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Stabilized oral pharmaceutical composition

a pharmaceutical composition and stability technology, applied in the field of orally deliverable pharmaceutical compositions, can solve the problems of limiting factors such as the size of the capsule or solution required to provide a therapeutic dose, the size of the solution is a practical problem, and the dose requirement is relatively high, so as to achieve infinite dose flexibility, ease of swallowing and dose flexibility

Inactive Publication Date: 2005-05-26
GAO PING +8
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent describes a new way to make medication containing a poorly water-soluble drug that can be taken as a solution or a suspension. The solution or suspension contains a high concentration of the drug and a solvent liquid made up of polyethylene glycol and other components. The drug is dissolved or solubilized in the solvent liquid, which makes it easier to absorb and act on in the body. The solution can be encapsulated in a gelatin capsule for easy swallowing. The medication can be used for pain relief or for the treatment and prevention of headaches or migraines. The invention provides a convenient and effective way to deliver poorly water-soluble drugs for therapeutic purposes."

Problems solved by technology

In addition, some, for example celecoxib, have relatively high dose requirements.
These properties present practical problems in formulating concentrated solutions of such drugs for rapid-onset, oral administration.
With respect to high dose, low solubility drugs, the size of the capsule or volume of solution required to provide a therapeutic dose becomes a limiting factor.
Such a volume can be inconvenient or unacceptable for consumption in imbibable form; this volume also presents particular problems where an encapsulated dosage form is desired because capsules that contain more than about 1.0 ml to about 1.5 ml of liquid are generally considered to be too large for comfortable swallowing.
Further, liquids that can easily migrate through a capsule wall, e.g., water in an amount greater than about 5% by weight of the solution, and low molecular weight water-soluble, volatile organic compounds such as alcohols, ketones, acids, amines and esters, are generally unsuitable for encapsulation.
However, we have now discovered that polyethylene glycol, when used as a solvent for an aminosulfonyl-comprising drug such as celecoxib, can result in drug instability.
This problem presents practical difficulties in forming a chemically stable solution of an aminosulfonyl-comprising drug using polyethylene glycol (which, as described above, can be otherwise advantageous) as a solvent.

Method used

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  • Stabilized oral pharmaceutical composition
  • Stabilized oral pharmaceutical composition
  • Stabilized oral pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0192] Six celecoxib solution formulations SF-1 to SF-6 were prepared having components as shown in Table 1. In each case the solvent liquid consisted of PEG-400, either alone (SF-1) or together with at least one free radical-scavenging antioxidant (SF-2 to SF-6). Celecoxib was present in solution at a concentration of 50 mg / g in all formulations. Antioxidant amounts are shown as % weight / weight.

TABLE 1Composition of celecoxib solution formulations SF-1 to SF-6FormulationComponentsSF-1Celecoxib, PEG-400SF-2Celecoxib, PEG-400, 0.1% vitamin ESF-3Celecoxib, PEG-400, 0.1% BHASF-4Celecoxib, PEG-400, 0.1% BHTSF-5Celecoxib, PEG-400, 0.1% propyl gallateSF-6Celecoxib, PEG-400, 0.05% BHA, 0.05% BHT

example 2

[0193] A gradient HPLC assay was used to determine impurities in celecoxib solution formulations SF-1 to SF-6 of Example 1 after storage at various temperatures for different periods of time. Solution formulation samples were drawn and were dissolved in methanol to obtain a celecoxib concentration of about 0.4 to about 0.5 mg / ml prior to injection. Chromatographic conditions were as follows: (a) flow rate: 1 ml / min.; (b) detection: UV 254 nm; (c) injection volume: 10 μl; (d) column: 5 μm Supercosil, LC-DP, 250×4.6 mm; (e) column temperature: 40° C.; (f) mobile phase A: 10 mM NH4AC or KH2PO4, pH 3; (g) mobile phase B: 100% acetonitrile; (h) running time: 45 minutes. Data are shown in Tables 2 and 3.

TABLE 2Impurity level (%) in formulations SF-1 to SF-5 following storagedays stored at 70° C.Formulation914162028333590SF-12.93.77.612.6SF-20.020.020.022.8SF-30.020.020.020.09SF-40.030.040.060.30SF-5NDNDND0.15

ND = None detected

[0194]

TABLE 3Impurity level (%) in formulations SF-1, SF-2, ...

example 3

[0196] Solution formulation SF-1 of Example 1 was bubbled with ethylene oxide, a putative source of free radicals, for 15 minutes, and was then stored at 70° C. for 10 days. After storage, the formulation was analyzed for the presence of impurities. Addition compounds detected therein were isolated by reversed-phase, semi-preparative HPLC. A 20×250 mm Kromasil C18 column was employed with either an isocratic or a gradient, acetonitrile-aqueous trifluoroacetic acid mobile phase. Detection was accomplished at 254 nm. Pooled fractions containing individual addition compounds, herein referred to as Peak 1, Peak 2 and Peak 3 addition compounds, were concentrated, desalted and reduced in chemical noise-causing components by trapping on a 7×300 mm Hamilton PRP-1 column. The eluent from the trapping column containing the individual addition compounds was freeze-dried to yield the final isolates. Peak 1 addition compound was 99% pure and Peak 2 addition compound was >99% pure by analytical H...

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Abstract

An orally deliverable pharmaceutical composition is provided comprising an aminosulfonyl-comprising drug, for example a selective cyclooxygenase-2 inhibitory drug such as celecoxib, and a solvent liquid comprising a polyethylene glycol and one or more free radical-scavenging antioxidants. At least a substantial part of the drug is in dissolved form in the solvent liquid. The composition has rapid-onset properties and is useful in treatment of cyclooxygenase-2 mediated conditions and disorders.

Description

[0001] This application claims priority of U.S. provisional patent application Ser. No. 60 / 284,589 filed on Apr. 17, 2001, and of U.S. provisional patent application Ser. No. 60 / 357,959 filed on Feb. 19, 2002.FIELD OF THE INVENTION [0002] The present invention relates to orally deliverable pharmaceutical compositions that comprise a drug of low water solubility, more particularly to such compositions where the drug is in dissolved form. BACKGROUND OF THE INVENTION [0003] Several compounds having a molecular structure that comprises an aminosulfonyl functional group (herein referred to as aminosulfonyl-comprising compounds) have been reported as having therapeutically and / or prophylactically useful selective cyclooxygenase-2 (COX-2) inhibitory effects, and have been disclosed as having utility in treatment or prevention of specific COX-2 mediated disorders or of such disorders in general. Among such compounds are a large number of substituted pyrazolyl benzenesulfonamides as reported...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/08A61K9/48A61K31/415A61K31/42A61K31/522A61K31/635A61K45/00A61K45/06A61K47/02A61K47/04A61K47/10A61K47/12A61K47/18A61K47/22A61K47/34A61K47/38A61K47/48A61P25/06A61P29/00A61P43/00C07D231/12C07D261/08C07D413/12
CPCA61K9/0019A61K9/4858A61K9/4866A61K31/415A61K31/42A61K31/635C07D413/12A61K47/12A61K47/22A61K47/38A61K47/48215C07D231/12C07D261/08A61K47/02A61K47/60A61P25/06A61P29/00A61P43/00A61K47/10
Inventor GAO, PINGHUANG, TIEHUAROBINS, RUSSELL H.BAUER, JULIANE M.GUIDO, JANE E.BRUGGER, ANDREW M.KARIM, AZIZHASSAN, FREDFORBES, JAMES C.
Owner GAO PING
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