US20030086976A1 - Pharmaceutical compositions for poorly soluble drugs - Google Patents

Pharmaceutical compositions for poorly soluble drugs Download PDF

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Publication number
US20030086976A1
US20030086976A1 US10/175,883 US17588302A US2003086976A1 US 20030086976 A1 US20030086976 A1 US 20030086976A1 US 17588302 A US17588302 A US 17588302A US 2003086976 A1 US2003086976 A1 US 2003086976A1
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US
United States
Prior art keywords
pharmaceutical composition
composition according
drug
suspension
azole antifungal
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.)
Abandoned
Application number
US10/175,883
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English (en)
Inventor
David Hayes
Angelo Morella
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.)
Mayne Pharma International Pty Ltd
Original Assignee
Individual
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
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Priority claimed from AUPQ4854A external-priority patent/AUPQ485499A0/en
Priority claimed from AUPQ7450A external-priority patent/AUPQ745000A0/en
Application filed by Individual filed Critical Individual
Assigned to F H FAULDING & CO. LIMITED reassignment F H FAULDING & CO. LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAYES, DAVID, MORELLA, ANGELO MARIO
Publication of US20030086976A1 publication Critical patent/US20030086976A1/en
Priority to US10/461,503 priority Critical patent/US6881745B2/en
Assigned to MAYNE PHARMA INTERNATIONAL PTY LTD reassignment MAYNE PHARMA INTERNATIONAL PTY LTD CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: F.H. FAULDING & CO. LIMITED
Priority to US11/763,578 priority patent/US8771739B2/en
Assigned to HALCYGEN PHARMACEUTICALS LIMITED reassignment HALCYGEN PHARMACEUTICALS LIMITED LICENSE AND DEVELOPMENT AGREEMENT Assignors: MAYNE PHARMA INTERNATIONAL PTY LTD (F/K/A FH FAULDING & CO LTD)
Abandoned legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to improved pharmaceutical compositions of drugs that are practically insoluble in aqueous media.
  • the present invention also relates to a process for preparing the compositions.
  • the present invention relates to improved dosage forms for the administration of the compositions.
  • the dosage forms in both applications are said to have good bioavailability in a form suitable for oral administration, and are both designed for dissolution in the stomach.
  • the present invention provides a pharmaceutical composition of a practically insoluble drug, wherein in vitro the composition forms a suspension.
  • the composition may be in the form of a solid dispersion of the practically insoluble drug and a polymer having acidic functional groups.
  • the term “practically insoluble” as used herein applies to drugs that are essentially totally water-insoluble or are at least poorly water-soluble. More specifically, the term is applied to any drug that has a dose (mg) to aqueous solubility (mg/ml) ratio greater than 100 ml, where the drug solubility is that of the neutral (for example, free base or free acid) form in unbuffered water. This meaning is to include, but is not to be limited to, drugs that have essentially no aqueous solubility (less than 1.0 mg/ml).
  • drug will be widely understood and denotes a compound having beneficial prophylactic and/or therapeutic properties when administered to, for example, humans. Further, the term “drug per se” is used throughout this specification for the purposes of comparison, and means the drug when in an aqueous solution/suspension without the addition of any excipients.
  • the particles in the cloudy suspension in vitro will generally be particles of a size greater than about 1 nm but less than about 10 micrometer.
  • In vitro dissolution testing of a pharmaceutical composition according to this form of the present invention reveals that particles in this size range are present when tested at a pH in the range of 5.5 to 7.5.
  • in vitro dissolution testing of a pharmaceutical composition according to this form of the present invention again reveals that particles in this size range are present when subsequently tested at a pH in the range of 5.5 to 7.5. This pre-treatment may be conducted to simulate in vivo conditions.
  • nanoparticulate form such as in the range of 1 nm to 450 nm
  • microparticulate form such as in the range of 0.45 micrometer to 10 micrometer.
  • the presence of such nanoparticles in vivo may be determined by testing for them in vitro, such as by passing the cloudy suspension through a 450 nm filter and having the suspension remain cloudy.
  • Such nanoparticles are preferably present regardless of whether the acidic pre-treatment step described above is utilised in the testing procedure.
  • the present invention additionally provides a pharmaceutical composition of a practically insoluble drug, wherein the composition forms a suspension in vitro at a pH in the range of 5.5 to 7.5, the suspension having particles in the size range of 1 nm to 10 micrometer, with or without a pre-treatment at acidic pH.
  • the suspension has at least a portion of its particles in the size range of 1 nm to 450 nm in vitro at a pH in the range of 5.5 to 7.5, again with or without a pre-treatment at acidic pH.
  • the pharmaceutical composition may therefore provide for acceptable absorption of the practically insoluble drug (where acceptable absorption is indicated by the extent of the absorption being greater than that of the crystallised form of the drug per se), in the intestines where the pH is expected to be in the range of 5.5 to 7.5.
  • the pharmaceutical composition may be administered with food or without food.
  • This is beneficial as many practically insoluble drugs are unable to be formulated in a manner that allows administration without food, particularly those typically formulated as solid dosage forms. This makes administration of these dosage forms cumbersome and quite inflexible for the patient.
  • the pharmaceutical composition of the present invention is preferably bioequivalent when administered under fed conditions compared to administration under fasted conditions.
  • the AUC for a composition administered under fed conditions is preferably within the range of 80 to 125% of the AUC under fasted conditions, when considering the 90% confidence interval for the ratio of the fed value to the fasted value (using natural log transformed data).
  • any practically insoluble drug may be beneficially used in the pharmaceutical composition of the present invention.
  • many drugs whether considered practically insoluble or not
  • versions crystalline forms, polymorphs, etc
  • drugs developed in the future that are also considered to be practically insoluble, are also to be included within the scope of the present invention.
  • azole antifungal drugs such as itraconazole and saperconazole
  • similar benefits will be available for other classes of drugs such as anti-hypertensives, immunosuppressants, anti-inflammatories, diuretics, antiepileptics, cholesterol lowering drugs, hormonals, hypoglycemics, antiviral drugs, nasal decongestants, antimicrobials, anti-arrthrytics, analgesics, anti-cancer drugs, anti-parasitics, proteins, peptides, CNS stimulants, CNS depressants, 5 HT inhibitors, anti-schizophrenics, anti-Alzheimer drugs, anti-psoriatics, steroidals, oligonucleotides, anti-ulcer drugs, proton pump inhibitors, anti-asthmatics, thrombolyitics and vitamins.
  • the polymers useful for forming the solid dispersion of the pharmaceutical composition of the present invention are those having acidic functional groups.
  • such polymers will be polycarboxylic acids.
  • Such polycarboxylic acids may be any polycarboxylic acid which, when in a solid dispersion with a practically insoluble drug, results in the formation of the abovementioned suspension, ideally in the preferred pH ranges, and preferably to provide acceptable absorption in the intestines.
  • Such polymers may be one or more of the group comprising hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethyl cellulose, methacrylic acid copolymer, shellac, cellulose acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate, and includes the various grades of each polymer such as HPMCAS-LF, HPMCAS-MF and HPMCAS-HG.
  • the polymer is a polycarboxylic acid such as a hydroxypropyl methylcellulose phthalate such as that available from Shin-Etsu Chemical Industry Co Ltd as HP-50, HP-55 or HP-55S.
  • a polycarboxylic acid such as a hydroxypropyl methylcellulose phthalate such as that available from Shin-Etsu Chemical Industry Co Ltd as HP-50, HP-55 or HP-55S.
  • an aqueous based enteric polymer such as the dispersion Eudragit L30D, or enteric polymers dissolved in water with the addition of ammonia or alkaline agents, may be useful.
  • the solid dispersion is formed by dispersing or dissolving the drug and the polymer in a suitable solvent, and subsequently spray drying to form the solid dispersion in the form of a powder.
  • suitable solvents or dispersion media include methylene chloride, chloroform, ethanol, methanol, propan-2-ol, ethylacetate, acetone, water or mixtures thereof.
  • excipients may then be blended into the powder (with or without milling or grinding) to form a composition suitable for use in dosage forms such as tablets and capsules.
  • the present invention therefore also provides a process for preparing a pharmaceutical composition of a practically insoluble drug, the process including dispersing in a solvent the drug and a polymer having acidic functional groups, and spray drying the dispersion to form a solid dispersion.
  • the present invention may thus provide a process for preparing a pharmaceutical composition of a practically insoluble drug, where the process includes the steps of:
  • dosage forms may include a range of traditional excipients such as disintegrants, diluents, fillers, lubricants, glidants, colourants and flavours.
  • Excipients such as colouring agents and pigments may also be added to dosage forms in accordance with the present invention, and suitable colouring agents and pigments may include titanium dioxide and dyes suitable for food.
  • compositions in accordance with the present invention it has been found that drugs previously considered to present bioavailability problems may be presented in dosage forms with superior bioavailability.
  • the inventive compositions have produced formulations that are not considered bioequivalents to, but have at least twice the bioavailability of, a commercially available itraconazole product (SporanoxTM).
  • SporanoxTM a commercially available itraconazole product
  • the inventive compositions have produced formulations that have reduced food effect and thus need not be administered with food (unlike SporanoxTM).
  • bioavailability of the drug as compared to the drug per se is improved by at least 50% and more preferably 100%, in terms of AUC.
  • This powder blend was then filled into size 0 gelatin capsules by hand. Each capsule was filled with 364 to 378 mg of powder, containing nominally 98 to 102 mg of itraconazole.
  • a solution was prepared by dispersing HP-50 (420 g) in methylene chloride (8400 g) and then adding itraconazole (280 g) and stirring to form a pale brown solution. This solution was then spray dried to form a powder.
  • a portion (292 g) of this spray dried powder was then blended with sodium starch glycolate (93.6 g) and colloidal silicon dioxide (Aerosil 200)(5.6 g) in a Collette mixer at high speed for 5 minutes.
  • Magnesium stearate (8.8 g) was added to the blend from the Collette mixer and the mixture tumble blended until uniform.
  • test capsules were utilised in a pharmacokinetic study. 8 male volunteers were dosed with one 100 mg capsule after an overnight (10 hour) fast. The capsules were dosed with 240 ml water. At appropriate time intervals blood samples were taken from the subjects and the concentration of itraconazole in the plasma determined. The study was performed in a randomised 2 way crossover fashion with subjects receiving 100 mg itraconazole as a marketed capsule (SporanoxTM) or as the test formulation described in example 2 above. The alternate dose was taken after a 2 week washout period.
  • the study was again conducted as a single dose, crossover study in 8 health male adult subjects, but under fed conditions.
  • the subjects commenced eating a standard high fat breakfast 20 minutes prior to dose administration, having fasted for at least 10 hours prior to that.
  • Example 3 Capsule
  • Example 2 Capsule Parameter (Fed) (Fasted) C max (ng/ml) 148.20 182.6 T max (h) 10.25 2.94 AUC (ng ⁇ h/ml) 1806 1776 AUC inf (ng ⁇ h/ml) 1997 1875

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US10/175,883 1999-12-23 2002-06-21 Pharmaceutical compositions for poorly soluble drugs Abandoned US20030086976A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/461,503 US6881745B2 (en) 1999-12-23 2003-06-16 Pharmaceutical compositions for poorly soluble drugs
US11/763,578 US8771739B2 (en) 1999-12-23 2007-06-15 Pharmaceutical compositions for poorly soluble drugs

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
AUPQ4854A AUPQ485499A0 (en) 1999-12-23 1999-12-23 Improved pharmaceutical compositions for poorly soluble drugs
AUPQ4854 1999-12-23
AUPQ7450A AUPQ745000A0 (en) 2000-05-12 2000-05-12 Improved pharmaceutical compositions for poorly soluble drugs
AUPQ7450 2000-05-12
PCT/AU2000/001592 WO2001047492A1 (fr) 1999-12-23 2000-12-22 Compositions pharmaceutiques ameliorees pour medicaments peu solubles

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2000/001592 Continuation WO2001047492A1 (fr) 1999-12-23 2000-12-22 Compositions pharmaceutiques ameliorees pour medicaments peu solubles

Related Child Applications (2)

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US10/461,503 Division US6881745B2 (en) 1999-12-23 2003-06-16 Pharmaceutical compositions for poorly soluble drugs
US11/763,578 Continuation US8771739B2 (en) 1999-12-23 2007-06-15 Pharmaceutical compositions for poorly soluble drugs

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US10/175,883 Abandoned US20030086976A1 (en) 1999-12-23 2002-06-21 Pharmaceutical compositions for poorly soluble drugs
US10/461,503 Expired - Lifetime US6881745B2 (en) 1999-12-23 2003-06-16 Pharmaceutical compositions for poorly soluble drugs
US11/763,578 Expired - Lifetime US8771739B2 (en) 1999-12-23 2007-06-15 Pharmaceutical compositions for poorly soluble drugs

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US11/763,578 Expired - Lifetime US8771739B2 (en) 1999-12-23 2007-06-15 Pharmaceutical compositions for poorly soluble drugs

Country Status (8)

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US (3) US20030086976A1 (fr)
EP (2) EP1239831B1 (fr)
JP (2) JP5159012B2 (fr)
AU (2) AU782469B2 (fr)
CA (1) CA2396380C (fr)
ES (1) ES2398643T3 (fr)
PT (1) PT1239831E (fr)
WO (1) WO2001047492A1 (fr)

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US20030225104A1 (en) 2003-12-04
JP5159012B2 (ja) 2013-03-06
EP1239831B1 (fr) 2012-10-31
AU782469B2 (en) 2005-08-04
CA2396380C (fr) 2015-04-21
EP2415462A1 (fr) 2012-02-08
AU2331801A (en) 2001-07-09
PT1239831E (pt) 2013-01-23
US8771739B2 (en) 2014-07-08
JP2003518483A (ja) 2003-06-10
JP2012236837A (ja) 2012-12-06
US20080260835A1 (en) 2008-10-23
EP1239831A1 (fr) 2002-09-18
AU7252900A (en) 2001-06-28
WO2001047492A1 (fr) 2001-07-05
CA2396380A1 (fr) 2001-07-05
US6881745B2 (en) 2005-04-19

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