replace gelatin films in the manufacture of capsules.
  • the poly(alkylene oxide) polymer containing films of the present invention are prepared by blending a poly(alkylene oxide) polymer component with an appropriate amount of water and optionally a plasticizer and/or other ingredients and extruding or otherwise forming a thin flexible film which is particularly suitable for the formation of capsule shells.
  • compositions of the present invention typically yield a film with mechanical properties in desired ranges, e.g., having a stress of less than 250 psi at a strain of 100% as determined by a mechanical tensile test in accordance with ASTM D882-97 and an Indentation Index of less than 8 as determined by the HH Indentation Test described hereinafter.
  • the poly(alkylene oxide) polymer containing films of the present invention can be used in known processes and apparatus for the manufacture of capsules for pharmaceutical, agricultural and other applications.
  • compositions of the present invention suitable for forming films useful in the manufacture of capsules comprise;
  • compositions may be formed into the films of the present invention by known means such as extrusion.
  • the thin, easily extensible, films of the present invention which are suitable for the preparation of capsules comprise;
  • the poly(alkylene oxide) polymers used to obtain the films of the present invention are prepared from alkylene oxide monomers containing from about 2 to 5 carbon atoms per molecule, e.g., ethylene oxide or propylene oxide, as well as copolymers and derivatives thereof. Polymers of a desired molecular weight may be obtained directly from the polymerization of the alkylene oxide monomers or by blending poly(alkylene oxide) polymers of different molecular weights.
  • the term "molecular weight” means number average molecular weight. Methods for determining number average molecular weight such as gel permeation chromatography, light scattering techniques and rheological measuring techniques are known to those skilled in the art. The molecular weights used in this specification were determined by rheological measurements. These alkylene oxide polymers useful in the present invention are water soluble and have a molecular weight of from about 100,000 to 8,000,000 g/mol.
  • the poly(alkylene oxide) polymers used to obtain the films of the present invention comprise ethylene oxide polymers.
  • the ethylene oxide polymers include, for example, homopolymers of ethylene oxide and copolymers of ethylene oxide with one or more polymerizable comonomers.
  • the particular comonomer is not critical to the present invention and may contain hydrocarbon substituents, such as, for example, alkyl, cycloalkyl, aromatic, alkene (also referred to as alkylene) or branched alkyl or alkene groups; provided, however, that the water solubility or water-dispersibility is maintained.
  • Methods of preparing ethylene oxide polymers useful in the present invention are well known in the art. See for example, U.S.
  • Poly(alkylene oxide) polymers useful in the present are commercially available, for example, from Union Carbide Corporation, a subsidiary of Dow Chemical Company, under the tradename POLYOX ® Water Soluble Resins. These homopolymers of ethylene oxide have a molecular weight of from about 100,000 to 8,000,000 g/mol.
  • a single molecular weight grade of poly(alkylene oxide) polymer or a blend of two or more grades of such polymers in appropriate proportions can be used.
  • the molecular weight of the poly(alkylene oxide) chosen for use in preparing a film of the present invention will largely be determined by the type of capsule to be manufactured and its intended use. In general, the molecular weight of the polymer is chosen on the basis of the time required for the capsules made therefrom to dissolve in the fluid environment present in the intended use.
  • the poly(alkylene oxide) polymer component will normally have a molecular weight in the range of 200,000 to 400,000 g/mol., whereas higher molecular weight polymers are suitable for slower dissolving capsules.
  • the poly(alkylene oxide) containing polymer component of the compositions from which the films of the present invention are formed may comprise additional polymers in order to achieve desired properties.
  • Such other polymers include, for example, naturally occurring and synthetic neutral, cationic, and anionic polymers, e.g., polysaccharides and derivatives thereof, hyaluronic acid, other cross- linked polyalkylene oxides, polyvinyl pyrrolidones, polycaprolactones, polyvinyl acetates and polycarboxylic acids, polyacrylic acid and polyvinyl acetate.
  • the polysaccharides include naturally occurring, biosynthesized and derivatized carbohydrate polymers and mixtures thereof.
  • Such materials encompass high molecular weight polymers composed of monosaccharide units joined by glycosidic bonds.
  • These materials may include, for example, the entire starch and cellulose families; pectin; chitosan; chitin; the seaweed products such as agar and carrageenan; alginate; the natural gums such as guar, arabic and tragacanth; bio-derived gums such as xanthan; and the like.
  • Common polysaccharides include cellulosics conventionally employed for the preparation of cellulose ethers, such as, for example, chemical cotton, cotton linters, wood pulp, alkali cellulose and the like. Such materials are commercially available. The molecular weight of the polysaccharides typically ranges from about 10,000 to 2,000,000 grams per mole.
  • the polysaccharides are etherified by reacting the polysaccharide with an alkylene oxide, e.g., ethylene oxide, propylene oxide or butylene oxide or otherwise derivatized by techniques known to those skilled in the art.
  • an alkylene oxide e.g., ethylene oxide, propylene oxide or butylene oxide or otherwise derivatized by techniques known to those skilled in the art.
  • polymers When such other polymers are used in the film forming compositions of the present invention, they are typically present in amounts of less than about 70% by weight, and more typically from about 10 to 40% by weight, based on the total weight of the polymer component. Particularly good results have been obtained when the polymer component contains at least about 50% by weight poly (ethylene oxide).
  • the weight percentages of the various components of the film forming compositions of the present invention are based on the total weight of the composition, including the polymer component, water, plasticizers and other components as hereinafter described.
  • the poly(alkylene oxide) polymer containing compositions used to form the films of the present invention contain water in an amount of from about 14 to about 50% by weight, more preferably from about 20 to about 35% by weight, based on the total weight of the film forming composition.
  • higher molecular weight poly(alkylene oxide) polymers require larger amounts of water to achieve the same flexibility compared to low molecular weight poly(alkylene oxide) polymers.
  • the water should present in an amount sufficient to be effective as an internal plasticizer when the compositions are used to form the films of the present invention, e.g. by extrusion. Care must be taken to maintain the water content of the finished films of the present invention above about 14 % by weight when used in the manufacture of capsules to obtain the physical and mechanical properties necessary to make them suitable to replace gelatin based films.
  • plasticizers may also advantageously be included in the compositions from which the films of the present invention are formed. Such plasticizers modify the films' properties making them softer and more ductile and also help maintain the water content in the films, which is believed to enhance the flexibility and sealability of the films during the encapsulation step.
  • plasticizers which are particularly useful as plasticizers in the present invention are capable of forming hydrogen bonds with poly(alkylene oxide).
  • plasticizer compounds examples include pol hydric alcohols such as glycerin, propylene glycol, sorbitol and the like, carboxylic acids and their derivatives including adipic acid, triethyl citrate and the like, and sugars such as glucose, fructose, xylose and the like. All of the plasticizers may be used alone or in mixture thereof. Plasticizer compounds may be present in the film forming compositions of the present invention in an amount of from 1 to about 40% by weight, preferably from about 5 to about 30 % by weight.
  • the films of the present invention may be prepared with conventional apparatus by conventional film forming processes, preferably extrusion.
  • the polymer component containing the poly(alkylene oxide) having the selected molecular weight is first uniformly blended with water and optionally a plasticizer and any other components in a conventional mixer such as a Henchel mixer, V blender or Hobart mixer.
  • a conventional mixer such as a Henchel mixer, V blender or Hobart mixer.
  • the various components are added separately to an extruder with solid components being added by way of a metered feeder and liquid components being added by way of a metered pump, and formed into a homogeneous mixture inside the extruder.
  • the water content of the blended composition should be sufficient to avoid excessive extrusion torque but not so great as to produce films which lack sufficient tensile strength to maintain their shape.
  • Caution should be taken to avoid excess loss of water during film production and transportation.
  • the extruder and die temperatures are kept below the boiling point of water to prevent excess water evaporation.
  • the techniques and conditions to be employed in extruding the films of the present invention will be readily apparent to the skilled artesian and are described, for example, in U.S. Patent 3,941,865 which is incorporated herein by reference.
  • the films of the present invention are easily extensible and for most applications will have a thickness of from about 5 to about 50 mils.
  • the films of the present invention are preferably self sealing, that is, the films should be able to seal onto themselves with the help of elevated temperature, pressure, or both, and without the necessity of being solvated.
  • Capsule shells made from the films of the present invention have a very low water content, typically from 0 to about 5%, depending on film composition and resist moisture uptake even in relatively humid conditions while providing excellent mechanical strength.
  • the films of the present invention are ideal for encapsulating moisture sensitive materials and meet other standard requirements for capsules including maintenance of capsule shape under external pressure, good solubilit in gastro-intestinal fluid and stability for long term storage.
  • the processability of the film to form soft shell capsules can be determined by the tensile test and by the "HH Indentation Test".
  • stress is a measure, in pounds per square inch (psi), of the force per unit area required to achieve a certain strain and is determined in accordance with the procedures of ASTM D882-97.
  • Stress is determined by subtracting the length of a piece of film to be tested at rest from the length of the piece of film after it has been stretched and dividing that number by the length of the piece of film at rest.
  • HH Indentation Test measures the ability of a film to be deformed into a half capsule shape. The test is performed using a TA- XT2 Texture Analyzer (Stable Micro Systems, Haslemere, UK). A piece of film to be tested is placed between two plates which are bolted together. Each plate has a hole in its center exposing a circular section of the film sample approximately 0.6 inches in diameter. A probe comprising a cylindrical rod having a diameter of 0.5 inches and a rounded tip having a radius of 6.4mm is positioned to push against the exposed section of film.
  • the Indentation Index represents the amount of force, in pounds, required to move the probe a certain distance when the probe is moving at a certain speed.
  • the distance the probe travels represents the depth of the indentation the probe makes in the film.
  • the Indentation Index is determined using a film sample formed to a thickness of 25 mils with the probe moving at a speed of 1 mm/second and traveling a distance of 6.4 mm.
  • a film sample that is suitable to use on a typical soft-shell capsule encapsulation machine must have an Indentation Index value of less than 8.
  • the freshly extruded film was placed in an incubator with circulating air under controlled condition of 50% relative humidity at 25 °C. Samples were taken at different time intervals to determine the water content in the films. The results, which are shown in Table 1, indicate that the poly(ethylene oxide) based films lose water readily.
  • a mixture of POLYOX WSR N-750, glycerin and water was extruded on a Brabender ® Conical Twin Screw Extruder (Model CTSE- V) operated at low temperatures (feed 25-45 °C, barrel 50-90 °C, die 80-110 °C).
  • the extruded film was collected in the same manner as described in Example 1.
  • the screw speed was 20 to 50 rpm, and the torque was -2000 mg.
  • the solid POLYOX WSR N-750 powder was meter-fed into the extruder with a K-Tron Volumetric Feeder Model K2MV-720, and the liquid containing water and glycerin was metered into the extruder with a MasterFlex Peristaltic Pump Model PM- 77914. Both the solid and liquid addition rates were controlled, so that the composition contains POLYOX WSR N-750/glycerin in a ratio of 4:1, and the water content in the finished extruded film was about 30 wt% .
  • Indentation tests were also performed to evaluate the processability of the extruded film in making soft shell capsule. This test was performed on a TA-XT2 Texture Analyzer (Stable Micro Systems, Haslemere, UK) in accordance with procedures described previously herein to measure the extension and elasticity of the film.
  • EXAMPLE 5 Poly(ethylene oxide) having a molecular weight of 200,000 g/gmol (POLYOX WSR N-80) and glycerin in a weight to weight ratio of 5:1 were first mixed for 2 minutes with a mortar and pestle. Water was then added slowly to the mixture in an amount sufficient to provide a total of 20 wt.% and the mixing was continued for an additional 10 minutes. The doughy mixture (-20 g) was transferred to a Brabender head mixer (D-51, No 507) operated at 80 °C and 10 RPM. After mixing for 5 minutes, an aliquot of hot mixture was taken out, placed between two aluminum plates and pressed on a hydraulic press at 2000 PSI and 90 °C. After pressing for 2 minutes, the film was released from the mold and sealed in a plastic bag. The mechanical properties of the compressed film are presented in Table 9. Table 9
  • Ellipsoidal shaped capsules were prepared from films of the previous examples on a small mold that simulates the action of an encapsulation rotary die. The film was heated gently just prior to sealing when water content was below 20% and required no heating when water content was about 30%. The resulting capsules had strong seals. The finished (dry) capsules appeared opaque and had a smooth surface and a strong seam. They retained their shapes well under external force. The capsules were filled with vegetable oil or poly(ethylene glycol). These capsules ruptured within 30 minutes in a dissolution test defined by U.S. Pharmacopeia, 24 rev.;.U.S. Pharmacopeial Convention: Rockville, MD, 2000; pp. 1941-1942 by stirring (50 rpm) at 37 °C in 0.1 N HC1 (1000 mL). In general, the capsules dissolve faster with higher plasticizer contents and thinner shells. Results of the disintegration test are presented in Table 11.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Manufacture Of Macromolecular Shaped Articles (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

L'invention concerne de nouvelles compositions contenant du poly(oxyde d'alkylène) et des films produits à partir de ces compositions, qui conviennent pour remplacer les films à base de gélatine dans la fabrication de gélules.
EP01928586A 2000-07-21 2001-04-17 Compositions et films pour fabrication de gelules Withdrawn EP1305011A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US22005200P 2000-07-21 2000-07-21
US220052P 2000-07-21
PCT/US2001/012459 WO2002007711A1 (fr) 2000-07-21 2001-04-17 Compositions et films pour fabrication de gelules

Publications (1)

Publication Number Publication Date
EP1305011A1 true EP1305011A1 (fr) 2003-05-02

Family

ID=22821853

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01928586A Withdrawn EP1305011A1 (fr) 2000-07-21 2001-04-17 Compositions et films pour fabrication de gelules

Country Status (8)

Country Link
EP (1) EP1305011A1 (fr)
JP (1) JP2004504445A (fr)
KR (1) KR20030023709A (fr)
AU (1) AU2001255429A1 (fr)
BR (1) BR0112599A (fr)
CA (1) CA2416257A1 (fr)
MX (1) MXPA03000624A (fr)
WO (1) WO2002007711A1 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8765167B2 (en) 2001-10-12 2014-07-01 Monosol Rx, Llc Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US7357891B2 (en) 2001-10-12 2008-04-15 Monosol Rx, Llc Process for making an ingestible film
US8900498B2 (en) 2001-10-12 2014-12-02 Monosol Rx, Llc Process for manufacturing a resulting multi-layer pharmaceutical film
US20110033542A1 (en) 2009-08-07 2011-02-10 Monosol Rx, Llc Sublingual and buccal film compositions
US20190328679A1 (en) 2001-10-12 2019-10-31 Aquestive Therapeutics, Inc. Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US10285910B2 (en) 2001-10-12 2019-05-14 Aquestive Therapeutics, Inc. Sublingual and buccal film compositions
US8603514B2 (en) 2002-04-11 2013-12-10 Monosol Rx, Llc Uniform films for rapid dissolve dosage form incorporating taste-masking compositions
US20070281003A1 (en) 2001-10-12 2007-12-06 Fuisz Richard C Polymer-Based Films and Drug Delivery Systems Made Therefrom
US11207805B2 (en) 2001-10-12 2021-12-28 Aquestive Therapeutics, Inc. Process for manufacturing a resulting pharmaceutical film
US8900497B2 (en) 2001-10-12 2014-12-02 Monosol Rx, Llc Process for making a film having a substantially uniform distribution of components
US6949256B2 (en) 2002-01-18 2005-09-27 Banner Pharmacaps, Inc. Non-gelatin capsule shell formulation
AU2005291917B2 (en) * 2004-09-30 2012-02-16 The Hershey Company Sealed, edible film strip packets and methods of making and using them
US9149959B2 (en) 2010-10-22 2015-10-06 Monosol Rx, Llc Manufacturing of small film strips
US12427121B2 (en) 2016-05-05 2025-09-30 Aquestive Therapeutics, Inc. Enhanced delivery epinephrine compositions
US11273131B2 (en) 2016-05-05 2022-03-15 Aquestive Therapeutics, Inc. Pharmaceutical compositions with enhanced permeation
KR20190005199A (ko) 2016-05-05 2019-01-15 어퀘스티브 테라퓨틱스, 아이엔씨. 강화된 전달 에프네프린 조성물
US12433850B2 (en) 2016-05-05 2025-10-07 Aquestive Therapeutics, Inc. Enhanced delivery epinephrine and prodrug compositions
WO2023076281A1 (fr) 2021-10-25 2023-05-04 Aquestive Therapeutics, Inc. Compositions orales et nasales et méthodes de traitement

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5614217A (en) * 1995-06-07 1997-03-25 R.P. Scherer Corporation Capsule shell formulation to produce brittle capsules
WO1999040156A1 (fr) * 1998-02-06 1999-08-12 Union Carbide Chemicals & Plastics Technology Corporation Compositions polymeres d'oxyde d'alkylene

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0207711A1 *

Also Published As

Publication number Publication date
JP2004504445A (ja) 2004-02-12
KR20030023709A (ko) 2003-03-19
WO2002007711A1 (fr) 2002-01-31
MXPA03000624A (es) 2003-09-05
AU2001255429A1 (en) 2002-02-05
CA2416257A1 (fr) 2002-01-31
BR0112599A (pt) 2003-07-01

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