Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-01
2001-03-06
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S023000, C514S569000, C514S723000
Reexamination Certificate
active
06197787
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutical formulations comprising a poorly soluble drug substance and a pharmaceutically acceptable carrier.
BACKGROUND OF THE INVENTION
Poorly soluble drug substances have been formulated in pharmaceutically acceptable carriers by finely dividing them, by grinding, into nanoparticles having an effective average particle size of less than 400 nm in order to achieve satisfactory bioavailabiity. However, to keep the nanoparticles from coagulation various surface active agents were used. Such agents may not be desirable and they also reduce the overall amount of the drug which otherwise could be contained in an effective dosage formulation.
Solid dispersions have also been used to increase the dissolution rate and bioavailability of drugs that are poorly water soluble. The carriers used have been physiologically inert compounds that are readily water soluble, such as polyethylene glycols. Two techniques which have been used to prepare solid dispersions are the fusion technique and the solvent technique. In the fusion technique, the drug substance is dissolved in a molten carrier and the mixture cooled to form a solid. In the solvent technique, drug substance and carrier are dissolved in a solvent, followed by removal of the solvent by evaporation or freeze drying.
The preparation of solid dispersions featuring good pharmaceutical properties is difficult. Problems which frequently occur during preparation include: degradation of drug substance at the temperature of the molten carrier; reaction of the drug with the molten carrier; and incomplete solidification of the product, e.g., the carrier remaining largely amorphous. Solid dispersions prepared from esters of p-aminobenzoic acid and xylitol are disclosed, for example, by Sirenius et al.,
J. Pharm. Sci.,
66, No. 6, Jun. 1979.
The present invention is directed to pharmaceutical formulations containing poorly soluble drug substances and particularly to SR 48692 which has shown considerable promise as an NT-antagonist for the treatment of psychosis. SR48692 and a method for the preparation thereof are described by Boigegrain et al in U.S. Pat. No. 5,420,141 (Example 13). SR48692 has the structural formula:
SR48692 has proven to be unusually difficult to formulate into pharmaceutical compositions, due in part to its very low solubility, even in organic solvents.
PCT/US87/02629 discloses a solvent system for enhancing the solubility of an acidic, basic or amphoteric pharmaceutical agent to produce a concentrated solution suitable for soft gelatin capsule filling. The solvent system comprises polyethylene glycol containing 0.2-1.0 mole equivalents of an ionizing agent per mole equivalent of pharmaceutical agent and 1-20% water. Attempts to formulate SR48692 in such a solvent system were not successful.
Sheen et al. in
Int. J. Pharm.,
118(2), 221-7, 1995, disclose a solid dispersion of a poorly water-soluble drug, RP69698 prepared by a melting method with water-soluble carriers in which RP69698 is highly soluble. When incorporated into a solid dispersion, the formulation contains PEG 3350, Transcutol and Labrasol.
SUMMARY OF THE INVENTION
We have now discovered that poorly soluble drug substances may be incorporated into pharmaceutically acceptable carriers containing certain solvents and employing processes disclosed herein.
The invention can be practiced with a wide variety of drug substances. The drug substance preferably is present in an essentially pure form. The drug substance may be poorly soluble and must be soluble in at least one liquid medium. By “poorly soluble” it is meant that the drug substance has a solubility in an aqueous medium of less than about 10 mg/ml, and preferably of less than about 1 mg/ml.
Suitable drug substance can be selected from a variety of known classes of drugs including, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-phannaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators and xanthines. Preferred drug substances include those intended for oral administration. A description of these classes of drugs and a listing of species within each class can be found in Martindale, the extra Pharmacopoeia, Twenty-ninth Edition, the Pharmaceutical Press, London, 1989, the disclosure of which is hereby incorporated by reference in its entirety. The drug substances are commercially available and/or can be prepared by techniques known in the art.
Preferred drug substances for the purposes of the present invention include Naproxyn and compound SR48692.
Naproxyn is (S)-6-methoxy-(&agr;-methyl-2-naphthaleneacetic acid, having the chemical structure
is well known in the prior art, and its preparation is disclosed, for example, in U.S. Pat. Nos. 3,904,682 and 4,009,197.
SR48692 is disclosed in U.S. Pat. No. 5,420,141 in Example 13, having the chemical structure
said patent is incorporated herein by reference.
Solid Dispersions IA and IB
IA) We have discovered, as disclosed in prior application Ser. No. 08/813,946, that the combination of Transcutol (diethyleneglycol monoethyl ether) and xylitol provides a carrier for solid pharmaceutical dispersions which can reduce impurities and/or degradation products. The dispersion maintains a high degree of crystallinity, exhibits acceptable hygroscopicity, rapidly dissolves in water and has good bioavailability.
In accordance with the invention, there is provided a solid dispersion comprising a poorly soluble drug substance, Transcutol and xylitol.
In another embodiment of the invention, there is provided a method of preparing such dispersion comprising the steps of dissolving a poorly soluble drug substance in Transcutol and adding the solution to xylitol.
IB) During further research we have discovered that Transcutol can be replaced with propylene glycol using a spray granulation process within a fluid bed. The process comprises the steps of:
a) preparing a drug solution by adding SR48692, or another desired poorly soluble drug, to a system containing propylene glycol and aqueous sodium hydroxide; optionally adding this solution to an aqueous xylitol solution; and
b) adding the drug solution to a seed powder, such as xylitol, dicalcium phosphate dihydrate, or a combination of lactose monohydrate and microcrystalline cellulose by spraying the drug solution on the seed powder.
Concentrated Solutions IIA and IIB
IIA We have discovered, as disclosed in prior application Ser. No. 08/808,761, that SR48692, or other poorly soluble drug, may be incorporated as the active ingredient in polyethylene glycol (PEG), NaOH, and H
2
O wherein the mole equivalent of NaOH per mole equivalent of the active ingredient is at least 1.0.
The formulations were prepared by adding aqueous NaOH to the polyethylene glycol. The active ingredient SR48692 was added to the PEG-NaOH until a solution is formed. Alternatively, the active ingredient was dispersed in the PEG with mixing. The NaOH solution was added resulting in dissolution of the active ingredient. Thereafter, the solution formulations were encapsulated in a soft gelatin capsule according to techniques known in the art in order to form a pharmaceutical dosage form.
IIB) During further resea
Franson Nancy M.
Guillot Micael A.
Laughlin Sharon M.
Rocco William L.
Alexander Michael D.
Dupont Paul E.
Sanofi-Synthelabo
Spivack Phyllis G.
LandOfFree
Pharmaceutical formulations containing poorly soluble drug... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical formulations containing poorly soluble drug..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical formulations containing poorly soluble drug... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2516942