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Pharmaceutical compositions for poorly soluble drugs

Inactive Publication Date: 2003-05-08
MAYNE PHARMA INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0057] By utilising compositions in accordance with the present invention, it has been found that drugs previously considered to present bioavailability problems may be presented in dosage forms with superior bioavailability. For instance, and as will be described in more detail below with respect to two examples, where the drug is itraconazole the inventive compositions have produced formulations that are not considered bioequivalents to, but have at least twice the bioavailability of, a commercially available itraconazole product (Sporanox.TM.). Additionally, and again in comparison with Sporanox.TM., the inventive compositions have produced formulations that have reduced food effect and thus need not be administered with food (unlike Sporanox.TM.).
[0058] Furthermore, the present invention also provides a pharmaceutical composition in the form of a solid dispersion of a polymer with acidic functional groups (preferably a polycarboxylic acid such as a hydroxypropyl methylcellulose phthalate) and an azole antifungal drug (such as itraconazole), wherein in vitro the composition forms a suspension. Preferably, the composition upon administration forms a suspension at a pH in the range of 4.0 to 8.0, but more preferably in the range 5.5 to 7.5, and may provide acceptable absorption in the intestines.
[0062] For formulations in accordance with the present invention containing drugs other than itraconazole it is preferred that the bioavailability of the drug as compared to the drug per se is improved by at least 50% and more preferably 100%, in terms of AUC.

Problems solved by technology

Drugs that are totally water-insoluble, or are at least poorly water-soluble, are usually characterised by low absorption and poor bioavailability, and present special difficulties when formulating dosage forms therefor.
Indeed, it has been reported that the bioavailability of many practically insoluble drugs is limited by their dissolution rates and solubility, which in turn are understood to be controlled by the surface area that they present for dissolution.
For example, a commercially available itraconazole dosage form (Sporanox.TM.) is only prescribed for use with food because of relatively poor bioavailability results when administered under fasted conditions.

Method used

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  • Pharmaceutical compositions for poorly soluble drugs
  • Pharmaceutical compositions for poorly soluble drugs

Examples

Experimental program
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Effect test

example 2

[0069] To produce the solid dispersion, a solution was prepared by dispersing HP-50 (420 g) in methylene chloride (8400 g) and then adding itraconazole (280 g) and stirring to form a pale brown solution. This solution was then spray dried to form a powder.

[0070] A portion (292 g) of this spray dried powder was then blended with sodium starch glycolate (93.6 g) and colloidal silicon dioxide (Aerosil 200)(5.6 g) in a Collette mixer at high speed for 5 minutes. Magnesium stearate (8.8 g) was added to the blend from the Collette mixer and the mixture tumble blended until uniform.

[0071] This powder blend was then filled into size 0 gelatin capsules by hand. Each capsule was filled with 345 to 359 mg of powder, containing nominally 98 to 102 mg of itraconazole.

[0072] These test capsules were utilised in a pharmacokinetic study. 8 male volunteers were dosed with one 100 mg capsule after an overnight (10 hour) fast. The capsules were dosed with 240 ml water. At appropriate time intervals bl...

example 3

3 Example 3 Capsule Example 2 Capsule Parameter (Fed) (Fasted) C.sub.max (ng / ml) 148.20 182.6 T.sub.max (h) 10.25 2.94 AUC (ng .multidot. h / ml) 1806 1776 AUC.sub.inf (ng .multidot. h / ml) 1997 1875

[0083] It can be seen from these results that the example formulation produces plasma profiles considered bioequivalent in terms of AUC under fasting and fed conditions, due to the AUC under fed conditions being about 102% of the AUC under fasted conditions, which is well within the range of 80 to 120%. This is an indication that the total amount of drug absorbed over time is essentially equivalent under fed and fasted conditions.

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Abstract

The present invention provides a pharmaceutical composition of a practically insoluble drug, wherein the composition may be administered with food or without food. The composition may be in the form of a solid dispersion of the practically insoluble drug and a polymer having acidic functional groups, and the composition may in vitro form a suspension.

Description

[0001] The present invention relates to improved pharmaceutical compositions of drugs that are practically insoluble in aqueous media. The present invention also relates to a process for preparing the compositions. Furthermore, the present invention relates to improved dosage forms for the administration of the compositions.[0002] Drugs that are totally water-insoluble, or are at least poorly water-soluble, are usually characterised by low absorption and poor bioavailability, and present special difficulties when formulating dosage forms therefor. For the purposes of this specification, such drugs will be referred to as being "practically insoluble".[0003] Indeed, it has been reported that the bioavailability of many practically insoluble drugs is limited by their dissolution rates and solubility, which in turn are understood to be controlled by the surface area that they present for dissolution. As such, attempts to improve the bioavailability of these practically insoluble drugs h...

Claims

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Application Information

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IPC IPC(8): A61K9/10A61K9/14A61K9/16A61K9/20A61K9/48A61K31/496A61K31/497A61K47/32A61K47/36A61K47/38A61P31/10A61P43/00
CPCA61K9/146A61K31/496A61K9/4866A61K9/1652A61P31/10A61P43/00
Inventor HAYES, DAVIDMORELLA, ANGELO MARIO
Owner MAYNE PHARMA INT
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