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WO2004062643A1 - Dispersions seches - Google Patents

Dispersions seches Download PDF

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Publication number
WO2004062643A1
WO2004062643A1 PCT/DK2003/000023 DK0300023W WO2004062643A1 WO 2004062643 A1 WO2004062643 A1 WO 2004062643A1 DK 0300023 W DK0300023 W DK 0300023W WO 2004062643 A1 WO2004062643 A1 WO 2004062643A1
Authority
WO
WIPO (PCT)
Prior art keywords
particulate material
pharmaceutically acceptable
process according
dispersion
carrier
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/DK2003/000023
Other languages
English (en)
Inventor
Kirsten Schultz
Tue Hansen
Per Holm
Anders Buur
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.)
Veloxis Pharmaceuticals AS
Original Assignee
Lifecycle Pharma AS
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 Lifecycle Pharma AS filed Critical Lifecycle Pharma AS
Priority to AU2003205543A priority Critical patent/AU2003205543A1/en
Priority to PCT/DK2003/000023 priority patent/WO2004062643A1/fr
Publication of WO2004062643A1 publication Critical patent/WO2004062643A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/1611—Inorganic 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to a process for the preparation of a solid pharmaceutically particulate material by spray-drying an aqueous dispersion comprising an active substance together with a lipid material and one or more pharmaceutically acceptable carriers.
  • the particulate material obtained by the process has suitable properties with respect to non-cohesiveness, density and particle size, which enables it to be further processed into a solid dosage form such as, e.g. tablets.
  • compositions can be prepared that have improved physico-chemical properties e.g. with respect to release of the active substance from the composition as evidenced by in vitro dissolution test and/or improved pharmacological properties e.g. with respect to bioavailability and efficacy.
  • the invention also relates to a particulate material obtained by use of the process and to pharmaceutical compositions comprising such particulate material.
  • micronisation of the drug substance employment of the drug substance in amorphous form, preparation of solid solutions or oil-containing compositions such as, e.g. emulsions etc.
  • gastrointestinal absorption is improved by emulsification of lipophilic drug substances compared with solid dosage forms like e.g. tablets and capsules.
  • the drug substance is already dissolved in the emulsified lipid phase and therefore it increases the possibility of solubilizing the drug substance in mixed micelles in order to be transported across the unstirred water layer of the gastrointestinal membrane. Accordingly, liquid emulsions as transport systems for drug substances with poor aqueous solubility have been in focus during the last decades.
  • liquid emulsions suffer from stability problems and normally patients find emulsions difficult to administer and to dose correctly and, therefore, research is ongoing in the field of preparing dry emulsions which can be reconstituted to liquid emulsions.
  • dry emulsions has not resulted in particulate material with suitable properties for the preparation of solid dosage forms.
  • compositions for oral use comprising e.g. active substances with relatively low water solubility and that release the active substance from the composition in a suitable manner to enable an absorption of the active substance into the circulatory system.
  • the present invention provides a process for the preparation of a solid pharmaceutical particulate material comprising an active substance, which is suitable for use in the preparation of e.g. solid dosage forms like e.g. tablets, capsules and sachets.
  • the process comprises spray drying of a dispersion comprising:
  • one or more active substances at least one of which is on solid form at room temperature, ii) one or more lipids, iii) a first pharmaceutically acceptable carrier which is water-soluble at room temperature, iv) optionally, a second pharmaceutically acceptable carrier, and v) water, and the particulate material obtained having a volume median particle diameter of at least about 20 ⁇ m such as, e.g., at least about 25 ⁇ m, at least about 30 ⁇ m, at least about 40 ⁇ m or at least about 50 ⁇ m determined as described herein.
  • the invention also relates to a process for the preparation of a solid pharmaceutical particulate material comprising an active substance, the process comprises spray drying of a dispersion comprising:
  • the particulate material obtained having a volume median particle diameter of at least about 20 ⁇ m such as, e.g., at least about 25 ⁇ m, at least about 30 ⁇ m, at least about 40 ⁇ m or at least about 50 ⁇ m determined as described herein.
  • the particulate material obtained may have a relatively high load of a lipid material, which due to its solubility properties enables a relatively high load of an active substance with a relatively low aqueous solubility.
  • the lipid material may be liquid or it may be solid at room temperature and normally it has an oily, sticky or waxy character.
  • a relatively high load of lipid material can be incorporated into a particulate material which appears as a particulate powder in solid form without any substantial oily, sticky or waxy appearance.
  • the particulate material obtained by the novel process has suitable properties with respect to bulk density and particle size and has in itself or after addition of suitable pharmaceutically acceptable excipients suitable properties with respect to flowability and compactability.
  • the solid pharmaceutical particulate material obtained has a bulk density of at least about 0.15 g/ml such as, e.g., at least about 0.18 g/ml, at least about 0.2 g/ml, at least about 0.3 g/ml, at least about 0.4 g/ml such as, e.g., from about 0.2 to about 1.5 g/ml, from about 0.3 to about 1.4 g/ml, from about 0.4 to about 1.3 g/ml.
  • the particulate material obtained has a particle size which is sufficiently large to avoid any substantial problems relating to cohesiveness (particulate material having a volume median particle diameter below about 20-40 ⁇ m is often very cohesive and, accordingly, unsuitable for use in the preparation of solid dosage forms without any pretreatment).
  • the particulate material obtained is suitable for use in the preparation of solid dosage forms. It has turned up that a particulate material according to the invention has suitable properties for being processed into solid dosage forms even in those cases where the particulate material has a mean particle size of about 20-40 ⁇ m.
  • the median particle size of a particulate material obtained according to the invention is at least about 15 ⁇ m and normally it is at least about 25 ⁇ m or at least about 50 ⁇ m.
  • the dispersion employed comprises an aqueous and a lipid phase. It may be in the form of an emulsion comprising a lipid and an aqueous phase, normally an oil-in-water emulsion or a microemulsion or it may be in the form of a dispersion comprising solid particles e.g. in the aqueous phase and/or in the lipid phase.
  • the dispersion is normally prepared in a process step before the step of spray-drying and, accordingly, it may be necessary to add pharmaceutically acceptable additive to the dispersion in order to ensure a sufficient stability of the dispersion (e.g. with respect to physical stability of the dispersion and/or chemical stability of the active substance and/or other components employed) or to ensure e.g. a suitable viscosity of the dispersion.
  • Such additives may be surface active agents such as, e.g. emulsifying agents, suspending agents, wetting agents, preservatives, pH adjusting agents, viscosity increasing
  • lipid material may either be in liquid or in solid or semi-solid form at room temperature.
  • powders have been prepared comprising the vitamin as oil.
  • the present invention focus on a particulate material comprising either a drug substance (liquid, solid or semi-solid at room temperature) together with a lipid material in solid or semi-solid form at room temperature, or a drug substance in solid form at room temperature together with a lipid material in liquid, solid or semi- solid form at room temperature.
  • lipid materials for use in a process according to the invention and being on liquid form at room temperature are i) substituted and/or unsubstituted monoglycerides and/or diglycerides such as, e.g., Akoline MCM®, Alkoline 3084®, glycerol monooleate such as, e.g. Arlacel 186®, Myverol 18-99®, Peceol; glycerol monolinoleat such as, e.g.
  • Maisine 35-1® ii) substituted and/or unsubstituted triglycerides, iii) hydrogenated and/or unhydrogenated glycerides, iv) oils such as, e.g., vegetable oils, marine oils, mineral oils and/or synthetic oils, v) short chain triglycerides such as, e.g., triacetin, vi) medium chain triglycerides such as, e.g., Miglyol 812®, Captex 355®, Neobee M5®, Akomed®; vii) long chain triglycerides such as, e.g.
  • lipid material for use in the present invention examples include i) substituted and/or unsubstituted monoglycerides and/or diglycerides such as, e.g., glyceryl monostearate (e.g. GRINDTEK MSP 90, MSP 90F, MSP 52, MSP 40, MSP 40F, MSP 32-3, MSP 32-6 or P 40), glyceryl laurate, glyceryl myristate, glyceryl oleate (e.g.
  • glyceryl monostearate e.g. GRINDTEK MSP 90, MSP 90F, MSP 52, MSP 40, MSP 40F, MSP 32-3, MSP 32-6 or P 40
  • glyceryl laurate glyceryl myristate
  • glyceryl oleate e.g.
  • GRINDTEK MOR 90 or 40 lard monoglyceride, palm kernel glyceride etc.; Imwitor 742 ® and Grindtek ® series from Danisco, glyceryl palmitostearate; iii) substituted and/or unsubstituted triglycerides such as, e.g., Akosoft ® ; iv) hydrogenated and/or unhydrogenated glycerides; v) PEG glycerides such as, e.g., Gelucire 33/01 ® , Gelucire 43/01 ® , Gelucire 39/01 ® , Labrafac CC ® , other PEG derivatives such as, e.g.
  • acetylated glycerides such as, e.g. Grindtek AML 60 ® ; vii) higher fatty acids such as, e.g., lauric acid, myristic acid, palmitic acid, stea
  • Suitable lipid materials for use in the present invention are:
  • Fatty acid esters such as, e.g., cetyl palmitate (Estol 3694) or fatty acid esters of propylene glycol such as, e.g., propylene glycol stearate;
  • Fatty acid esters of polyglycerol such as, e.g., polyglyceryl-3-oleate, polyglyceryl-3- stearate (e.g. GRINDTEK PEG 55 or PEG 55-6), or polyglyceryl-3-ester of dimerised soya bean oil;
  • Acetylated fatty acid esters of glycerol such as, e.g., acetylated lard monoglyceride or acetylated palm kernel glyceride.
  • the particulate material prepared according to the invention may comprise one or more lipid materials such as one or more of the lipid materials exemplified above.
  • the content of the lipid material in a particulate material prepared according to the invention is at least about 15% w/w such as, e.g., at least about 20% w/w, at least about 25% w/w, at least about 30% w/w, at least about 35% w/w, at least about 40% w/w such as, e.g. from about 20% w/w to about 85% w/w or from about 25% w/w to about 80% w/w, from about 30% w/w to about 80% w/w, from about 35% w/w to about 80% w/w or from about 40% w/w to about 80% w/w.
  • the particulate material obtained by a process according to the invention comprises one or more, same or different therapeutically and/or prophylactically active substances.
  • the particulate material may also or alternatively comprise a cosmetically active substance (i.e. a substance that is employed in cosmetic compositions) or a food or nutrient substance.
  • a therapeutically and/or prophylactically active substance includes any biologically and/or physiologically active substance that has a function on an animal such as, e.g. a mammal like a human.
  • the term includes drug substances, hormones, genes or gene sequences, antigen- comprising material, proteins, peptides, nutrients like e.g. vitamins, minerals, lipids and carbohydrates and mixtures thereof.
  • the term includes substances that have utility in the treatment and/or preventing of diseases or disorders affecting animals or humans, or in the regulation of any animal or human physiological condition.
  • the term also includes any biologically active substance, which has an effect on living cells or organisms.
  • a process according to the invention is especially suitable for use for the preparation of particulate material comprising an active substance that has an aqueous solubility at 25 °C and pH of 7.4 of at the most about 3 mg/ml such as, e.g., at the most about 2 mg/ml, at the most about 1 mg/ml, at the most about 750 //g/ml, at the most about 500 / g/ml, at the most about 250 //g/ml, at the most about 100 / g/ml, at the most about 50 //g/ml, at the most about 25 g/ml, at the most about 20 //g/ml or at the most about 10 //g/ml.
  • solubility of the active substance may be much lower such as, e.g., at the most about 1 /g/ml, at the most about 100 ng/ml, at the most about 75 ng/ml such as about 50 ng/ml.
  • active substances suitable for use in a particulate material according to the invention are in principle any active substance such as, e.g. freely water soluble as well as more slightly or insoluble active substances.
  • active substances suitable for use are e.g. antibacterial substances, antihistamines and decongestants, anti-inflammatory agents, antiparasitics, antivirals, local anesthetics, antifungals, amoebicidals or trichomonocidal agents, analgesics, antianxiety agents, anticlotting agents, antiarthritics, antiasthmatics, antiarthritic, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antiglaucoma agents, antimalarials, antimicrobials, antineoplastics, antiobesity agents, antipsychotics, antihypertensives, antitussives, auto-immune disorder agents, anti-impotence agents, anti-Parkinsonism agents, anti-Alzheim
  • Anti-inflammatory drugs like e.g. ibuprofen, indometacin, naproxen, nalophine;
  • Anti-Parkinsonism agents like e.g. bromocriptine, biperidin, benzhexol, benztropine etc.
  • Antidepressants like e.g. imipramine, nortriptyline, pritiptyline, etc.
  • Antibiotics like e.g. clindamycin, erythomycin, fusidic acid, gentamicin, mupirocine, amfomycin, neomycin, metronidazol, sulphamethizole, bacitracin, framycetin, polymyxin B, acitromycin etc,
  • Antifungal agents like e.g. miconazol, ketoconaxole, clotrimazole, amphotericin B, nystatin, mepyramin, econazol, fluconazol, flucytocine, griseofulvin, bifonazole, amorofine, mycostatin, itrconazole, terbenafine, terconazole, tolnaftate etc.
  • Antimicrobial agents like e.g.metronidazole, tetracyclines, oxytetracylines, penicillins etc.
  • Antiemetics like e.g. metoclopramide, droperidol, haloperidol, promethazine etc.
  • Antihistamines like e.g. chlorpheniramine, terfenadine, triprolidine etc.
  • Antimigraine agents like e.g. dihydroergotamine, ergotamine, pizofylline etc.
  • Coronary, cerebral or peripheral vasodilators like e.g. nifedipine, diltiazem etc.
  • Antianginals such as, e.g., glyceryl nitrate, isosorbide dinitrate, molsidomine, verapamil etc.
  • Calcium channel blockers like e.g. verapamil, nifedipine, diltiazem, nicardipine etc.
  • Hormonal agents like e.g. estradiol, estron, estriol, polyestradiol, polyestriol, dienestrol, diethylstilbestrol, progesterone, dihydroprogesterone, cyprosterone, danazol, testosterone etc.
  • Contraceptive agents like e.g. ethinyl estradiol, lynestrenol, etynodiol, norethisterone, mestranol, norgestrel, levonorgestrel, desodestrel, medroxyprogesterone etc.
  • Antithrombotic agents like e.g. heparin, warfarin etc.
  • Diuretics like e.g. hydrochlorothiazide, flunarizine, minoxidil etc.
  • Antihypertensive agents like e.g. propanolol, metoprolol, clonidine, pindolol etc.
  • Corticosteroids like e.g. beclomethasone, betamethasone, betamethasone-17- valerate, betamethasone-dipropionate, clobetasol, clobetasol- 17-butyrate, clobetasol- propionate, desonide, desoxymethasone, dexamethasone, diflucortolone, flumethasone, flumethasone-pivalte, fluocinolone acetonide.fluocinoide, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisonebuteprate.methylprednisolone, triamcinolone acetonide, hacinonide, fluprednide acetate, alklometasone-dipropionate, fluocortolone, fluticason-propionte, mometasone-furate, desoxymethasone, diflurason-diacetate, halquinol,
  • Dermatological agents like e.g. nitrofurantoin, dithranol, clioquinol, hydroxyquinoline, isotretionin, methoxsalen, methotrexate, tretionin, trioxalen, salicylic acid, penicillamine etc.
  • Steroids like e.g. estradiol, progesterone, norethindrone, levonorgestrel, ethynodiol, levonorgestrol, norgestimate, gestanin, desogestrel, 3-keton-desogesterel, demegestone, promethoestrol, testosterone, spironolactone and esters thereof etc.
  • Nitro compounds like e.g. amyl nitrates, nitroglycerine and isosorbide nitrate etc.
  • Opioids like e.g. morphine, buprenorphine, oxymorphone, hydromorphone, codeine, tramadol etc.
  • Prostaglandins such as, e.g., a member of the PGA, PGB, PGE or PGF series such as, e.g. minoprostol, dinoproston, carboprost, eneprostil etc.
  • Peptides like e.g. growth hormone releasing factors, growth factors (e.g. epidermal growth factor (EGF), nerve growth factor (NGF), TGF, PDGF, insulin growth factor (IGF), fibroblast growth factor (aFGF, bFGF etc.), somatostatin, calcitonin, insulin, vasopressin, interferons, IL-2 etc., urokinase, serratiopeptidase, superoxide dismutase, thyrotropin releasing hormone, lutenizing hormone releasing hormone (LH- RH), corticotrophin releasing hormone, growth hormone releasing hormone (GHRH), oxytocin, erythropoietin (EPO), colony stimulating factor (CSF) etc.
  • growth factors e.g. epidermal growth factor (EGF), nerve growth factor (NGF), TGF, PDGF, insulin growth factor (IGF), fibroblast growth factor (aFGF, bFGF etc.
  • intersting active substances for incorporation into a particulate material according to the present invention are e.g. tacrolimus, sirolimus, losartan, irbetan, valsartan, candesartan-celexetil etc.
  • the amount of active substance incorporated in a particulate material may be selected according to known principles of pharmaceutical formulation.
  • the dosage of the active substance present in a particulate material according to the invention depends inter alia on the specific drug substance, the age and condition of the patient and of the disease to be treated.
  • a particulate material according to the invention may comprise a cosmetically active ingredient and/or a food ingredient.
  • a cosmetically active ingredient and/or a food ingredient.
  • Specific examples include vitamins, minerals, vegetable oils, hydrogenated vegetable oils, etc.
  • the particulate material according to the invention may of course comprise more than one active substance.
  • a further amount of the same or of another active substances may be added in a subsequent processing step.
  • a particulate material according to the invention comprises a first and, optionally, a second pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to denote a pharmaceutically acceptable excipient, i.e., any material, which is inert in the sense that it substantially not have any therapeutic and/or prophylactic effect per se.
  • any pharmaceutically acceptable excipients may be incorporated in a particulate material according to the invention
  • three groups of pharmaceutically acceptable excipients are of particular interest as excipients in the dispersion which is subject to spray drying, namely so-called matrix forming agents, density modifying agents and particle size modifying agents.
  • the agents or a mixture of agents are important in order to obtain a particulate material that has properties that are suitable for formulating and/or filling the material into solid dosage forms.
  • the particulate material obtained should essentially not adhere to pharmaceutical equipment, it should be compressible etc.
  • the function of the first and/or second pharmaceutically acceptable excipient is to impart and/or improve these properties.
  • the type of excipient and the concentration thereof depends on the amount and properties of active substance itself.
  • the active substance has unsuitable or at least not optimal properties for pharmaceutical formulation and/or it is present in a relatively low amount.
  • the main function of the first and second pharmaceutically acceptable excipient is to ensure that the particulate material obtained has a suitable properties with respect to e.g. bulk, mass, anti-adhesiveness, particle size, pycnometer density, flowability and/or compressibility.
  • a matrix forming agent is intended to provide the particulate material with bulk and mass.
  • a matrix forming agent may be soluble or insoluble in water.
  • matrix forming agents that are water soluble are denoted "a first pharmaceutically acceptable carrier" and they have a solubility in water of at least about 10 mg/ml.
  • Suitable examples of matrix forming agents for use in the present invention include but are not limited to
  • water soluble polymers such as, e.g., nnethylcellulose, carboxymethylcellulose and salts thereof, ethylhydroxyethylcellulose, ethylmethylcelluose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate-copolymer (PVP-PVA), gelatine or hydrolysed gelatine, gum acacia, gum arabicum, pectin, modified starch, alginate or a polyglycerol fatty acid ester, and combinations thereof,
  • PVA polyvinylalcohol
  • PVP polyvinylpyrrolidone
  • PVP-PVA polyvinylpyrrolidone-polyvinylacetate-copolymer
  • low molecular weight water soluble substances such as, e.g., mono-, di- and oligosaccharides, especially glucose, fructose, maltose, sucrose, lactose, trehalose, maltodextrin and inulin or polyhydroxy compounds, especially, xylitol, mannitol, sorbitol, lactitol, maltitol and isomalt, and combinations thereof, and
  • the matrix forming substance is dissolved or suspended in water to form or partly form the aqueous phase of the dispersion.
  • the matrix forming substance is normally present in the particulate material in a concentration of at least about 10% w/w such as, e.g. from about 10% to about 85% w/w, from about 15% to about 85% w/w, from about 20% to about 80% w/w, from about 25% to about 80% w/w, from about 30% to about 75% w/w or from about 35% to about 65% w/w.
  • first pharmaceutically acceptable carriers denoted "first pharmaceutically acceptable carriers”
  • second pharmaceutically acceptable carriers In general it is advantageous to include such a second pharmaceutically acceptable carrier in the particulate material, but as shown in the examples herein it is also possible to obtain a suitable particulate material without any use of such a second pharmaceutically acceptable carrier depending on the choice of first pharmaceutically acceptable carrier.
  • the density modifying substances and/or the particle size increasing substances may be water soluble or substantially water insoluble.
  • the water soluble substances generally have a water solubility of at least about 10 mg/ml whereas the substantially water insoluble substances generally have a water solubility of less than about 10 mg/ml such as, e.g., at the most about 3 mg/ml at room temperature.
  • the density modifying substances increase the bulk density of the particulate material obtained according to the invention and, accordingly, such substances may in themselves have a relatively high pycnometric density. It is contemplated that the density increasing substance must have a pycnometric density of at least about 0.7 g/ml such as, e.g. at least about 0.8 g/ml, at least about 0.9 g/ml, at least about 1.0 g/ml or at least about 1.1 g/ml such as, e.g. from about 0.7 to about 2.0 g/ml, from about 0.8 to about 1.8 g/ml, from about 0.9 to about 1.7 g/ml or from about 0.9 to about 1.6 g/ml.
  • Examples of density increasing substances are: inorganic salts such as, e.g., Bentonite, calcium carbonate, calcium phosphate (dibasic anhydrous), calcium phosphate (tribasic), calcium silicate, calcium sulphate, colloidal silicon dioxide, kaolin, magnesium alumino anhydride, magnesium aluminium metasilicate, magnesium carbonate, magnesium oxide, magnesium trisilicate, soft silicic anhydride, talc, titanium dioxide, and cellulose compounds such as, e.g., cellulose (e.g. microcrystalline), cellulose (e.g. powdered) and cellulose (e.g. silicified microcrystalline), and combinations thereof.
  • inorganic salts such as, e.g., Bentonite, calcium carbonate, calcium phosphate (dibasic anhydrous), calcium phosphate (tribasic), calcium silicate, calcium sulphate, colloidal silicon dioxide, kaolin, magnesium alumino anhydride, magnesium aluminium metasilicate, magnesium carbonate
  • Magnesium alumino metasilicate is sold under the name Neusilin and is obtainable from Fuji Chemical Industries.
  • Neusilin is normally used in order to improve filling capacity and compression property of powders and granules when added.
  • Neusilin is also believed to reduce weight variation and to improve hardness and disintegration of tablets.
  • Neusilin has an adsorption capability, which makes it suitable for use when processing waxy materials like oil extracts and waxes into pharmaceutical composition.
  • Neusilin UFL2 and US2 are said to be suitable for such a use.
  • the invention relates to a process, wherein - as a pharmaceutically acceptable excipient - magnesium aluminosilicate and/or magnesium aluminometasilicate such as, e.g, Neusilin S1 , Neusilin FH2, Neusilin US2, Neusilin UFL2 or the like is used.
  • a pharmaceutically acceptable excipient such as, e.g, Neusilin S1 , Neusilin FH2, Neusilin US2, Neusilin UFL2 or the like is used.
  • Other suitable substances are contemplated to be bentonite, calcium silicate, kaolin, magnesium trisilicate, montmorillonite, saponite, silicium dioxide and/or titanium dioxide.
  • the second composition comprises magnesium aluminosilicate and/or magnesium aluminometasilicate such as, e.g, Neusilin
  • the particulate material obtained has an content of carrier of at least about 30% v/v such as, e.g., at least about 40% v/v, at least about 50% v/v, at least about 60% v/v, at least about 70% v/v, at least about 75% v/v, at least about 80% v/v, at least about 85% v/v or at least about 90% v/v.
  • Neusilin magnesium aluminometasilicate
  • the present inventors have found that specific qualities of magnesium aluminometasilicate (Neusilin) have excellent properties as glidants or anti-adhesive most likely due to the porous structure of Neusilin.
  • Neusilin may advantageously be added in order to reduce any adherence of the particulate material to the manufacturing equipment in particular to the spray dryer or tabletting machine.
  • Examples of density increasing substances which are water soluble, are mono-, di-, oligo and polysaccharides such as dextranes, dextrin, dextrose, fructose, inulin, lactose, maltodextrin, maltose, sucrose, trehalose; polyhydroxy compounds such as isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol; inorganic salts such as potassium chloride, sodium chloride; polyethylene glycol with an average molecular weight of at least 1000 and derivatives thereof.
  • mono-, di-, oligo and polysaccharides such as dextranes, dextrin, dextrose, fructose, inulin, lactose, maltodextrin, maltose, sucrose, trehalose
  • polyhydroxy compounds such as isomalt, lactitol, maltitol, mannitol, sorbi
  • any substance that contribute to the solid material in the dispersion may act as a particle size increasing substance.
  • Such substances impart mass and/or volume and, accordingly, size to the resulting particles.
  • Combinations of a water soluble and a substantially water insoluble density and/or particle size modifier are also within the scope of the present invention.
  • the density and/or particle size modifying substance is normally present in the particulate material in a concentration of at most about 70% w/w such as, e.g., from about 2% to about 70% w/w, from about 2% to about 60% w/w, from about 2% to about 50% w/w, from about 5% to about 50% w/w, from about 7.5% to about 45% w/w, from about 10% to about 40% w/w, from about 12.5% to about 35% w/w or from about 15% to about 30% w/w.
  • 70% w/w such as, e.g., from about 2% to about 70% w/w, from about 2% to about 60% w/w, from about 2% to about 50% w/w, from about 5% to about 50% w/w, from about 7.5% to about 45% w/w, from about 10% to about 40% w/w, from about 12.5% to about 35% w/w or from about 15% to about 30% w/w.
  • compositions such as those described above may also be added in another suitable step of the process of the invention.
  • pharmaceutically acceptable excipient includes the term “cosmetically acceptable excipient” and is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. Such an excipient may be added with the purpose of making it possible to obtain a pharmaceutical, nutritional and/or cosmetic composition, which has acceptable technical properties.
  • excipients for use in a particulate material according to the invention or for the further processing of such a material include but are not limited to fillers, diluents, disintegrants, binders, lubricants, plasticisers etc. or mixture thereof.
  • the choice of excipients is normally made taken such different uses into considerations.
  • Other pharmaceutically acceptable excipients for use in a particulate material of the invention (and/or in the dispersion and/or in the further processing of the particulate material) are e.g.
  • suitable fillers, diluents and/or binders include lactose (e.g. spray-dried lactose, ⁇ -lactose, /?-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), silicified microcrystalline cellulose (e.g. ProSolv SMCC90 of Penwest Pharmaceuticals Co), hydroxypropylcellulose, L- hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g.
  • lactose e.g. spray-dried lactose, ⁇ -lactose, /?-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®
  • microcrystalline cellulose variant grades of Avicel
  • Methocel E, F and K Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.
  • diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
  • disintegrants are e.g. alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e.g. Primogel® and Explotab®) etc.
  • binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.
  • Glidants and lubricants may also be included or added to a particulate material according to the invention.
  • examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.
  • Suitable surfactants such as, e.g., hydrophobic and/or hydrophilic surfactants as those disclosed in WO 00/50007 in the name of Lipocine, Inc.
  • suitable surfactants are i) polyethoxylated fatty acids such as, e.g. fatty acid mono- or diesters of polyethylene glycol or mixtures thereof such as, e.g. mono - or diesters of polyethylene glycol with lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid, and the polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG
  • PEG 25 PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000, ii) polyethylene glycol glycerol fatty acid esters, i.e.
  • esters like the above- mentioned but in the form of glyceryl esters of the individual fatty acids; iii) glycerol, propylene glycol, ethylene glycol, PEG or sorbitol esters with e.g. vegetable oils like e.g. hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil, peanut oil, hydrogenated palm kernel oil and the like, iv) polyglycerized fatty acids like e.g.
  • vegetable oils like e.g. hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil, peanut oil, hydrogenated palm kernel oil and the like
  • polyglycerized fatty acids like e.g.
  • glyceryl monooleate glyceryl dioleae, glyceryl mono- and/or dioleate, glyceryl caprylate, glyceryl caprate etc.
  • sterol and sterol derivatives viii) polyethylene glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as esters of PEG with the various molecular weights indicated above, and the various Tween ® series
  • polyethylene glycol alkyl ethers such as, e.g. PEG oleyl ether and PEG lauryl ether
  • sugar esters like e.g.
  • sucrose monopalmitate and sucrose monolaurate xi) polyethylene glycol alkyl phenols like e.g. the Triton® X or N series; xii) polyoxyethylene-polyoxypropylene block copolymers such as, e.g., the
  • Pluronic® series the Synperonic® series, Emkalyx®, Lutrol®, Supronic® etc.
  • the generic term for these polymers is "poloxamers" and relevant examples in the present context are Poloxamer 105, 108, 122, 123, 124, 181 , 182, 183, 184, 185, 188, 212, 215, 217, 231 , 234, 235, 237, 238, 282, 284, 288, 331 , 333, 334, 335, 338, 401 , 402, 403 and 407; xiii) sorbitan fatty acid esters like the Span® series or Ariacel® series such as, e.g.
  • the concentration of the surfactant(s) is normally in a range of from about 0,1 -75% w/w such as, e.g., from about 0.1 to about 20% w/w, from about 0.1 to about 15% w/w, from about 0.5 to about 10% w/w, or alternatively, in certain cases where higher concentrations are desired from about 20 to about 75% w/w such as, e.g. from about 25 to about 70% w/w, from about 30 to about 60% w/w.
  • the process according to the invention involves spray drying of a dispersion.
  • Spray drying is a commonly applied method in the field of pharmaceutical technology and is applied due to advantages with respect to e.g. i) easy and continuous operation, ii) applicability to heat sensitive and/or heat resistant materials, iii) it lead to particles with substantially consistent quality etc.
  • the process comprises the following steps:
  • a second pharmaceutically acceptable carrier such as, e.g. a second pharmaceutically acceptable carrier to obtain a feed composition, e) feeding the feed composition - optionally together with feeding of a second pharmaceutically acceptable carrier in powder form - into a suitable spray drier, f) drying the feed composition, and g) collecting the thus dried particulate material.
  • the feed composition should have a suitable viscosity as it is sprayed through a nozzle or atomizer and into the drying chamber of the spray dryer. If the viscosity is too high, the dispersion may be too "thick" and can have a tendency of adhering to the nozzle, which may result in that the delivery through the nozzle is stopped.
  • a particulate material may have good tabletting properties including good flowability and compactability in itself or after addition of suitable pharmaceutically acceptable excipients. It has no or minimal adherence to the tabletting equipment either in itself or after addition of lubricants. It is an excellent alternative for incorporation of active substances with very low water solubility and/or with a very low bioavailability.
  • a particulate material of the invention is excellent for a further processing into e.g. tablets.
  • tablets are normally easier and cheaper to produce and tablets are often preferred by the patient.
  • a tablet formulation is relatively easy to adjust to specific requirements, e.g. with respect to release of the active substance, size etc.
  • the particulate material may also be coated with a film coating, an enteric coating, a modified release coating, a protective coating, an anti-adhesive coating etc.
  • Suitable coating materials are e.g. methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, gelatin, methacrylic acid copolymer, polyethylene glycol, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein.
  • Plasticizers and other ingredients may be added in the coating material.
  • the same or different active substance may also be added in the coating material.
  • the process according to the invention may further comprise a step of increasing the properties such as, e.g., the mean particle size, the flowability, the stability and/or the compactability of the particulate material obtained.
  • the particulate material may be processed into pharmaceutical compositions without any increase in particle size, but - if advantageous - the particle size may be increased by employment of various different pharmaceutical technologies.
  • the technologies include roller compaction, wet granulation, moisture-activated granulation, melt granulation or a controlled agglomeration process involving spraying of a melt onto the particulate material.
  • the technologies are well-known to persons skilled in the art except the latter method of controlled agglomeration.
  • a controlled agglomeration process has been invented by the same Applicant and is disclosed in a co-pending PCT application No. PCT/DK02/00472 filed on 5 July 2001.
  • the content of this application is hereby incorporated by reference.
  • the purpose of increasing the particle size is to obtain a solid material, which is suitable for further processing into a solid dosage form notably for oral use.
  • the dosage form may be in the form of tablets, capsules, sachets etc.
  • particulate material obtained according to the present invention may be subject to a method for controlled agglomeration, i.e. a controlled growth in particle size of a particulate material.
  • Controlled agglomeration is provided using a process for the preparation of a particulate material (see below). Controlled agglomeration
  • the invention also provides a process for the preparation of a particulate material that has been subject to a controlled agglomeration process.
  • the process of the invention further comprising
  • a first composition comprising a carrier, which has a melting point of about 5 °C or more such as, e.g., about 10 °C or more, about 20°C or more or about 25 °C or more and which is present in the first composition in liquid form, on a second composition comprising a material in solid form, the second composition having a temperature of at the most a temperature corresponding to the melting point of the carrier and/or of the carrier composition such as, e.g., a temperature of at least about 2 °C, at least about 5 °C or at least about 10 °C lower than the melting point of the carrier and/or of the carrier composition, and ii) mixing or other means of mechanical working the second composition onto which the first composition is sprayed to obtain the particulate material.
  • the process enables incorporation in a solid material of a high load of a carrier of a type that e.g. due to its solubility properties enables a high load of therapeutically and/or prophylactically active substances with a relatively low aqueous solubility.
  • the carrier is normally solid or semi-solid and normally it has a sticky, oily or waxy character.
  • the carrier mentioned in this aspect of the invention includes all lipids mentioned herein before.
  • the carrier may also be fluid at room temperature or even at temperature below 5 °C and in such cases it is contemplated that the process is carried out by employment of cooling of the second composition.
  • a particulate material with a high load of carrier may be prepared and the resulting particulate material appears as a particulate powder in solid form.
  • the particulate material obtained by the novel method has excellent properties with respect to flowability, bulk density, compactability and thus, it is suitable for use in the preparation of e.g. tablets.
  • the particulate material may have a high load of a carrier of substantially sticky character the particulate material prepared has minimal, if any, adherence to tablet punches and/or dies during manufacture of tablets.
  • an important step in the process for the preparation of a particulate material according to the invention is the addition of a carrier or a carrier composition.
  • the carrier is of a type, which has a melting point of at least about 25 °C such as, e.g., at least about 30 °C at least about 35 °C or at least about 40 °C.
  • the melting point may not be too high, thus, the carrier normally has a melting point of at the most about 300 °C such as, e.g., at the most about 250 °C, at the most about 200 °C, at the most about 150 °C or at the most about 100 °C.
  • a relatively high temperature may promote e.g. oxidation or other kind of degradation of the substance.
  • the melting point is determined by DSC (Differential Scanning Calorimetry).
  • the melting point is determined as the temperature at which the linear increase of the DSC curve intersect the temperature axis.
  • Suitable carriers are generally substances, which are used in the manufacture of pharmaceuticals as so-called melt binders or solid solvents (in the form of solid dosage form), or as co-solvents or ingredients in pharmaceuticals for topical use.
  • the carrier may be hydrophilic, hydrophobic and/or they may have surface-active properties.
  • hydrophilic and/or hydrophobic carriers are suitable for use in the manufacture of a pharmaceutical composition comprising a therapeutically and/or prophylactically active substance that has a relatively low aqueous solubility and/or when the release of the active substance from the pharmaceutical composition is designed to be immediate or non-modified.
  • Hydrophobic carriers are normally used in the manufacture of a modified release pharmaceutical composition. The above-given considerations are simplified to illustrate general principles, but there are many cases where other combinations of carriers and other purposes are relevant and, therefore, the examples above should not in any way limit the scope of the invention. Examples on a suitable carrier are a hydrophilic carrier, a hydrophobic carrier, a surfactant or mixtures thereof.
  • a suitable hydrophilic carrier is selected from the group consisting of: polyether glycols such as, e.g., polyethylene glycols, polypropylene glycols; polyoxyethylenes; polyoxypropylenes; poloxamers and mixtures thereof, or it may be selected from the group consisting of: xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinon monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid, Gelucire 50/13, other Gelucire types such as, e.g., Gelucire 44/14 etc., Gelucire 50/10, Gelucire 62/05, Sucro-ester 7, Sucro-ester 11 , Sucro-ester 15, maltose, mannitol and mixtures thereof.
  • polyether glycols such as, e.g., polyethylene glycols, polypropy
  • a hydrophobic carrier for use in a process of the invention may be selected from the group consisting of: straight chain saturated hydrocarbons, sorbitan esters, paraffins; fats and oils such as e.g., cacao butter, beef tallow, lard, polyether glycol esters; higher fatty acid such as, e.g.
  • stearic acid myristic acid, palmitic acid, higher alcohols such as, e.g., cetanol, stearyl alcohol, low melting point waxes such as, e.g., glyceryl monostearate, hydrogenated tallow, myristyl alcohol, stearyl alcohol, substituted and/or unsubstituted monoglycerides, substituted and/or unsubstituted diglycerides, substituted and/or unsubstituted triglycerides, yellow beeswax, white beeswax, carnauba wax, castor wax, japan wax, acetylate monoglycerides; NVP polymers, PVP polymers, acrylic polymers, or a mixture thereof.
  • alcohols such as, e.g., cetanol, stearyl alcohol, low melting point waxes such as, e.g., glyceryl monostearate, hydrogenated tallow, myristyl
  • the carrier is a polyethylene glycol having an average molecular weight in a range of from about 400 to about 35,000 such as, e.g., from about 800 to about 35,000, from about 1 ,000 to about 35,000 such as, e.g., polyethylene glycol 1 ,000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000, polyethylene glycol 5,000, polyethylene glycol 6000, polyethylene glycol 7,000, polyethylene glycol 8,000, polyethylene glycol 9,000 polyethylene glycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000, or polyethylene glycol 35,000.
  • polyethylene glycol may be employed with a molecular weight from about 35,000 to about 100,000.
  • the carrier is polyethylene oxide having a molecular weight of from about 2,000 to about 7,000,000 such as, e.g. from about 2,000 to about 100,000, from about 5,000 to about 75,000, from about 10,000 to about 60,000, from about 15,000 to about 50,000, from about 20,000 to about 40,000, from about 100,000 to about 7,000,000 such as, e.g., from about 100,000 to about 1 ,000,000, from about 100,000 to about 600,000, from about 100,000 to about 400,000 or from about 100,000 to about 300,000.
  • the carrier is a poloxamer such as, e.g. Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or other block copolymers of ethylene oxide and propylene oxide such as the Pluronic® and/or Tetronic® series.
  • Suitable block copolymers of the Pluronic® series include polymers having a molecular weight of about 3,000 or more such as, e.g. from about 4,000 to about
  • a viscosity from about 200 to about 4,000 cps such as, e.g., from about 250 to about 3,000 cps.
  • Suitable examples include Pluronic® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 etc.
  • Suitable block copolymers of the Tetronic® series include polymers having a molecular weight of about 8,000 or more such as, e.g., from about 9,000 to about 35,000 and/or a viscosity (Brookfield) of from about 500 to about 45,000 cps such as, e.g., from about 600 to about 40,000.
  • the viscosities given above are determined at 60 °C for substances that are pastes at room temperature and at 77 °C for substances that are solids at room temperature.
  • the carrier may also be a sorbitan ester such as, e.g., sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesqui-isostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan tri-isostearate, sorbitan trioleate, sorbitan tristearate or mixtures thereof.
  • sorbitan ester such as, e.g., sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesqui-isostearate, sorbitan sesquiole
  • the carrier composition may of course comprise a mixture of different carriers such as, e.g., a mixture of hydrophilic and/or hydrophobic carriers.
  • the carrier is a surfactant or a substance having surface-active properties. It is contemplated that such substances are involved in the wetting of e.g. slightly soluble active substance and thus, contributes to improved solubility characteristics of the active substance.
  • surfactants are given herein before. In order to be suitable for use as a carrier, the criteria with respect to melting point and/or viscosity discussed herein must be fulfilled. However, the list below encompasses surfactants in general, because surfactants may also be added to the carrier composition in the form of pharmaceutically acceptable excipients.
  • the carrier may be employed as such or in the form of a carrier composition.
  • a carrier composition comprises one or more carriers optionally together with one or more other ingredients.
  • the carrier composition may comprise a mixture of hydrophilic and/or hydrophobic carriers and/or surfactants.
  • the carrier composition may also further comprise one or more therapeutically and/or prophylactically active substances and/or one or more pharmaceutically acceptable excipients.
  • Suitable excipients for use in a carrier composition are surfactants such as, e.g., hydrophobic and/or hydrophilic surfactants as those described above.
  • Suitable excipients in a carrier composition may be solvents or semi-solid excipients like, e.g. propylene glycol, polyglycolised glycerides including Gelucire 44/14, complex fatty materials of plant origin including theobroma oil, carnauba wax, vegetable oils like e.g. almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soya oil, olive oil, castor oil, palm kernels oil, peanut oil, rape oil, grape seed oil etc., hydrogenated vegetable oils such as, e.g.
  • solvents or semi-solid excipients like, e.g. propylene glycol, polyglycolised glycerides including Gelucire 44/14, complex fatty materials of plant origin including theobroma oil, carnauba wax, vegetable oils like e.g. almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soya oil, olive oil, castor oil, palm kernels oil, peanut
  • additives in the carrier composition may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc.
  • the carrier composition may also contain e.g. stabilising agents.
  • the concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1 % w/w to about 5% w/w.
  • the requirements with respect to the melting point mentioned above normally also apply to the carrier composition, especially in those cases where a minor amount of water is included in the carrier composition.
  • the carrier composition when the carrier composition is heated the carrier composition may be in the form of two or more phases (e.g. two distinct liquid phase, or a liquid phase comprising e.g. an active substance dispersed therein).
  • the melting point is not a true melting point but merely a heating point where the carrier composition becomes in a liquid form, which is suitable for use in a spraying device. Often such a heating point will for practical purposes correspond to the melting point of the carrier itself.
  • the total concentration of carrier(s) in the carrier composition is normally in a range of from about 5 to about 100% w/w such as, e.g., from about 10 to about 99.5% w/w, from about 15 to about 99% w/w, from about 15 to about 98% w/w, from about 15 to about 97% w/w, from about 20 to about 95% w/w such as at least about 25% w/w, at least about 30% w/w, at least about 35% w/w, at least about 40% w/w, at least about 45% w/w, at least about 50% w/w, at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 98% w/w.
  • the carrier or the carrier composition is brought on liquid form by heating the carrier and/or the carrier composition to a temperature, which causes the carrier and/or the carrier composition to melt, and the carrier in liquid form (i.e. as a solution or a dispersion) is sprayed on the second composition.
  • the carrier or the carrier composition in melted or liquidized form is sprayed on a second composition.
  • the carrier or the carrier composition should have a suitable viscosity. If the viscosity is too high, the carrier or carrier composition will be too "thick" and will have a tendency of adhering to the nozzle, which may result in that the delivery through the nozzle is stopped.
  • a viscosity of the carrier and/or the carrier composition is suitably if the viscosity (Brookfield DV-III) is at the most about 800 mPas at a temperature of at the most 100 °C such as, e.g., at the most 700, at the most 600, at the most 500 mPas. In those cases where the melting point of the carrier or the carrier composition is more than about 80 °C, the viscosity values mentioned above are at a temperature of about 40 °C above the melting point.
  • the concentration of the carrier is from about 5 to about 95% w/w such as, e.g. from about 5 to about 90% w/w, from about 5 to about 85% w/w, from about 5 to about 80% w/w, from about 10 to about 75% w/w, from about 15 to about 75% w/w, from about 20 to abut 75% w/w, from about 25% to about 75% w/w, from about 30% to about 75% w/w. from about 35% to about 75% w/w, from about 25% to about 70% w/w, from about 30% to about 70% w/w, from about 35% to abut 70 % w/w. from about 40% to about 70% w/w, from about 45% to about 65% w/w or from about 45% to about 60% w/w.
  • the concentration of the carrier in the particulate material obtained by a controlled agglomeration process is from about 5 to about 95% v/v such as, e.g.
  • aqueous medium e.g. together with a binder in order to build up agglomerates of a suitable size.
  • the agglomeration suitably takes place under water-free or substantially water-free conditions.
  • the process is also very useful when active substances or other ingredients are employed which are susceptible to water (e.g. degradation under aqueous conditions).
  • water or an aqueous medium may of course be incorporated in the carrier composition.
  • the carrier composition normally is essentially non-aqueous, water may be present to a certain extent and then the concentration of water in the carrier composition is the most about 20% w/w water such as at the most about 15% w/w, at the most abut 10% w/w, at the most about 5% w/w or at the most about 2.5% w/w.
  • Second composition is the most about 20% w/w water such as at the most about 15% w/w, at the most abut 10% w/w, at the most about 5% w/w or at the most about 2.5% w/w.
  • the carrier or carrier composition is sprayed on a second composition.
  • the second composition should initially have a temperature which is at least about 10 °C such as, e.g., at least about 15 °C, at least about 20 °C, at least about 25 °C, or at least about 30 °C below the melting point of the carrier or carrier composition (or, as discussed above, the heating point of the carrier composition).
  • a temperature difference of at least about 10 °C it is not always necessary.
  • the second composition may have a temperature of at the most a temperature corresponding to the melting point of the carrier and/or of the carrier composition such as, e.g., a temperature of at least about 2 °C, at least about 5 °C.
  • a temperature corresponding to the melting point of the carrier and/or of the carrier composition such as, e.g., a temperature of at least about 2 °C, at least about 5 °C.
  • No external heating of the second composition is normally employed during the process of the invention, but in some cases it may be advantageous to employ a cooling via the inlet air.
  • the temperature of the second composition may increase to a minor extent due to the working of the composition. However, the temperature must (or will) not be higher than at the most the melting point of the carrier or carrier composition such as, e.g.
  • a process of the invention can be carried out without any heating of the second composition, i.e. it can be carried out at ambient or room temperature (i.e. normally in a range of from about 20 °C to about 25 °C).
  • melt granulation methods involve external heating of the material that is to be granulated (or agglomerated) together with a melt binder.
  • the second composition comprises pharmaceutically and/or cosmetically acceptable excipients and, furthermore, a therapeutically and/or prophylactically active substance may be present in the second composition.
  • excipients for use in a second composition examples include fillers, diluents, disintegrants, binders, lubricants etc. or mixture thereof.
  • the choice of excipients is normally made taken such different uses into considerations.
  • Other pharmaceutically acceptable excipients for use in a second composition (and/or in the carrier composition) are e.g. acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, flavors and perfumes, humectants, sweetening agents, wetting agents etc.
  • suitable fillers, diluents and/or binders include lactose (e.g. spray-dried lactose, ⁇ -lactose, ⁇ -lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), silicified microcrystalline cellulose (e.g. ProSolv SMCC90 of Penwest Pharmaceuticals Co), hydroxypropylcellulose, L- hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g.
  • Methocel E, F and K Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.
  • diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
  • disintegrants are e.g. alginic acid or alginates , microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e.g. Primogel® and Explotab®) etc.
  • binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.
  • Glidants and lubricants may also be included in the second composition.
  • examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.
  • excipients which may be included in the second composition (and/or in the carrier composition) are e.g. colouring agents, taste-masking agents, pH-adjusting agents, solubilizing agents, stabilising agents, wetting agents, surface active agents, antioxidants, agents for modified release etc.
  • a magnesium aluminometasilicate in the particulate material. It may be a part of the second composition or it may be added subsequently in order to facilitate a further processing of the particulate material (e.g. to prepare solid dosage forms like capsules or tablet).
  • a controlled agglomeration process may be carried out in a high or low shear mixer or in a fluid bed.
  • the carrier or the carrier composition is sprayed on the second composition, which is loaded into the mixer or the fluid bed.
  • the carrier or the carrier composition is heated to a temperature above the melting point of the carrier and/or the carrier composition and the second composition has not been subject to any heating and has normally ambient temperature.
  • the difference in temperature between the carrier and the second composition makes the carrier solidify rapidly which in turn leads to a controlled growth of the particle size.
  • the inventors have found that by employing such conditions it is possible to control the agglomeration process so that the growth in particle size is controlled.
  • the possibility of controlling the agglomeration makes it possible to obtain a particulate material that has a very high load of carrier(s) - much higher than described when conventional methods like e.g. melt granulation is employed. As discussed above, a high load of carrier has shown to be of importance especially when particulate material is prepared containing a slightly water-soluble, sparingly water soluble or insoluble active substances.
  • a controlled agglomeration process may be carried out in a fluid bed.
  • the second composition is normally kept in a fluidized state by incoming air at ambient temperature.
  • the carrier or carrier composition is sprayed on the fluidized second composition and in order to keep the carrier or carrier composition on a liquid form and/or to avoid any clotting of the spraying device, the spraying device is kept at a suitable temperature above the melting point of the carrier or carrier composition.
  • the spraying is performed through a spraying device equipped with temperature controlling means.
  • the particulate material obtained by a controlled agglomeration process has a geometric weight mean diameter d gw of >10 //m such as, e.g., >20 //m, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000 such as, e.g. from about 100 to about 1500 //m, from about 100 to about 1000 //m or from about 100 to about 700 ⁇ m.
  • the geometric weight mean diameter d gw is at the most about 400 ⁇ m or at the most 300 ⁇ m such as, e.g., from about 50 to about 400 ⁇ m such as, e.g., from about 50 to about 350 ⁇ m, from about 50 to about 300 ⁇ m, from about 50 to about 250 ⁇ m or from about 100 to about 300 ⁇ m.
  • the particulate material obtained by a process according to the invention may be used as such or it may be further processed to the manufacture of a pharmaceutical and/or a cosmetic composition by addition of one or more suitable pharmaceutically and/or cosmetically acceptable excipients.
  • the particulate material obtained may be provided with a coating to obtain coated particles, granules or pellets.
  • Suitable coatings may be employed in order to obtain composition for immediate or modified release of the active substance and the coating employed is normally selected from the group consisting of film-coatings (for immediate or modified release) and enteric coatings or other kinds of modified release coatings, protective coatings or anti-adhesive coatings
  • the particulate material obtained by a process of the invention is especially suitable for further processing into tablets.
  • the material may possess suitable properties for tabletting purposes, but in some cases it may be suitable to add further therapeutically and/or prophylactically active substances and/or excipients to the particulate material before the manufacture of tablets.
  • a suitable release pattern can be designed in order to obtain a relatively fast release of an active substance followed by a modified (i.e. often prolonged) release of the same or a different active substance.
  • a particulate material obtained by a process according to the invention may be employed in any kind of pharmaceutical compositions in which the use of a solid particulate material is applicable.
  • relevant pharmaceutical compositions are e.g. solid, semi-solid, fluid or liquid composition or compositions in the form of a spray.
  • the particulate material may also be incorporated in a suitable drug delivery device such as, e.g. a transdermal plaster, a device for vaginal use or an implant.
  • Solid compositions include powders, and compositions in dosage unit form such as, e.g. tablets, capsules, sachets, plasters, powders for injection etc.
  • Semi-solid compositions include compositions like ointments, creams, lotions, suppositories, vagitories, gels, hydrogels, soaps, etc.
  • Fluid or liquid compositions include solutions, dispersions such as, e.g., emulsions, suspension, mixtures, syrups, etc.
  • the solid dosage form comprises at least about 10% w/w such as, e.g., at least about 15% w/w, at least about 20% w/w, at least about 25% w/w, at least about 30% w/w, at least about 35% w/w, at least about 40% w/w, at least about 45% w/w, at least about 50% w/w, at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w or at least about 95% w/w such as, e.g. about 100% w/w of the solid pharmaceutical particulate material according to the invention.
  • a particulate material according to the invention may have a relatively high content of the lipid material employed.
  • the lipid content in a unit dose of the solid dosage form is at least 5% w/w such as, e.g. from about 5% w/w to about 80% w/w, from about 15% w/w to about 80% w/w, from about 20% w/w to about 75%o w/w, from about 20% w/w to about 70% w/w, from about 20% w/w to about 65% w/w, from about 20% w/w to about 60% w/w or from about 20% w/w to about 55% w/w.
  • the invention also relates to any pharmaceutical composition comprising a particulate material obtainable by a process of the invention.
  • the invention in another aspect, relates to a method for improving the bioavailability of a therapeutically and/or prophylactically active substance having an aqueous solubility at 25 °C and pH of 7 of at the most about 3 mg/ml, the method comprising subjecting the active substance to a process described herein. All the details and particulars mentioned above under the main aspect of the invention apply mutatis mutandis to other aspects of the invention.
  • the bulk density was measured by pouring 25 ml of the powder in question in a 25 ml graduated cylinder and determining the weight of the 25 ml.
  • the bulk density is given as the untapped bulk density in g/ml.
  • the pycnometric density was determined by measuring the volume occupied by a known mass of powder, which is equivalent to the volume of gas (He) displaced. The measurements were performed with an AccuPyc 1330, Micromeritics apparatus.
  • Average tablet hardness was tested employing a Schleuniger Model 6D apparatus and performed in accordance with the general instructions for the apparatus.
  • volume median particle diameter was determined by employment of laser diffraction, dispersing the particulate material obtained (or the starting material) in air. The measurements were performed at 1 bar dispersive pressure in a Helos KF, Sympatec, which records the distribution of the equivalent spherical diameter.
  • the volume median particle diameter of the lipid incorporated in the dry dispersion was determined by employment of laser diffraction, dispersing the particulate material obtained in water. The measurements were performed with a cuvette, stirring rate 50 rpm, in a Helos KF, Sympatec, which records the distribution of the equivalent spherical diameter.
  • the volume median particle diameter of the particulate material obtained in Example 5 was determined by dispersing the material in medium chain triglycerides (Miglyol 812N from Condea) and performing the measurements with a cuvette; stirring rate 50 rpm, in a Helos KF, Sympatec, which records the distribution of the equivalent spherical diameter.
  • medium chain triglycerides Moglyol 812N from Condea
  • the aqueous solubility at 22°C and pH 7.1 was determined by suspending a well- defined and excessive amount of the substance under investigation in a well-defined amount of 0.1 M phosphate buffer solution. The dispersion is stirred and samples are withdrawn after suitable time periods. The samples are filtered and the filtrate analysed to obtain the concentration of the substance in the sample. The concentration of the substance in the sample is then calculated according to methods well known for a person skilled in the art. The solubility is reached when the concentrations of the substance in two consecutive samples are considered identical. Determination of intrinsic solubility
  • the intrinsic solubility in water was determined as described above at high pH-values using phosphate and sodium hydroxide as buffers.
  • an active drug substance As example on an active drug substance is employed a substance that is poorly water- soluble irrespective of whether it is in the form of the base or the hydrochloride salt.
  • the characteristics of the active substance are
  • HPMC Hydroxypropylmethylcellulose
  • Magnesium stearate (from Superfos Kemi)
  • Polyethylene glycol 6000 (from Superfos Kemi)
  • Poloxamer 188 (Lutrol F-68 from BASF) Silicified microcrystalline cellulose (ProSolv SMCC90 from Penwest Pharmaceuticals
  • High-speed colloid mill Ultra Turrax T25 basic from IKA Labortechnik
  • High-pressure homogeniser EmulsiFlex C5 from Avestin
  • Magnetic stirrer IKAMAG RCT from IKA Labrotechnik
  • Spray dryer Mobile Minor 2000 from Gea Niro
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 140°C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 83°C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 140°C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 83°C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 200° C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 115° C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 140° C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 90° C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 180° C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 100° C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 140° C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 83° C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode. No product was collected as the particles stuck to the drying chamber.
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 200° C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 100° C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • the inlet temperature was approximately 140° C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 83° C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • 113 g powder was collected having a volume median particle diameter of 108 ⁇ m.
  • the pycnometric density was 1.41 g/cm 3 and the bulk density was 0.52 g/ml. Tablets having a weight of approximately 200 mg were compressed using the powder.
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 120° C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 75° C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • Redispersion of the particulate material obtained in water gave particles having a size above 10 ⁇ m and the volume median diameter of the lipid in the powder was 8.14 ⁇ m.
  • 10 g of the dry dispersion was mixed with 4.0 g silicified microcrystalline cellulose and 1.0 g magnesium alumino metasilicate (Neusilin UFL2) in a Turbula mixer for 2 min. Following addition of 2% magnesium stearate mixing continued for 0.5 min. Tablets having a weight of approximately 200 mg were compressed using the powder. The tablets had an average tablet hardness of 52 N.
  • the dispersion was fed into the spray dryer.
  • the inlet temperature was approximately 120° C and the spray rate of the dispersion was adjusted in such a manner that the outlet temperature was maintained at about 75° C.
  • the atomisation of the dispersion was performed with a two-fluid nozzle operating at about 0.5 bar in counter-current mode.
  • 120 g of the dry dispersion was mixed with 3.0 g Aerosil 200 and fluidised in a fluid bed Strea-1.
  • the fluidised material was preheated to a product temperature of 40 °C.
  • a melt of polyethylene glycol 6000 with a temperature of 90°C was pumped to a special constructed binary nozzle positioned up-stream in the fluid bed chamber and the melt was applied to the fluidised material at a flow rate of 10 g/min.
  • 40 g of PEG was applied to the material resulting in a agglomerated product having a volume median particle diameter of 296 ⁇ m.
  • the agglomerated product was sieved through a mesh size of 0.7 mm and mixed with 0.5% magnesium stearate in a Turbula mixer for 0.5 min. 9 mm tablets having a weight of approximately 230 mg and a weight variation of 0.75% were compressed using the agglomerated product.
  • the tablets had an average tablet hardness of 15 N and a mean disintegration time of 19 minutes.
  • Example 11 In vivo study in dogs - Serum concentrations and pharmacokinetics of an active substance AS after single oral administration of different formulations to Beagle dogs
  • Formulation A is the reference formulation containing 0.675 g AS and 37.5 g HP- ⁇ -cyclodextrin pr. 250 mL solution
  • formulation B contains 0.5 g AS dissolved in 24.5 g medium chain triglyceridesand formulation D and E corresponds to the formulations obtained in Example 1 herein (formulation D is in the form of particulate material loaded into gelatine capsules and formulation E is in the form of tablets)
  • formulation D is in the form of particulate material loaded into gelatine capsules and formulation E is in the form of tablets
  • Serum concentrations of AS were determined by liquid-liquid extraction followed by LC-MS/MS analysis.
  • Lower limit of quantification (LOQ) was 0.22 pmol per 500 ⁇ L serum sample (corresponding to LOQ 0.44 nmol/L).
  • Non-compartmental pharmacokinetic analysis was performed using WinNonlinTM Professional (Version 3.2) from Pharsight Cooperation.
  • the later parameter was calculated as AUCo_jnf* est x dose re f / x dose* es t, where the doses were corrected according to the body weight recorded for each dog.
  • Results reported as ⁇ LOQ are calculated as missing data in WinNonlinTM and AUC's are calculated using Linear Up/Log Down method.
  • Results ⁇ LOQ at time predose and following " ⁇ LOQ's" until quantifiable concentrations above LOQ are treated as 0.
  • the linear trapezoidal rule is used any time that the concentration data is increasing, and the logarithmic trapezoidal rule is used any time that the concentration data is decreasing.
  • WinNonlin estimates the rate constant, lambda z, associated with the terminal elimination phase and non-compartmental parameters are extrapolated to infinity.
  • the formulation D prepared according to the present invention resulted in a bioavailability that is higher than that of the reference formulation.
  • the bioavalilability at infinity has the same order of magnitude, but the T ma ⁇ value is shorter (corresponding to a faster onset of the effect) and C max is higher for formulation D.

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Abstract

L'invention concerne un procédé de préparation de matériau pharmaceutique sous forme de particules solides par atomisation d'une dispersion aqueuse comprenant un principe actif, un matériau lipidique et un ou plusieurs supports acceptables sur le plan pharmaceutique. Le matériau en particules obtenu à l'aide du procédé possède des propriétés adéquates par rapport à la non-cohésivité, la densité, la granulométrie, ce qui lui permet de subir un processus de mise sous forme de dose solide, notamment de tablettes. Il est possible, au moyen de ce procédé d'incorporer une quantité relativement importante de matériau lipidique dans un matériau particulaire, rendant le procédé adapté à l'utilisation de préparation de compositions pharmaceutiques contenant un principe actif thérapeutique et/ou prophylactique dont la solubilité dans l'eau est relativement faible, dont la biodisponibilité est relativement faible et sujet à la décomposition chimique. L'utilisation du procédé de l'invention permet de préparer des compositions pharmaceutiques dont les propriétés physico-chimiques sont améliorées, par exemple par rapport à la libération du principe actif comme le montre un test de dissolution in vitro et/ou dont les propriétés pharmacologiques sont améliorées, par exemple par rapport à la biodisponibilité et à l'efficacité.
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WO2008084698A1 (fr) 2006-12-28 2008-07-17 Astellas Pharma Inc. Composition pharmaceutique à libération entretenue de tacrolimus
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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
US10471036B2 (en) 2003-09-09 2019-11-12 3M Innovative Properties Company Antimicrobial compositions and methods
WO2005105145A1 (fr) 2004-04-30 2005-11-10 Bkg Pharma Aps Traitement de maladies infectieuses
EP2260870A2 (fr) 2004-04-30 2010-12-15 BKG Pharma ApS Traitement de maladies infectieuse par des mélanges de dérivés de thioxanthène avec des agents anti-infectieux
US10918618B2 (en) 2005-03-10 2021-02-16 3M Innovative Properties Company Methods of reducing microbial contamination
US9826770B2 (en) 2005-03-10 2017-11-28 3M Innovative Properties Company Antimicrobial compositions comprising esters of hydroxycarboxylic acids
WO2008041553A1 (fr) 2006-09-26 2008-04-10 Astellas Pharma Inc. Préparation à libération entretenue de tacrolimus
WO2008084698A1 (fr) 2006-12-28 2008-07-17 Astellas Pharma Inc. Composition pharmaceutique à libération entretenue de tacrolimus
EP2301545A1 (fr) 2007-01-05 2011-03-30 BKG Pharma ApS Dérivés du thioxanthène pour leur utilisation dans le traitement des maladies infectieuses.
EP2778166A1 (fr) 2009-04-20 2014-09-17 BKG Pharma ApS Dérivés de thioxanthène pour le traitement de maladies infectieuses
EP2246349A1 (fr) 2009-04-20 2010-11-03 BKG Pharma ApS Traitement de maladies infectieuses
WO2010122012A1 (fr) 2009-04-20 2010-10-28 Bkg Pharma Aps Dérivés de thioxanthène pour le traitement de maladies infectieuses
EP2441444A1 (fr) * 2010-10-14 2012-04-18 Deva Holding Anonim Sirketi Formulations de cetyl myristate et/ou cetyl palmitate
WO2012049639A1 (fr) * 2010-10-14 2012-04-19 Deva Holding Anonim Sirketi Formulations de myristate de cétyle et/ou de palmitate de cétyle
EP2543364A1 (fr) * 2010-10-14 2013-01-09 Deva Holding Anonim Sirketi Formulations de cetyl myristate et/ou cetyl palmitate
EP2441445A1 (fr) * 2010-10-14 2012-04-18 Deva Holding Anonim Sirketi Revêtement de particules de cetyl myristate et/ou cetyl palmitate
WO2012049640A1 (fr) * 2010-10-14 2012-04-19 Deva Holding Anonim Sirketi Revêtement de particules de myristate de cétyle et/ou de palmitate de cétyle
WO2012089763A1 (fr) * 2010-12-29 2012-07-05 Deva Holding Anonim Sirketi Formulations et granulations par séparation de l'association de myristate de cétyle et de palmitate de cétyle
WO2012089759A1 (fr) * 2010-12-29 2012-07-05 Deva Holding Anonim Sirketi Formulations de particules de myristate de cétyle et/ou de palmitate de cétyle
WO2012089764A1 (fr) * 2010-12-29 2012-07-05 Deva Holding Anonim Sirketi Procédé de préparation d'une suspension de myristate de cétyle et/ou de palmitate de cétyle
WO2012089762A1 (fr) * 2010-12-29 2012-07-05 Deva Holding Anonim Sirketi Granulés de myristate de cétyle et/ou de palmitate de cétyle à densité apparente élevée
EP2471386A1 (fr) * 2010-12-29 2012-07-04 Deva Holding Anonim Sirketi Formulations de cetyl myristate et/ou cetyl palmitate en suspension
EP2471528A1 (fr) * 2010-12-29 2012-07-04 Deva Holding Anonim Sirketi Une méthode de préparation pour suspension de cetyl myristate et/ou cetyl palmitate
EP2471387A1 (fr) * 2010-12-29 2012-07-04 Deva Holding Anonim Sirketi Formulations de cetyl myristate et/ou cetyl palmitate en suspension
EP2471385A1 (fr) * 2010-12-29 2012-07-04 Deva Holding Anonim Sirketi Formulations de cetyl myristate et/ou cetyl palmitate en suspension
EP2526936A1 (fr) * 2011-05-23 2012-11-28 Deva Holding Anonim Sirketi Repartition granulometrique de cetyl myristate et/ou cetyl palmitate
WO2013130767A1 (fr) 2012-02-29 2013-09-06 Pulmatrix, Inc. Poudres sèches pouvant être inhalées
CN103099797A (zh) * 2013-02-19 2013-05-15 青岛正大海尔制药有限公司 甘糖酯胶囊及其制备方法

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