Galenical formulations

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form

Reexamination Certificate

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Details

C514S011400, C514S937000, C514S938000, C514S941000

Reexamination Certificate

active

06565859

ABSTRACT:

This invention relates to galenic formulations containing macrolides, e.g. compounds of the rapamycin class. In particular this invention relates to galenic formulations which are in the form of micro-emulsions, micro-emulsion preconcentrates, emulsion or emulsion-preconcentrate.
The macrolide may contain e.g. 1, 2 or 3 ring oxygen or nitrogen or other atoms besides carbon atoms. It may have side chains, e.g. in the form of fused rings, or substituents,e.g. oxy groups. It may contain double bonds. It may contain e.g. from 15 to 35 ring atoms e.g. of carbon.
Rapamycin is a macrolide antibiotic produced by
Streptomyces hygroscopicus
. It has been found to be pharmaceutically useful in a variety of applications, particularly as an immunosuppressant for use in the treatment and prevention of organ transplant rejection and autoimmune diseases. Rapamycin has the following structure:
(Kesseler, H., et al., Helv. Chim. Acta (1993) 76: 117; U.S. Pat. No. 3,929,992). Large numbers of derivatives of rapamycin have been synthesized, including for example those disclosed in U.S. Pat. Nos. 5,221,670 and 5,221,740, certain acyl and aminoacyl-rapamycins (see for example U.S. Pat. No. 4,316,885, U.S. Pat. No. 4,650,803, and U.S. Pat. No. 5,151,413), and carbonates and amide esters (see for example EP 509795 and 515140) 27-desmethyl-rapamycin (see for example WO 92/14737), 26-dihydro-rapamycin (see for example U.S. Pat. No. 5,138,051), alkoxyester derivatives (see for example U.S. Pat. No. 5,233,036), and certain pyrazole derivatives (U.S. Pat. No. 5,164,399).
Rapamycin and its structurally similar analogs and derivatives are termed collectively as “compounds of the rapamycin class” in this specification.
Compounds of the rapamycin class are extremely potent immunosuppressants and have also been shown to have antitumor and antifungal activity. However their utility as pharmaceuticals especially on oral administration has been restricted by their very low solubility, low and variable bioavailability and their high toxicity. Little is known concerning the causes of these properties and the site of absorption. Thus low bioavailability may be thought to due to due to extensive metabolism of the macrolide ring and not solvable by a galenical formulation. Therefore there is a need for an acceptable pharmaceutical composition that contains compounds of the rapamycin class.
FK506 is a macrolide immunosuppressant that is produced by
Streptomyces tsukubaensis
No 9993. The structure of FK506 is given in the appendix to the Merck Index, as item A5. Also a large number of related compounds which retrain the basic structure and immunological properties of FK506 are also known. These compounds are described in a large number of publications, for example EP 184162, EP 315973, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/13889, WO 91/19495, EP 484936, EP 532088, EP 532089, WO 93/5059 and the like. Little is known concerning the biopharmaceutical properties of such compounds. These compounds are termed collectively “FK506 compounds” in this specification.
It has now been surprisingly found that stable compositions containing macrolides that offer high absorption efficiency, can be obtained by formulating the macrolide with certain carrier media.
Accordingly, this invention provides a pharmaceutical composition comprising a macrolide and a carrier medium comprising a hydrophilic phase, a lipophilic phase and a surfactant.
In another aspect the invention provides a pharmaceutical composition which comprises an orally administrable active agent which is other than a cyclosporin and a microemulsion preconcentrate carrier medium therefor which comprises
i) a reaction product of castor oil and ethylene oxide,
ii) a transesterification product of a vegetable oil and glycerol comprising predominantly linoleic acid or oleic acid mono-, di- and tri-glycerides, or a polyoxyalkylated vegetable oil,
iii) 1,2 propylene glycol and
iv) ethanol.
The pharmaceutical composition is stable and results in surprisingly high and consistent absorption efficiency when administered orally. Therefore the macrolide may be administered in lower doses, which alleviates toxicity problems. For example, in animal trials in which the pharmaceutical compositions are administered orally, the pharmaceutical compositions resulted in high bioavailabilities. Hence the pharmaceutical compositions have very surprising properties which offer great advantages.
Preferably the composition is in the form of a “microemulsion preconcentrate” or “emulsion preconcentrate”, in particular of the type providing o/w (oil-in-water) microemulsions or emulsions. However the composition may be in the form of a microemulsion or an emulsion which additionally contains an aqueous phase; preferably water.
A “microemulsion preconcentrate” is defined in this specification as being a formulation which spontaneously forms a microemulsion in an aqueous medium, for example, in water or in the gastric juices after oral application.
A “microemulsion” is a non-opaque or substantially non-opaque colloidal dispersion that is formed spontaneously or substantially spontaneously when its components are brought into contact. A microemulsion is thermodynamically stable and contains dispersed particles of a size less than about 2000 Å. Generally microemulsions comprise droplets or particles having a diameter of less than about 1500 Å; typically from 30 to 1000 Å. Further characteristic can be found in British patent application 2 222 770 A; the disclosure of which is incorporated herein by reference.
An “emulsion preconcentrate” is defined in this specification as being as being a formulation which spontaneously forms an emulsion in an aqueous medium, for example, in water or in the gastric juices after oral application. The emulsion formed is opaque, thermodynamically stable and contains dispersed droplets of a size greater than about 100 nm, more usually greater than about 200 nm. Often bimodal size range distributions are obtained. The emulsion preconcentrates are preferably of the type providing o/w (oil-in-water) emulsions.
A “pharmaceutical composition” means a composition in which the individual components or ingredients are themselves pharmaceutically acceptable and, when a particular form of administration is foreseen, are suitable or acceptable for that form of administration.
The lipophilic phase may comprise 10 to 85% by weight of the carrier medium; preferably 15 to 70% by weight, more preferably 20 to 60% by weight and even more preferably about 25% by weight.
The surfactant may comprise 5 to 80% by weight of the carrier medium; preferably 10 to 70% by weight, more preferably 20 to 60% by weight and even more preferably about 40% by weight.
The hydrophilic phase may comprise 10 to 50% by weight of the carrier medium; preferably 15 to 40% by weight, more preferably 20 to 35% by weight and even more preferably about 30% by weight.
The macrolide is preferably present in an amount of 1 to 15% by weight of the composition; more preferably about 2 to 10%.
The macrolide may be rapamycin or an O-substituted derivative in which the hydroxy in position 40 of the formula illustrated above is replaced by —OR
1
in which R
1
is hydroxyalkyl, hydroalkoxyalkyl, acylaminoalkyl and aminoalkyl; for example 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin and 40-O-(2-acetaminoethyl)-rapamycin. These O-substituted derivatives may be produced by reacting Rapamycin (or dihydro or deoxorapamycin) with an organic radical attached to a leaving group (for example RX where R is the organic radical which is desired as the O-substituent, such as an alkyl, allyl, or benzyl moiety, and X is a leaving group such as CCl
3
C(NH)O or CF
3
SO
3
) under suitable reaction conditions. The conditions may be acidic or neutral conditions, for example in the presence of an acid like trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their respective pyridinium or substituted pyridiniu

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