Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • 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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

• the present invention relates to oral formulations of taxoids.
• taxoids used in the formulations according to the invention are preferably of the general formula (I)
• Ri is H, acyl (C 2 -C 4 ), alkyl (C ⁇ -C 3 ).
• R 2 is OH, alkoxy or R and R 3 are methylene
• R 3 is CH 3 or R 2 and R 3 are methylene
• R 4 is OCOCH 3 or OCOOCH 3 ,
• R is phenyl or alkoxy (C 3 -C ) or alkenyloxy (C 3 -C 4 ), preferably phenyl or tert- butoxy,
• R is aryl, preferably phenyl, optionally substituted or alkyl (C 2 -C ) or alkylen (C 2 - C 4 ).
• taxoids used in the formulations according to the invention are for example the taxoids of formula (la) to (If) below Formula la : (Docetaxel)
• Taxoids of general formula (la) to (If) and their applications are known. These taxoids are particularly advantageous for their use as chemotherapeutic agents.
• taxoids are poorly water-soluble compounds.
• the molecules are slightly lipophilic with a relatively high molecular weight.
• taxoids are administered intravenously, in particular using formulations consisting of PS 80 or cremophor at high content. It was the aim of the current invention to develop taxoid formulations for oral administration.
• WO 95/24893 describes delivery systems for hydrophobic drugs.
• This application describes compositions comprising a digestible oil, a lipophilic surfactant and a hydrophilic surfactant that are intended for the formulation of hydrophobic active ingredients and for the enhancement of their bioavailability.
• WO 99/49848 describes pharmaceutical dosage forms for anticancer drugs, e.g. paclitaxel in which the active drug is formulated as stable self-emulsifying preconcentrate.
• WO 99/49848 describes compositions comprising an anticancer drug in a carrier system comprising at least one hydrophobic component selected from tri-, di- or monoglycerides, free fatty acids, fatty acid esters or derivatives thereof, and a hydrophilic component selected from hydroxyalkane, dihydroxyalkane or polyethylene glycol (PEG), and comprising at least one surfactant.
• a carrier system comprising at least one hydrophobic component selected from tri-, di- or monoglycerides, free fatty acids, fatty acid esters or derivatives thereof, and a hydrophilic component selected from hydroxyalkane, dihydroxyalkane or polyethylene glycol (PEG), and comprising at least one surfactant.
• PEG polyethylene glycol
• EP 0 152 945 Bl describes transparent multi-component systems for pharmaceutical application containing one or several active ingredients in a system composed of an oil component, surfactants, co-surfactant and optionally water.
• EP 0 670 715 Bl describes compositions for pharmaceutical use intended to be ingested, able to form a microemulsion, comprising at least an active ingredient, a lipophilic phase, a surfactant, a co-surfactant and a hydrophilic phase of special composition.
• EP 0 334 777 Bl describes a micro-emulsion with pharmaceutical use comprising a water-soluble phase and a lipidic phase, comprising at least one surface-active agent based on Polyethylenglycol and at least one co-surfactant based on polyglycerol.
• the present invention relates to a semi-solid formulation for the oral administration of taxoids comprising at least one taxoid and at least one polymeric material that is chosen among Nitamin E TPGS® and Gelucire
• the taxoid is of general formula (I) :
• Ri is H, acyl (C 2 -C 4 ), alkyl (C ⁇ -C 3 );
• R 2 is OH, alkoxy or R 2 and R 3 are methylene;
• R 3 is CH 3 or R 2 and R 3 are methylene;
• I is OCOCH 3 or OCOOCH 3 ;
• R is phenyl or alkoxy (C 3 -C 4 ) or alkenyloxy (C 3 -C ), preferably phenyl or tert- butoxy;
• R' is aryl, preferably phenyl, optionally substituted or alkyl (C 2 -C 4 ) or alkylen (C 2 - C 4 ).
• a more preferred taxoid is chosen among compounds of formula (la) to (If) :
• the semi-solid formulation of the invention is particularly suitable for taxoids of formula (lb) and (lc).
• a convenient semi-solid formulation according to the invention may contain up to 200 mg taxoid per g of polymeric material, more preferably between 50 and 200 mg taxoid per g of polymeric material.
• Suitable taxoid content may be adapted to the need of a patient, for example taxoid concentration within the polymeric material of e.g. 5 mg/g, 10 mg/g, 20 mg/g, 30 mg/g, 40 mg/g, 50 mg/g, 60 mg/g, 70 mg/g, 80 mg/g, 90 mg/g, 100 mg/g, 150 mg/g or 200 mg/g.
• the semi-solid formulations of the invention may optionally further contain at least one additional additive chosen from stabilizing agents, preservatives, agents which make it possible to adjust the viscosity, or agents that can modify the organoleptic properties.
• the invention concerns a process for preparing a formulation as defined above, wherein there is prepared, where appropriate, the mixture of principal excipients, after heating, for melting the semisolid excipients, and then, if necessary, the mixture with the additional additives, and then the taxoid and stirring is maintained in order to obtain a homogeneous mixture.
• the strategy has been to obtain a formulation able to enhance taxoid solubilisation in aqueous medium by using amphiphilic- and lipid-based formulations able to form a colloidal system (fine emulsion or micellar solution) in vivo.
• amphiphilic polymers (micelle or emulsion formation)
• Phospholipids lipidic vesicles formation
• SMES self-microemulsifying systems
• oil + surfactant + co-surfactant microemulsion formation
• the solubility of taxoids in the excipient was the first screening step for the choice of the excipient and the selection of the prototypes. Then, the prototypes (liquid or semi- solid) were manufactured, and characterized in terms of in vitro behaviour in simulated GI " media and chemical stability. Finally, the physical properties and stability of the semi-solid prototypes have been investigated.
• Oils (medium-chain triglycerides, fatty acids, ...)
• Amphiphilic surfactants with hydrophilic character (HLB>10) (PEO sorbitan fatty acids, castor oil ethoxylates, fatty acid ethoxylates.)
• Amphiphilic surfactants with lipophilic character (HLB ⁇ 10) (glycerides of fatty acids: glyceryl oleate/linoleate, oleoyl macrogol glycerides; derivatives of propylene glycol: PG caprylate/linoleate,)
• the solubility of taxoid of formula lb at room temperature has been determined by X ray diffraction. Taking into account the solubility of a taxoid of formula lb, for the 3 categories of drug delivery systems the following excipients were retained: Nitamin E TPGS for micelle formation Phosal 75SA and Phospholipon 90H for lipidic vesicle formation Labrasol and Gelucire 44/14 for emulsion formation Microemulsion formation: as surfactant Myrj 45, PS80, Cremophor EL, Labrasol; as co-surfactant: Maisine, Capryol 90, Peceol, Lauroglycol 90, Imwitor 988; as oil: Miglyol 812N, Edenor.
• the excipients were formulated as binary systems with the drug, at the following concentrations:
• Nitamin E TPGS 50, 100 mg/g formulation
• the ratio between the excipients in the retained formulations was as follow: ratio surfactant to co-surfactant 3:1 and with oil concentration of 20%.
• the dosage may vary according to the degree or the nature of the condition to be treated.
• the quantity of active product in a composition according to the invention will be determined such that a suitable dosage can be prescribed.
• the quantity of taxoids varies as a function of its solubility in the mixture and also as a function of the appropriate dosage for the treatment of patients.
• care should be taken not to load more than 10% w/w of taxoid drug so as to avoid microemulsion destabilization to occur.
• compositions are prepared such that a unit dose contains from 0.1 to 50 mg of active product.
• compositions may comprise 0.2 to 50 mg. However, this quantity may optionally be lower and may vary from 0.2 to 10 mg.
• composition further comprises certain additional additives
• the latter may be stabilizing agents, preservatives, agents which make it possible to adjust the viscosity, or agents that can modify, for example, the organoleptic properties.
• the stabilizing agents may be, for example, antioxidants chosen in particular from ⁇ -tocopherol, ascorbyl palmitate, BHT (butyl hydroxytoluene), BHA (butyl hydroxyanisole), propyl gallate or malic acid for example.
• the preservatives may, by way of example, be chosen from sodium metabisulfite, propylene glycol, ethanol or glycerin.
• agents capable of adjusting the viscosity there may be mentioned, for example, lecithins, phospholipids, propylene glycol alginate, sodium alginate or glycerin.
• the agents capable of modifying the organoleptic properties of the composition are, by way of example, malic acid, fumaric acid, glycerin, vanillin or menthol.
• the latter may constitute from 0.001% to 5% by weight of the total composition.
• the pharmaceutical composition may be obtained by mixing, where appropriate, the principal excipients (after heating for melting the semisolid excipients), and then, if necessary, mixing with the additional additives, followed by the addition of the taxoid and maintaining stirred in order to obtain a homogeneous mixture.
• the compositions according to the invention may be provided in the semipasty state.
• They are particularly suitable for presentation in the form of hard gelatin capsules or soft gelatin capsules, or in the form of an oral solution.
• compositions according to the invention are particularly advantageous because of their good stability, both physically and chemically, and the enhancement of the bioavailablity which they offer upon oral administration of taxoids.
• FIGURES Figure 1 Taxoid of formula lb relase profile of different formulations at 100 mg/g in simulated gastric medium
• Figure 2 Taxoid of formula lb relase profile of semi-solid formulations at 50 and 100 mg/g in simulated gastric medium
• Figure 3 Particle size of Taxoid of formula lb formulations in simulated gastric medium
• Figure 4 Particle size of Taxoid of formula lb formulations leading to droplets ⁇ 50 nm in simulated gastric medium
• Example 1 Preparation of Prototypes 1.1 Materials Taxoid of formula lb Miglyol 812N (Condea Vista Company, Cranford, NJ, USA ) Labrasol (Gattefosse, Saint Priest, F) Gelucire 44/14 (Gattefosse, Saint Priest, F) • Vitamin E TPGS (Eastman Chemical, Anglesey, UK) Cremophor EL (BASF AG, Ludwigshafen, DE) Capryol 90 (Gattefosse, Saint Priest, F) Lauroglycol 90 (Gattefosse, Saint Priest, F) • Peceol (Gattefosse, Saint Priest, F)
• the weighed drug was dispersed in the melted excipient, and then maintained under mechanical stirring at 50-60°C until dissolution.
• the mass was poured into a hard gelatine capsule (size 0) and kept refrigerated overnight. The gelatine shell was then removed to avoid compatibility issues at this step.
• the stability was evaluated by mean of the potency determined by HPLC, as well as evaluation of relative substances.
• the prototypes analysed for drug dosage and stability studies are showed in the table below.
• Table 4 Composition of the simulated gastro-intestinal media
• Fasted intestinal medium (Fassif) For 500 ml
• the formulations (100 mg drug/g formulation, 500 mg formulation in a hard gelatin capsule) were diluted 1:500 in the gastric medium (1 capsule/250 mL), than incubated 2 hours at 37°C under stirring (50 rpm) in a USP standard dissolution apparatus.
• Example 3 particle size analysis after incubation in gastric medium (USP)
• the aim of this part of the study was to evaluate, by particle size measurement, the colloidal stability and the self-emulsifying properties of the emulsion/microemulsion/micellar solution of taxoid of formula lb formulations after incubation in the gastric medium.
• the analyses are carried out on a Siemens-Bruker D5000 Matic diffractometer, using the parafocusing Bragg-Brentano ( ⁇ -2 ⁇ )- type geometry. If enough of the product is available, the powder is deposited on a concave aluminum sample holder. Otherwise a thin layer of the product is deposited on a single-crystalline silicon wafer, cut out according to the (510) crystallographic orientation that impedes any Bragg reflection (by ensuring the systematic extinction of the corresponding diffraction band).
• a 50 M multicanal Braun linear detector completes the setup. It has a 10°-wide detection window in angle 26. Diagrams were recorded in the following conditions: a 1.5 to 50.0 degree scan in angle 2 ⁇ , 10 to 30 seconds' counting time per degree in 2 ⁇ according to the amount of powder to be analysed, and ambient conditions of pressure, temperature and % relative humidity. 4.1.2 Physical characterization Taxoid of formula lb semi-solid formulations for this part of the study were manufactured and characterized by T.Borovac (DEA report «Conception et characterisation des matrices semi-solides cooperatees a unisme actif peu hydrosoluble et destine a la urgent orale», CRS meeting, July 19, 2003.

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• 2003
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