Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-08-29
2004-11-23
Tate, Christopher R. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S008100, C514S007600, C514S217050
Reexamination Certificate
active
06821951
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to processes for making pharmaceutical formulations or compositions containing an antifungal compound, in particular, the incorporation of an echinocandin/carbohydrate complex into an oral formulation or composition to enhance stability.
BACKGROUND OF THE INVENTION
Oral formulations of pharmaceutical drugs may be administered to patients via sachets, chewable or conventional tablets, capsules or oral solutions and suspensions. The formulation that is developed for a particular drug is dependent on a variety of issues. For example, it is well-known in the art that an oral formulation should be sufficiently stable, have an acceptable appearance and be prepared from generally accepted, safe excipients.
Stability is an important consideration when designing a formulation, especially for oral applications. For practical and commercial reasons, it is desirable to maintain sufficient formulation stability for at least two years. Therefore, a primary formulation design goal is to optimize shelf-life and stability at the selected storage condition (e.g., room temperature).
The instability of the echinocandin compounds make them particularly difficult to formulate. Most of the formulations tested to date have a shelf life of less than one year at room temperature. Generally, a shelf life of at least two years is desirable. Therefore, there is a need for an oral formulation containing an echinocandin compound having improved thermal stability.
SUMMARY OF THE INVENTION
Applicants have discovered that the incorporation of one or more carbohydrates into an echinocandin formulation at specific process stages provides a significant improvement in thermal stability. In one embodiment of the present invention, a process is provided for preparing an oral pharmaceutical formulation which comprises (i) mixing an echinocandin compound or a echinocandin/carbohydrate complex and at least one carbohydrate in a solvent or mixture of solvents to form a pharmaceutical solution; (ii) spraying the solution onto a layer of fluidized granular diluent or carrier (e.g., a granular carbohydrate); and (iii) removing the excess solvent or solvents. The pharmaceutical solution may optionally contain surfactants, flavorings, colorants and/or processing aids. Oral granular pharmaceutical formulations prepared by the process described above are also provided, as well as medicaments prepared therefrom such as sachets and chewable tablets.
In another embodiment of the present invention, a process is provided for preparing an oral pharmaceutical formulation comprising the steps of: (i) mixing an echinocandin compound or echinocandin/carbohydrate complex, at least one carbohydrate, and a soluble granulating agent (e.g., polyvinylpyrrolidone) in a solvent or mixture of solvents to form a pharmaceutical solution; (ii) spraying the solution onto a layer of fluidized non-granular diluent or carrier (e.g., carbohydrate powders); and (iii) removing the excess solvent or solvents. The pharmaceutical solution may optionally contain surfactants, flavorings, colorants and/or processing aids. Oral granular pharmaceutical formulations prepared by the process described above are also provided, as well as medicaments prepared therefrom such as sachets and chewable tablets.
In yet another embodiment of the present invention, a method is provided for treating a fungal infection in a mammal in need thereof which comprises administering an oral formulation prepared by one of the processes described above to the mammal.
The term “echinocandin” refers to a compound having the following general structure:
wherein:
R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, heteroaryl group, or combinations thereof;
R
1
, R
2
, R
3
, R
6
, R
7
, and R
10
are independently hydroxy or hydrogen;
R
4
is hydrogen, methyl or —CH
2
C(O)NH
2
;
R
5
and R
11
are independently methyl or hydrogen;
R
8
is —OH, —OPO
3
H
2
, —OPO
3
HCH
3
, —OPO
2
HCH
3
, or —OSO
3
H; and
R
9
is —H, —OH, or —OSO
3
H.
“Echinocandin B” or “ECB” refers to a echinocandin compound as described above where R
1
, R
2
, R
3
, R
6
, R
7
, R
8
, and R
10
are hydroxy groups; R
4
, R
5
, and R
11
are methyl groups; R
9
is a hydrogen. In the natural product, R is a linoleoyl group. In a particularly useful semi-synthetic compound, R has both a rigid and a flexible component, for example, a compound where R is represented by the following formula
The term “alkyl” refers to a hydrocarbon radical of the general formula C
n
H
2n+1
containing from 1 to 30 carbon atoms unless otherwise indicated. The alkane radical may be straight, branched, cyclic, or multi-cyclic. The alkane radical may be substituted or unsubstituted. Similarly, the alkyl portion of an alkoxy group or alkanoate have the same definition as above.
The term “alkenyl” refers to an acyclic hydrocarbon containing at least one carbon-carbon double bond. The alkene radical may be straight, branched, cyclic, or multi-cyclic. The alkene radical may be substituted or unsubstituted.
The term “alkynyl” refers to an acyclic hydrocarbon containing at least one carbon carbon triple bond. The alkyne radical may be straight, or branched. The alkyne radical may be substituted or unsubstituted.
The term “aryl” refers to aromatic moieties having single (e.g., phenyl) or fused ring systems (e.g., naphthalene, anthracene, phenanthrene, etc.). The aryl groups may be substituted or unsubstituted. Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.)
The term “heteroaryl” refers to aromatic moieties containing at least one heteroatom within the aromatic ring system (e.g., pyrrole, pyridine, indole, thiophene, furan, benzofuran, imidazole, pyrimidine, purine, benzimidazole, quinoline, etc.). The aromatic moiety may consist of a single or fused ring system. The heteroaryl groups may be substituted or unsubstituted.
“Echinocandin/carbohydrate complex” refers to a crystalline complex formed between an echinocandin compound and a carbohydrate when the echinocandin is crystallized or recrystallized from a solvent in the presence of the carbohydrate. A more detailed description of the echinocandin/carbohydrate complexes may be found in Larew, et al., filed on Mar. 3, 1999 entitled “Echinocandin/Carbohydrate Complexes” and incorporated herein by reference.
“Carbohydrate” refers to an aldehydic or ketonic derivative of polyhydric alcohols represented by the formulas C
n
(H
2
O)
n
(e.g., glucose, C
6
(H
2
O)
6
; sucrose, C
12
(H
2
O)
11
). Carbohydrates include compounds with relatively small molecules, such as the simple sugars (e.g., monosaccharides, disaccharides, etc.), as well as macromolecular (polymeric) substances such as starch, glycogen, and cellulose polysaccharides. Sugars are carbohydrates (saccharides) having the general composition (CH
2
O)
n
and simple derivatives thereof. Although the simple monomeric sugars (glycoses) are described as polyhydroxy aldehydes or ketones, e.g., HOCH
2
—(CHOH)
4
—CHO for aldohexoses (e.g., glucose) or HOCH
2
—(CHOH)
3
—COCH
2
OH for 2-ketoses (e.g., fructose), the structures are commonly written as five (furanose) or six(pyranose) membered ring cyclic ethers, e.g.
The term “granular” diluents or carriers refer to materials where approximately 70% by weight of the material has a particle size greater than 150 microns.
The term “non-granular” or “powder” diluents or carriers refer to materials where approximately 70% by weight of the material has a particle size less than 150 microns.
The term “granulating agent” refers to a binder that causes the diluent or carrier to bind together to form larger aggregates or granules upon spraying the agent onto the diluent powder surface in the presence of a solvent or solvents.
REFERENCES:
patent: 3293482 (1966-12-01), Wolkstein
patent: 3978210 (1976-08-01), Mizuno et al.
patent: 4293482 (1981-10-01), Abbott et al.
patent: 4293483 (1981-10-01), Debono
patent: 4293489 (1981-10-01), Debono
patent: 4299763 (1981-11-01), Abbott et al.
p
Schwier John Richard
Taylor Jerry
Audet Maury
Eli Lilly and Company
Morrison & Foerster / LLP
Tate Christopher R.
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