WO1999040943A1 - Systemes d'administration avec action dissolvante et procede de fabrication - Google Patents

Systemes d'administration avec action dissolvante et procede de fabrication Download PDF

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Publication number
WO1999040943A1
WO1999040943A1 PCT/US1998/019750 US9819750W WO9940943A1 WO 1999040943 A1 WO1999040943 A1 WO 1999040943A1 US 9819750 W US9819750 W US 9819750W WO 9940943 A1 WO9940943 A1 WO 9940943A1
Authority
WO
WIPO (PCT)
Prior art keywords
active
solubilizer
parts
eutectic
particles
Prior art date
Application number
PCT/US1998/019750
Other languages
English (en)
Inventor
B. Arlie Bogue
Original Assignee
Fuisz International Ltd.
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 Fuisz International Ltd. filed Critical Fuisz International Ltd.
Priority to EP98948412A priority Critical patent/EP1058561A1/fr
Priority to JP2000531194A priority patent/JP2003522097A/ja
Priority to AU94989/98A priority patent/AU9498998A/en
Publication of WO1999040943A1 publication Critical patent/WO1999040943A1/fr

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to solubilizing delivery systems in which poorly soluble materials therein dissolve readily in aqueous solutions and processes for their manufacture. More particularly the solubilizing delivery systems are combinations of an active agent/solubilizer eutectic composition in intimate contact with particles of the active agent.
  • active agents are pharmaceutical materials or drugs the solubilizing delivery system products may thereafter be combined with suitable amounts of conventional pharmaceutical ingredients to make comestible units or oral dosage forms, such as tablets or capsules.
  • the invention relates to solubilizing delivery systems and the method of producing them wherein particles of at least one active agent and at least one solubilizing agent, such as surface active agents (solubilizer), are processed at low temperatures, i.e., at temperatures below the melting points of both, and preferably from below the formation temperature of a eutectic of the active and solubilizer combination to below the temperature at which the active dissolves in the solubilizer.
  • the processing further involves combining of ingredients at the above stated processing temperatures in the presence of forces sufficient to produce a active/solubilizer eutectic which is at least partially coated onto, or in intimate contact with, particles of the active.
  • the particles are a crystalline form of the active ingredient at least partially surrounded or enveloped by a eutectic mixture of the active and solubilizer(s).
  • the eutectic may also contain crystals of the active.
  • the solubilizing/active systems produced by this invention have superior aqueous solubility at pH 5.2 compared to the active alone and contain from about 10% to about 95% active, and preferably from about 30% to about 90% active, and most preferably from about 40% to about 80% active.
  • a drug/solubilizer solubilizing delivery system contains particles of a drug coated, at least partially, with a eutectic of the drug/solubilizer mixture.
  • This product upon ingestion, results in a blood plasma profile that indicates that the active is made available for uptake by the body much more quickly than drug alone would be available.
  • the product is also able to deliver a larger amount of the drug than the eutectic alone. It is believed that during dissolution of the solubilizing delivery system the rapidly dissolving eutectic provides an initial amount of active followed by the solubilizer wetted particulate or crystalline form of the drug.
  • the invention relates to methods of making particulate active/solubilizer products by combining each ingredient under controlled temperature and processing conditions to yield particles of particulate (such as crystalline) actives coated with a eutectic of the active and solubilizer, and products comprising the particulate, eutectic coated solid active.
  • a eutectic is a combination of substances whose melting point is lower than that cf any other combination of the same ingredients. Typically, eutectics melt at temperatures below the melting points of either individual ingredient.
  • Actives or active agents as used herein means any substance or material which one would like to improve the solubility or dissolution characteristics of. Pharmaceutical materials are the most preferred active. Such materials and ingredients will be readily apparent to the skilled artisan upon reading this invention.
  • a drug/solubilizer solubilizing delivery system of the invention has a dissolution profile such that about 80%, or more of the drug will dissolve in water at pH 5.2 in about 5 minutes or less at 37 degrees C.
  • the method involves mixing from about 10% to about 95%, more preferably from about 30% to about 90%, and most preferably from about 40% to about 80% of particles of at least one active agent with from about 90% to about 5%, more preferably from about 10% to about 70%, and most preferably from about 20% to about 60% of at least one solid solubilizing agent (stabilizer) at temperatures from below the formation temperature of a eutectic of the drug/solubilizer mixture to below the temperature where the drug melts or dissolves in the solubilizer, and under sufficient forces to at least partially coat the particles of active with the eutectic material formed; and recovering the processed drug/solubilizer product.
  • the particle size of the recovered product can be further reduced according to known milling processes, for example. If milling or other particle size reduction methods are utilized care must be taken to insure that the temperatures created do not raise much above the original processing temperature or again, large crystals of active may form in the eutectic
  • the active agent is a solid substance, preferably crystalline in nature, of generally poor water solubility. It is also preferable that the size of the particulate, or crystalline solid substance be small, preferably less than about lO ⁇ , with less than from about 6 ⁇ being most preferred.
  • the active agent is preferably a drug whose rapid dissolution and release is desirable, but whose solubility properties inhibit rapid dissolution.
  • useful drugs are analgesics, H2 antagonists, non-steroidal anti-inflammatory agents, anti- cholesterolemics, anti-allergy agents and anti-migraine agents. Ibuprofen (IBP), etoprofen and Naproxen are especially preferred drug substances.
  • Suitable drugs include Dextromethorphan, Chlorpheniramine Maleate, 4- Acetamidophenol (APAP), Sodium Naproxen, Diphenhydramine, Diltiazem HC1, Cimetidine, and Fexofenadine.
  • Any active agent, or drug which forms a eutectic with the solubilizer are contemplated as being usable and encompassed by this invention. While the action of the processing equipment may cause some attrition, its is generally desirable that the drug be supplied in a finely divided state to facilitate formation of the eutectic and coating.
  • the particle size of the drug before processing will be less than about l O ⁇ , and preferably less than 6 ⁇ .
  • the solubilizers employed generally may have both a hydrophobic and hydrophilic (HLB) character.
  • HLB hydrophobic and hydrophilic
  • an important characteristic of the solubilizing agent is its ability to form a eutectic with the material it is to be processed with.
  • the melting point of the solubilizer, or combination of solubilizers should be less than the melting temperature of the active.
  • Polyoxyethylene/polyoxypropylene surfactants such as the Pluronics/Lutrols made by the Pluronics/Lutrols made by the Pluronics/Lutrols made by the Pluronics/Lutrols made by the Pluronics/Lutrols made by the Pluronics/Lutrols made by the Pluronics/Lutrols made by the Pluronics/Lutrols made by
  • Pluronic or Lutrol F68 is especially preferred.
  • Other useful surfactants include PEG- 1000, PEG 2000 and the like.
  • useful solubilizers might be salts or other pharmaceutically acceptable compounds which form a eutectic and melt at temperature lower than the drug with which they are to be combined. Among these is urea.
  • solubilizer delivery systems of the invention it is preferred that from about 90% to about 5%, more preferably from about 10% to about 70%, and most preferably from about 20% to about 60% solid solubilizer be utilized in the solubilizer delivery systems of the invention. Enough solubilizer must be present, in any event, to sufficiently coat or envelop the particles of active to enhance their dissolution.
  • the method of the invention involves contacting solid particles of the active, including drug, and the solubilizer under conditions suitable to form the delivery system products of the invention. Following production of the products, the particulate product will generally be sized and employed, along with other pharmaceutical additives, in dosage forms.
  • the temperatures at which the ingredients are contacted are from below the formation point of the combination's eutectic to below the temperature at which the active will dissolve in the solubilizer so that the drug does not totally dissolve in the eutectic.
  • temperatures are too high, one or both of the ingredients can, upon cooling crystallize too quickly, resulting in crystal reformation which are too large to take advantage of the wetting properties of the solubilizer/eutectic.
  • Typical temperatures used in the invention range from at or below the standard eutectic formation temperature to below the temperature at which the active melts or readily dissolves in the solubilizer utilized. It has been found by X-ray diffraction that upon cooling crystals of the active and solubilizer form in the eutectic material. These crystals, however are very small unless the active is dissolved or present in the eutectic at too high a concentration.
  • using the combination of temperature and force, especially shear force it is possible to form the eutectic and coat the particles of active at a temperature which is below the "normal" eutectic formation temperature at normal atmospheric pressure.
  • processing temperature be sufficiently high to control the viscosity of the mixture to allow for the forces to enable the coating of the active particles.
  • preferred temperatures are from about 35 to about 45 degrees C.
  • the forces used during processing include but are not limited to centrifugal, shear and pressure. Shear and centrifugal forces are preferred. No matter what forces the materials are subjected to, however, the forces should to be sufficient to coat the eutectic material onto crystals, or particles of the active. Generally the higher, or more intense or prolonged the forces, the more thorough the coating. Additionally, sufficient amounts of ingredients must be used to sufficiently coat, or envelop the active .particles or the enhanced dissolution properties will not be fully realized.
  • D. Devices The method of the invention is carried out on any device which provides the temperature and force conditions that facilitate eutectic formation and optional coating/encapsulation of the particles of active.
  • Suitable devices include extruders, flash flow spinning heads and the like.
  • One highly preferred device is a multiple zone extruder having a length to diameter ratio L/D sufficient to coat or encapsulate particles of the active with the active/solubilizer eutectic material.
  • flash flow spinning heads are useful. Inside the device, the feedstock particles lose their resistance to liquid flow and become "liquiform.” In this state, the eutectic is physically transformed from its original solid state, through a liquid state and back to a solid state instantaneously. While the particles undergo this transformation, they are acted upon by centrifugal force, or another shearing force, which force separates them into discrete eutectic coated particles.
  • U. S. Patent sets out the details of the liquiflash, flash flow processes.
  • the solubilizing delivery system particles may thereafter be ground by known methods such as milling and optionally screened to separate particles of a size sufficient for the dosage form in which they will be included.
  • the size reduction method should, however be monitored to prevent the delivery system particle from reaching temperatures above those used during their manufacture otherwise large crystal formation could occur.
  • the particles may be mixed with various pharmaceutical ingredients, e.g., sweeteners, fillers, perfumes, flow control agents, binders, and the like in suitable amounts.
  • Such dosage forms can include tablets and capsules and other oral dosage forms.
  • the active agent and solubilizer are to be combined in active:solubilizer ratios of about 95:5 to 10:90, preferably about 90: 10 to about 25:75, most preferably about 80:20 to about 40:60, with appropriate ratios being determined by the character of the ingredients.
  • the active ingredients be present in amounts that are as high as possible without detracting from the improved dissolution of the invention.
  • IBP and the surfactant Lutrol (Pluronic) F68 are used in the inventive process, particles of IBP are coated (at least partially, and preferably completely) with a eutectic mixture of the IBP and Lutrol F68. 80% of the solubilizing delivery system so produced will dissolve in 37°C degree water at a pH of 5.2 in five (5) minutes as measured by a Beckman/Hanson Automated Dissolution System as described below.
  • the preferred ratios of IBP to Lutrol F68 are from about 60:40 to about 75:25.
  • Ketoprofen or Naproxen and a solubilizer, or solubilizers such as Lutrol F68 with which they form a eutectic will be particularly useful.
  • active agents such as drugs have been particularly discussed and are exemplified below, the invention encompasses any combination of ingredients where improved solubility or dissolution of one ingredient (the active) is beneficial. As indicated the active must also form a eutectic with a solubilizer, or combination of solubilizers which can be coated onto particles of that ingredient. Such materials and ingredients will be readily apparent to the skilled artisan upon reading of this invention.
  • Example I Poloxamer 188 NF (Lutrol F68) was milled by passing the material through an Apex 1 14 mill with a 20 screen with the hammers forward. The feed rate was 4 RPM with a mill speed of 4590 RPM. The mill was allowed to cool for 15 minutes and then the material was run through again at the same settings.
  • IBP micronized Ibuprofen
  • Lutrol F68 milled Lutrol F68
  • the ingredients were mixed for about five minutes at speed II with the chopper off to produce a 60:40 IBP:Lutrol mixture. This mixture was used as a feedstock as follows:
  • the feedstock was fed to the spinning head disclosed in U. S. Application Serial No. 08/874,215, filed June 13, 1997.
  • the head speed was increased to 60Hz while the heating elements were raised to a temperature which produced liquiflash conditions.
  • the spinning head forced the material through its orifices and the product was permitted to free fall a distance of from six to eight feet below the head. It comprises eutectic coated particles containing 60:40 IBP:solubilizer.
  • Example II The same IBP/Lutrol F68 mixture as in Example I was made up as described in Example I. Instead of processing the mixture in a spinning head, however, an extruder manufactured by AVP was used as follows:
  • Dissolution test result shown in Chart 1 below also support the requirement for sufficient force and low temperatures.
  • Example III Extrudate Milling Pass the extrudant though an Apex 1 14 Mill with no mesh and the hammers forward. Feed the mixture very slowly at a feed rate of 4 RPM and the mill at 4590 RPM and allow the top of the feeder to clear before continuing to feed. Care should be taken to not allow the milling process to generate too much heat.
  • Example IV Ibuprofen Dissolution Studies Microparticles of the milled extrudate and liquiflash formed IBP:Lutrol material of Examples I - III were tested for dissolution according to the following procedure. Some results are shown in Chart 1 below. Instrumentation:

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

Dans cette invention, on mélange des combinaisons agent actif/agent tensioactif, en recourant à des conditions de traitement sélectionnées, afin de placer au moins partiellement un mélange eutectique fait de cette combinaison en contact étroit avec les particules de l'agent actif. Cette opération de mélange améliore la solubilité des agents actifs, tout en permettant de dissoudre des concentrations plus élevées de l'agent actif à des débits supérieurs à ceux actuellement possibles.
PCT/US1998/019750 1998-02-16 1998-09-22 Systemes d'administration avec action dissolvante et procede de fabrication WO1999040943A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP98948412A EP1058561A1 (fr) 1998-02-16 1998-09-22 Systemes d'administration avec action dissolvante et procede de fabrication
JP2000531194A JP2003522097A (ja) 1998-02-16 1998-09-22 可溶化デリバリーシステムおよび製造方法
AU94989/98A AU9498998A (en) 1998-02-16 1998-09-22 Solubilizing delivery systems and method of manufacture

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IE19980115A IE980115A1 (en) 1998-02-16 1998-02-16 Solubilizing delivery systems and method of manufacture
IE980115 1998-02-16

Publications (1)

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WO1999040943A1 true WO1999040943A1 (fr) 1999-08-19

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PCT/US1998/019750 WO1999040943A1 (fr) 1998-02-16 1998-09-22 Systemes d'administration avec action dissolvante et procede de fabrication

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EP (1) EP1058561A1 (fr)
JP (1) JP2003522097A (fr)
AU (1) AU9498998A (fr)
CA (2) CA2247994A1 (fr)
IE (1) IE980115A1 (fr)
WO (1) WO1999040943A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005048990A2 (fr) * 2003-11-13 2005-06-02 Alza Corporation Dispersions de melange a l'etat fondu
WO2005065653A1 (fr) * 2003-12-19 2005-07-21 E.I. Du Pont De Nemours And Company Enrobage intime d'ibuprofene avec des poloxameres afin d'ameliorer la dissolution aqueuse
BG66007B1 (bg) * 1999-12-09 2010-10-29 The Boots Company Plc Компресиран таблетен състав съдържащ нестероидно противовъзпалително средство
WO2013143688A1 (fr) 2012-03-26 2013-10-03 Glatt Ag Granulés d'ibuprofène de saveur masquée
US8951569B2 (en) 2009-09-17 2015-02-10 Basf Se Pellets coated with coatings containing active substances
US9393192B2 (en) 2002-07-29 2016-07-19 Alza Corporation Methods and dosage forms for controlled delivery of paliperidone and risperidone
US10258572B2 (en) 2013-04-18 2019-04-16 Shandong Luye Pharmaceutical Co., Ltd. Pharmaceutical compositions of goserelin sustained release microspheres

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007516259A (ja) * 2003-12-09 2007-06-21 メッドクリスタルフォームズ、エルエルシー 活性剤との混合相共結晶の調製方法

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WO1997002017A1 (fr) * 1995-07-03 1997-01-23 Elan Corporation, Plc Formulations a liberation lente pour medicaments faiblement solubles

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US5340591A (en) * 1992-01-24 1994-08-23 Fujisawa Pharmaceutical Co., Ltd. Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine
WO1993025190A1 (fr) * 1992-06-10 1993-12-23 Eastman Kodak Company Nanoparticules de medicaments anti-inflammatoires non steroidiens modifiees en surface
TW487582B (en) * 1995-08-11 2002-05-21 Nissan Chemical Ind Ltd Method for converting sparingly water-soluble medical substance to amorphous state

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EP0349509A1 (fr) * 1988-06-07 1990-01-03 "PHARLYSE", Société Anonyme Composition pharmaceutique à base d'un anti-inflammatoire non stéroidien, son procédé de préparation et son utilisation
WO1997002017A1 (fr) * 1995-07-03 1997-01-23 Elan Corporation, Plc Formulations a liberation lente pour medicaments faiblement solubles

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Title
HAWLEY, A. R. ET AL: "Physical and chemical characterization of thermosoftened bases for molten filled hard gelatin capsule formulations", DRUG DEV. IND. PHARM. (1992), 18(16), 1719-39 CODEN: DDIPD8;ISSN: 0363-9045, vol. 18, no. 16, 1992, pages 1719 - 1739, XP000612180 *
MURA, P. ET AL: "Solid dispersions of ibuprofen in urea. Effects of urea on dissolution", FARMACO, ED. PRAT. (1986), 41(12), 377-87 CODEN: FRPPAO;ISSN: 0430-0912, vol. 41, no. 12, 1986, pages 377 - 387, XP002091277 *
TANEJA, L. N. ET AL: "Solid dispersions of ketoprofen. In vitro characterization and bioavailability assessment", INDIAN DRUGS (1997), 34(2), 72-77 CODEN: INDRBA;ISSN: 0019-462X, vol. 34, no. 2, February 1997 (1997-02-01), pages 72 - 77, XP002091278 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BG66007B1 (bg) * 1999-12-09 2010-10-29 The Boots Company Plc Компресиран таблетен състав съдържащ нестероидно противовъзпалително средство
US9393192B2 (en) 2002-07-29 2016-07-19 Alza Corporation Methods and dosage forms for controlled delivery of paliperidone and risperidone
WO2005048990A2 (fr) * 2003-11-13 2005-06-02 Alza Corporation Dispersions de melange a l'etat fondu
WO2005048990A3 (fr) * 2003-11-13 2005-10-13 Alza Corp Dispersions de melange a l'etat fondu
WO2005065653A1 (fr) * 2003-12-19 2005-07-21 E.I. Du Pont De Nemours And Company Enrobage intime d'ibuprofene avec des poloxameres afin d'ameliorer la dissolution aqueuse
US8951569B2 (en) 2009-09-17 2015-02-10 Basf Se Pellets coated with coatings containing active substances
WO2013143688A1 (fr) 2012-03-26 2013-10-03 Glatt Ag Granulés d'ibuprofène de saveur masquée
US10258572B2 (en) 2013-04-18 2019-04-16 Shandong Luye Pharmaceutical Co., Ltd. Pharmaceutical compositions of goserelin sustained release microspheres

Also Published As

Publication number Publication date
IE980115A1 (en) 2000-02-09
EP1058561A1 (fr) 2000-12-13
CA2247877A1 (fr) 1999-08-16
JP2003522097A (ja) 2003-07-22
AU9498998A (en) 1999-08-30
CA2247994A1 (fr) 1999-08-16

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