Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-06-29
2002-11-26
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S455000, C424S456000, C424S469000, C424S458000, C424S489000
Reexamination Certificate
active
06485743
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method and composition of an oral preparation of itraconazole, an excellent azole antifungal drug. More particularly, it relates to a method and composition of an oral preparation of itraconazole having improved bioavailability, which is prepared by following steps of: i) dissolving itraconazole and hydrophilic polymer with solvent, ii) spray-drying said mixture, and iii) preparing the solid dispersions for oral preparation.
In other words, the present invention relates to an oral preparation of itraconazole, which has improved bioavailability by enhancing water solubility and rapidly being dissoluble regardless of food intake, prepared using a solid dispersions having itraconazole and pH-dependent, pharmaceutically safe, fastly dissolved at a low pH and hydrophilic polymer with the steps of i) dissolving and ii) spray-drying for the formation of an oral preparation of itraconazole having water-insoluble property.
BACKGROUND ART
Itraconazole or (±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yll]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, is a broadspectrum antifungal compound, and has been considered as an efficacious and safe drug.
Itraconazole has been developed as a broad antifungal agent for oral, parenteral and topical use and is disclosed in U.S. Pat. No. 4,267,179, but usually has been administered in oral route. Further, itraconazole is efficacious in oral administration, because it has a tendency of extensive tissue distribution [
Mycoses
32 (Suppl. 1), p67~87, 19891].
It has been reported that itraconazole has a pH-dependent solubility characterized in the ionization only at a low pH, such as, a gastric juice, and many attempts have been carried out to increase solubility and bioavailability, because itraconazole is almost insoluble in water (less than 1,&mgr;g/ml) and in diluted acidic solution(less than 5,&mgr;g/ml).
Generally, it has been reported that water insoluble drug has low dissolution property from the solid preparation. For increasing the solubility and dissolution rate of poorly water-soluble drugs, extensive studies of solubilization have shown that a wide variety of type of drugs can be efficiently solubilized by surfactants, hydrophilic carriers or pro-drugs, etc. Among them, a solid dispersion of drug and inert hydrophilic polymer has been suggested to enhance the solubility of insoluble drug. Further, many researches have been reported to enhance the solubility, dissolution rate and bioavailability of insoluble drug by preparing a solid dispersion of insoluble drug and inert carrier [{circle around (1)}
International Journal of Pharmaceutics
, Vol. 104, p169~174(1994), {circle around (2)}
International Journal of Pharmaceutics
, Vol. 143, p247~253(1996)].
The term “a solid dispersion” defines a system in a solid state comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. Many factors have been known to affect the solubility of a solid dispersion.
Prior references related to oral preparation for increasing bioavailability of itraconazole are as follows:
1) The solubility and bioavailability of a drug are increased by complex using cyclodextrin or its derivative in WO 85/02767 and U.S. Pat. No. 4,764,604,
2) The aerosol preparation is prepared by reducing the particle size of a drug in WO 90/11754,
3) The liposomal preparation for external use including itraconazole is prepared containing phospholipid and by solvent system in WO 93/15719,
4) The preparation for external use adhering to the nasal mucous membrane or the vaginal mucous membrane is prepared by emulsion or aqueous solution using cyclodextrin or its derivative in WO 95/31178,
5) The oral preparation to increase solubility and bioavailability of drug is disclosed in WO 94/05263, in which hydrophilic polymer such as hydroxypropyl methylcellulose is coated with about 25-30 mesh sugar spheres, and such preparation of itraconazole is commercially marketed as the trademark “SPORANOX”,
6) The solid dispersions comprising drug and hydrophilic polymer according to the melt-extrusion method is disclosed in WO 97/44014, in which bioavailability is improved by increasing dissolution rate of drug and food effect is minimized according to the food intake.
Generally, there is a solvent method, a melting method or a solvent-melting method, etc. for preparing solid dispersions using hydrophilic polymer as carrier. In the solvent methods, a freezing drying method, a drying method or a nitrogen-gas drying method has not a few drawbacks, low reproducibility of preparation, the higher cost of preparation and long time in the preparation, etc. In the melting method, the careful attention of working process is demanded because raising temperature over melting point affects the stability of drug and cooling condition of melting mixture also affects the property of preparation. Further, even though a solvent-melting method is carried out when a solvent method or a melting method cannot be used alone, it has not a few drawbacks, for example, a lot of manipulation steps and time.
However, the spray-drying method used in this invention has some advantages, for example, short preparation time and maintaining low temperature, because the drug and the carrier dissolved in a solvent are immediately dried after spraying. Therefore, because the stability of drug is not affected by raising temperature, the spray-drying method is efficient in industrialization.
A disclosed preparation of WO 94/05263 is concerned with the beads comprising a 25~30 mesh core, a coating film of a hydrophilic polymer and an antifungal agent, and a seal coating layer, and materials suitable for use in a fluidized bed granulator(Glatt™) with a Wurster bottom spray insert. A seal coating polymer layer is applied to the drug coated cores to prevent sticking of the beads which would have the undesirable effect of a concomitant decrease of the dissolution rate and of the bioavailability.
However, the reason why sugar sphere having appropriate dimensions(about 25-30 mesh) has to be used is to minimize the tendency toward agglomeration among sugar spheres in the drug coating process. In addition, during the preservation of the prepared beads filled in hard-gelatin capsules, sticking of the beads results in the undesirable decrease of the bioavailability. Therefore, a seal coating polymer layer has to be applied to the drug coated cores to prevent sticking of the beads. This is undesirable for demanding unnecessary step in the preparation.
On the other hand, the spraying rate in the preparation manufactured by said patent is regulated carefully to prevent undesirable drying or moisturization. Further, spraying air pressure is controlled to prevent formation of big bead and increasing of agglomeration during the coating process. Also, there is some drawbacks of spending the long time in drying, because fluidizing air volume has to be monitered carefully and inlet-air temperature has to be controlled.
The influence of food and dose on the oral bioavailability of itraconazole was studied. The relative systematic availability of itraconazole (PEG capsules) compared with solution averaged 40% in the fasting state but 102%(1.92 &mgr;g h/ml) in the post-prandial state. Food did not significantly affect the rate of absorption of the capsules. Areas under the curve at single doses of 50, 100 and 200 mg had a ratio of 0.3:1:3, suggesting non-linear itraconazole pharmacokinetics in the range of therapeutically used doses. It was also concluded from the study that to ensure optimal oral absorption, itraconazole may be administered either in capsules shortly after a meal or in solution, the absorption of which is not influenced by the presence of food in the stomach [Mycoses 32 (Suppl. 1), p67~87, 1989].
Meanwhile, the solid dispersions using the melt-extrusi
Hong Ji-Woong
Jung Jae-Young
Kim Kye-Hyun
Lee Kyu-Hyun
Lee Sang-Heon
Choongwae Pharma Corporation
Joynes Robert M.
Page Thurman K.
Schmidt Richard D.
Venable
LandOfFree
Method and composition of an oral preparation of itraconazole does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method and composition of an oral preparation of itraconazole, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method and composition of an oral preparation of itraconazole will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2917840