Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-12-18
2001-05-22
Lee, Howard C. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S489000, C514S951000
Reexamination Certificate
active
06235724
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a preparation for injection containing a lipid A analog or a pharmacologically acceptable salt thereof, and a process for preparing the same.
2. Prior Art
Lipid A, which is the main moiety causing activities of lipopolysaccharide (hereinafter referred to as LPS), has various biological activities such as macrophage stimulation, antitumor effect and pyrogenicity (for example, Haruhiko Takada and Shozo Kotani,
Protein, Nucleic Acid and Enzyme,
31(4), 361(1986)).
Various lipid A analogs have recently been synthesized and examined for their biological activities (Yuji Ogawa et al.,
Metabolism
26(5), 415(1989)). Lipid A analogs originally have the glycolipid structure. Thus most of the lipid A analogs are sparingly soluble or insoluble in water, so that it is difficult to prepare an injection with lipid A analogs. Therefore, various investigations have been carried out in order to obtain a highly transparent aqueous solution thereof. As a result, it has been proposed, for example, to a dd triethylamine, bovine serum albumin, lipids, or the like as a solubilizing agent (Y. B. Kim, et al,
Eur. J. Biochem.
31, 230(1972) and R. B. Ramsey, et al,
Blood,
56, 307(1980), J. Dijkstra, et al,
J. Immunol.,
138, 2663(1987)).
Furthermore, JP-A-4-198192 discloses a method employing basic amino acids or polyamines as a solubilizing agent. However, all of the pH of the aqueous solutions in the method are as high as around pH 10.
On the other hand, as a method of dispersing a lipid such as lecithin or the like in water to form aggregates of liposomes or the like, known is a method to add a lipid to a buffer having a pH around neutrality, followed by heating and sonication.
The method of solubilizing lipid A analogs using solubilizing agents is not satisfactory in view of the physical stability in water, chemical stability, pharmacological effects and safety, and hitherto has not been carried out on a practical basis. Moreover, a transparent solution of a lipid A analog could not be obtained also by the method of dispersing a lipid in a buffer having a pH around neutrality followed by sonication. Therefore, it has been eagerly desired to develop a practical injection containing a lipid A analog, that is, an injection which exhibits high transparency in the form of an aqueous solution, has pH ranging in values suitable for injection, and has excellent stability.
DISCLOSURE OF THE INVENTION
In order to overcome the above situation, the inventors of the present invention have intensively studied to find a highly transparent and stable preparation for injection containing a lipid A analog and a process for the preparation thereof. As a result, the present inventors discovered that the desired objects could be attained by the following embodiments. The present invention has been accomplished on the basis of this finding.
The present invention provides a preparation for injection prepared by dissolving a lipid A analog or a pharmacologically acceptable salt thereof in an alkaline aqueous solution and subsequently adding a buffer thereto.
The present invention also provides a process for preparing a preparation for injection, comprising dissolving a lipid A analog or a pharmacologically acceptable salt thereof in an alkaline aqueous solution and subsequently adding a buffer thereto.
Furthermore, the present invention provides a preparation for injection containing aggregates having an average particle diameter of 30 nm or less prepared by dissolving a lipid A analog or a pharmacologically acceptable salt thereof in an alkaline aqueous solution and subsequently adding a buffer thereto, and a process of the preparation thereof.
According to the present invention, it is possible to prepare a transparent and stable preparation for injection with a lipid A analog or a pharmacologically acceptable salt thereof (hereinafter referred to simply as a lipid A analog). This is therefore an object of the present invention.
Representative compounds of the lipid A analog of the present invention have a structure represented by the following chemical formula (I) or (II), and can be produced by the process disclosed in, for example, JP-A-5-194470 or WO96/39411.
wherein at least one of R
1
, R
2
, R
3
and R
4
is
wherein each L is O, N or C; each M is O or N; each E independently is an integer of 0 to 14; each G independently is N, O, S, SO or SO
2
; each m independently is an integer of 0 to 14; each n independently is an integer of 0 to 14; each p independently is an integer of 0 to 10; each q independently is an integer of 0 to 10, the rest of R
1
, R
2
1
R
3
and R
4
are, independently of one another,
wherein each L is O, N or C; each M is O or N; each x independently is an integer of 0 to 14; each y independently is an integer of 0 to 14; each z independently is an integer of 0 to 10; each G independently is N, O, S, SO or SO
2
, A
1
and A
2
are, independently of one another, H, OH, OCH
3
,
wherein each d independently is an integer of 0 to 5; each f independently is an integer of 0 to 5; each g independently is an integer of 0 to 5; each A
3
independently is
wherein each j independently is an integer of 0 to 14, X is H, (CH
2
)
t
CH
3
, (CH
2
)
t
OH, (CH
2
)
t
O(CH
2
)
v
CH
3
, (CH
2
)
t
OPO(OH)
2
, (CH
2
)
t
—CH═CH—(CH
2
)
v
CH
3
, (CH
2
)
t
—O—R
5
,
wherein t and v, are independently of one another, an integer of 0 to 14; R
5
is any of the above definitions of R
1
to R
4
,
Y is H, OH, O(CH
2
)
w
CH
3
, a halogen atom,
wherein w is an integer of 0 to 14.
wherein R
1
is a group selected from the groups consisting of
wherein J, K and Q are each a linear or branched alkyl group of 1 to 15 carbon atoms; L is O, NH
2
or CH
2
; M is O or NH; G is NH, O, S, SO or SO
2
,
R
2
is a linear or branched alkyl group of 5 to 15 carbon atoms, R
3
is a group selected from the groups consisting of
wherein E is N, O, S, SO or SO
2
; A, B and D are each a linear or branched alkyl group of 1 to 15 carbon atoms, R
4
is a group selected from the groups consisting of a linear or branched alkyl group of 4 to 20 carbon atoms and
wherein U and V are each a linear or branched alkyl group of 2 to 15 carbon atoms; W is a hydrogen atom or a linear or branched alkyl group of 1 to 5 carbon atoms, R
5
is a group selected from the groups consisting of a hydrogen atom, J′, —J′—OH, —J′—O—K′, —J′—O—K′—OH and —J′—O—PO(OH)
2
, wherein J′ and K′ are each a linear or branched alkyl group of 1 to 5 carbon atoms, R
6
is a group selected from the groups consisting of a hydroxyl group, a halogen atom, an alkoxy group of 1 to 5 carbon atoms, and an acyloxy group of 1 to 5 carbon atoms, A
1
and A
2
are, independently of one another, a group selected from the groups consisting of
wherein Z is a linear or branched alkyl group of 1 to 10 carbon atoms.
Preferred examples of the lipid A analog for use in the present invention include 6-O-[2-deoxy-6-O-methyl-4-O-phosphono-3-O-[(R)-3-Z-dodec-5-enoyloxydecyl]-2-[3-oxo-tetradecanoylamido]-b-O-phosphono-a-D-glucopyranose]tetrasodium, a-D-glucopyranose, 3-O-decyl-2-deoxy-6-O-[2-deoxy-3-O-(3-methoxydecyl)-6-O-methyl-2-[(1-oxo-11-octadecenyl)amino]-4-O-phosphono-b-D-glucopyranosyl]-2-[(1,3-dioxotetradecyl)amino]-, 1-(dihydrogenphosphate), disodium[6(2Z, 3R)]; and a-D-glucopyranose, 3-O-decyl-2-deoxy-6-O-[2-deoxy-3-O-(3-methoxydecyl)-6-O-methyl-2-[(1-oxo-11-octadecenyl)amino]-4-O-phosphono-b-D-glucopyranosyl]-2-[(1,3-dioxotetradecyl)amino]-, 1-(dihydrogenphosphate), tetrasodium[6(2Z, 3R)]. These compounds are represented by the following chemical structural formulae (III) and (IV).
The alkaline aqueous solution for use in the present invention may be an aqueous solution of the hydroxide of an alkali metal such as sodium hydroxide, potassium hydroxide or the like. However, an aqueous solution of sodium hydroxide is preferred. The concent
Asai Yasuyuki
Ashizawa Kazuhide
Ishibashi Yasuo
Iwamoto Kiyoshi
Onai Katsumi
Birch & Stewart Kolasch & Birch, LLP
Eisai Co. Ltd.
Lee Howard C.
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