JPS5929617A - Vinca alkaloid medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Vinca alkaloids are generally indole-sihydroindole comeric compounds. Two of the alkaloids obtained from the leaves of the plant Vinca rosea are vincristine (VCR).
) and vinblastine (VLB) are marketed for the treatment of human leukemia and related neoplasms. Another compound, pinchicin (VDS), is an amide derivative of vinblastine and is marketed for the treatment of neoplastic diseases in humans in European countries and is in clinical trials in the United States. The above three drugs are US patented Nα32θm22θ (vincristine).
, 3. θ9z/37C vinblastine) and Hisayu θ3
．． 9. ! rC pinchin). These drugs are administered intravenously to patients harboring susceptible neoplasms.

The conventional pharmaceutical preparations that have been used to date are lyophilized sulfate salts placed in vials that are reconstituted (redissolved) before use. The sulfate salt is prepared by adding a stoichiometric amount of sulfuric acid to a solution of the free base of the alkaloid. but,
In the case of Pinchin, the sulfate salt is unstable if produced by conventional methods, so the US patent is N1%. 239.211
Freeze-dried formulations are prepared using the special sulfate salts disclosed in 2.

Researchers and medical practitioners have long desired the advent of solutions of vincristine and other vinca alkaloids that are easy to use. Seventh, improper reconstitution of lyophilized products can generate airborne droplets that can be harmful to hospital personnel preparing intravenous solutions. Vincristine is a very powerful tumor cytolytic drug, and it is desirable to avoid contact between the two drugs as much as possible. It is also desirable to avoid contact with any cytolytic drugs, especially vincristine. Furthermore, a significant problem always arises at the time of reconstitution of lyophilized formulations. In other words, the amount of diluent used may not be appropriate.

This is when the wrong amount of drug is collected due to the different size of the vial. Vinca alkaloids have very small differences between toxic and therapeutic doses, and inadvertent overdosing of vincristine caused by incorrect intravenous concentrations has been documented in the literature (e.g.

Journal of Pediatrics,
f! , Otsu 7/C/97 Otsu) ; CancerChe
Motherapy Reports, 33.32
3 (/97.2) ;Journal of Ped
iatrics, 9ρ, lθ1I2c/977)).

Another disadvantage of lyophilized vincristine sulfate lies in the way the dose is calculated for an individual. Vincristine sulfate is present in whole number milligram amounts (i.e. 1 and 3q
It is provided in the form of a vial.

The dosage is usually 2q/m4 of body surface area for children.
, for adults, is calculated as 1'l/m4 of body surface area, so the actual dose will usually be a milligram dose with a decimal point, and therefore only a portion of the vial contents will be used. Again, the difference between toxic and effective doses of vincristine is small. Since human therapeutic doses are usually calculated in this way, some excess redissolved vincristine usually remains after treatment. This problem is less severe in large cancer hospitals where vincristine is used daily and leftover vincristine from one patient can be applied to the next patient.

However, the recommended shelf life of reconstituted vincristine is one day at refrigerated temperatures. Therefore, in many cases, the excess amount of reconstituted lyophilized vincristine is
It becomes necessary to discard items that have exceeded the period of time. Vincristine is a very expensive drug, so having to discard it increases the overall cost of maintaining a cancer hospital.

The physical changes observed over time in redissolved lyophilized vincristine (containing benzyl alcohol as a preservative; redissolved in 9 ql aqueous sodium chloride solution) are as follows:
General solution turbidity.

This is the appearance of precipitate.

Yet another problem with reconstituted vincristine formulations is the need to add preservatives to prevent microbial growth. Generally, vincristine solutions cannot be sterilized by heat, but can be sterilized by filtration. However, even if sterilization is achieved by filtration, preservatives are required to avoid contamination from the air in the diluent used to reconstitute the lyophilized product and in opened vials containing previously sterilized liquid. There must be. Otherwise, the excess must be disposed of immediately and cannot be stored for even the maximum recommended period of one day.

Vinblastine sulfate and vindesine sulfate both contain a less reactive N-methyl group in place of the N-formyl functionality present in vincristine;
Although stability issues are less severe as indicated by the recommended stability period of 3θ days for reconstituted materials, these reconstituted solutions have similar issues and considerations.

The present invention provides a stable and easy to use intravenous solution of cytolytic vinca alkaloid. With the formulation of the present invention, contact between hospital personnel and drug is minimized and errors at the point of reconstitution are avoided by using a single solution strength for all sizes of vials and syringes used. − I can do it.

In particular, according to one aspect of the present invention, the pH of at least a pharmaceutically acceptable salt of vinca dimer, a polyol, a formulation is from 30 to
An aqueous formulation consisting of an acetate buffer and a preservative sufficient to maintain θ is effective as a stable cytolytic agent.

The present invention is particularly applicable to the production of stable and easy-to-use solutions of vinca dimers such as vincristine sulfate, vinblastine sulfate, and vindesine sulfate. The present invention is also useful for producing stable, easy-to-use solutions of certain vinca dimers that are currently or soon to be in clinical trials as cytolytic agents. Compounds that will soon enter clinical trials include Hiroshi'-deoxy-l-sulfate.
These include formylleulocidine and leuroformin.

The present invention also includes: It may also provide stable, easy-to-use solutions of other vinca dimers that have not yet been determined for clinical use but may be marketed as clinically useful cytolytic agents in the future.

N-formyl vinca λ-mers such as vincristine or t'-deoxy-/-phorusa-milurocidine are
The stabilized formulations of the present invention are more preferred and useful because they degrade by yet another mechanism, ie, by loss of the N-formyl group, which is not present in vinblastine or vindesine.

Although pharmaceutically acceptable salts other than sulfates, such as phosphates, may be used in the stable solutions of the present invention, sulfates are preferred. , pharmaceutically acceptable salts are salts that are useful in chemotherapy for warm-blooded animals. Alkaloids are usually around 0θl
−λθη/lsl +preferably θ～/θ”f/
present in the formulation in a concentration of ml.

Polyols useful for the above-mentioned stable and easy-to-use solutions of the cytolytic vinca dimer include:

Derivatives from sugars such as mannitol and sorbitol, or sugars themselves such as lactose and sucrose. Other useful polyols are known to those skilled in the art. Lactose and especially mannitol are the preferred polyols used in the present invention. The polyol is usually present in the formulation at approximately lθ to lθθ da/yst.

The acetate buffer system utilized in the above stable solution has a pH of 3.
Maintain within the range of θ to θ. The preferred pH range varies depending on the particular vinca alkaloid. In the case of vincristine sulfate, the preferred range is lAV to lA.

A pH range of 32 to 3 g is particularly preferred. The molar concentration of the buffer system is approximately 0000! ; M to 002M, preferably 6002 to 007M. The molar ratio of acetate:vinca dimer is preferably approximately 20:/
or less. In the case of vindesine sulfate, as known to those skilled in the art, 3. At pH below O, the buffer consists only of acetic acid and no acetate is used. pl (at 3, θ, the concentration of acetic acid approaches 0 θ M, but in the preferred pH range of 3
2-3. In this case, it becomes approximately θθ2 to 0θ/M. The stabilizing effect of the acetate buffer is, in part, to prevent changes in the pH of the solution due to alkali leaching from the glass or stopper of the vial, and to prevent decomposition due to changes in pH caused by decomposition of alkaloids. That's true.

In general, the preservatives tested in solutions of vinca dimer are detrimental to potency, clarity and pharmaceutical elegance; among these, paraben esters (methyl and propyl) do not meet the above parameters. This is preferable because it has almost no effect. These parabens may be used alone or in combination in a total amount of /-2Q/me. Other strong preservatives include benzyl alcohol, phenol or m-cresol. The liquid preparation produced according to the present invention is sterilized by sieving.

Concerning the components present in a sterile, stable solution of the alkaloids described above, the concentration of chloride ions must be minimized since they are detrimental to the various cytolytic vinca lambda molecules.

In order to further illustrate the invention, the following examples are provided:
It is not limited to this.

Example 1 A stable and easy-to-use solution of vincristine sulfate is prepared as follows. 1mg vial contains vincristine sulfate, methylparaben/3mfj.

−／／− Propyl paraben 02■, mannitol lθθ~.

0.2M acetic acid solution 0θ2 evening! ;mt, 02M sodium acetate θθ2'l-! ; ytrl and total amount jmt
Contains 300ml of waste water. Vials containing drug 2 or j are similarly prepared in proportion to the greater amount of drug. The solution thus prepared is sterilized by filtration and placed into suitable glass vials of appropriate volume.

The vial may be purged with an inert gas such as nitrogen before being sealed with a suitable stopper.

Alternatively, filling a predetermined volume hypodermic syringe with a filter-sterilized solution provides an easy-to-use solution that can be injected immediately. The use of prefilled syringes further reduces exposure to patients or hospital or medical personnel by eliminating the need to transfer the contents of a vial to an empty syringe. Ideally, syringes should be calibrated and disposable.

Example λ As an example of a stable and easy-to-use solution of vinblastine sulfate, the following ingredients are shown. In the vial for lθ~--no2-, vinblastine sulfate lθ9. Methylparaben/3W, propylparaben 2~. Mannitol 1
000m9.02M acetic acid solution 0'l-jmt.

02M sodium acetate solution θθ9 and total volume lθt
Contains enough water to make ttl. The vial is processed as described in Example 1 above. The hypodermic syringe described above may be filled with vinblastine solution.

Example 3 As an example of a stable and easy-to-use solution of vindesine sulfate, the following content is shown. Vindesine sulfate jq for vial or syringe for jmy.

Methylparaben X, t*, propylparaben l~.

Mannitol jθθ~, 023 ml of 02M acetic acid solution and total volume! ; Contains enough water to make tprl. This solution may be used to fill a vial or syringe as described above.

Easy-to-use formulations of the type described above must be stable for a period of time before being placed in a pharmacy and for a reasonable shelf life. Vincristine sulfate formulations prepared according to the present invention remain physically and chemically acceptable for pharmaceutical use for one year at 3'C.

The stability of the formulation of the present invention was evaluated by determining the content and quality of vincristine using bianalytical high performance liquid chromatography and thin layer chromatography.

For example, 30 formulations of vincristine sulfate are
After being stored at 3'C for about 9 months, the initial concentration of 9 g ~
99 staff remained. These 30 pieces contained the following ingredients. Vincristine sulfate solution/q/πl,
Methylparaben solution 13 η/ml, propylparaben solution 02 η/ml. Mannitol solution/θ0 da/ml +
02M acetic acid solution 0θ23 per solution/ltl;! ;ml,
02M sodium acetate solution 0θ2'1 per solution/ml
It contained 3 ml and enough water to make up to volume.

This solution was sterilized by filtration, placed in a succinic acid-treated vial, and then sealed with Teflon and gray-butyl stoppers.
Koha Ste JL/F, Otsu 3.2 (Ste1mi Otsu 32
) Close the lid with a stopper (Teflon@ means E, I, duP).
ont dCNemours & Co, , Inc.
is a registered trademark for polytetrafluoroethylene resins and products. ) The final pH of the solution is approximately 41. It was B.

Patent applicant: Eli Lilly & Company 93

Claims (1)

[Scope of Claims] (1) At least a pharmaceutically acceptable salt, polyol, or preparation of Pincannimer is maintained at 3θ to jθ.
, an aqueous formulation consisting of m acetate buffer and a preservative. (2) Claims (1) in which the pinacanimer is pinkacrystin, vinblastine, vindesine, t'-deoxy-1-formylleulocidine or leuroformin.
). (3) The preparation according to claim (1), wherein the salt of vinca dimer is a salt of vincristine. (4) The preparation according to claim (3), wherein the polyol is a sugar or a sugar derivative. (5) Claims (1), (2), in which the preservative is methylparaben and/or propylparaben;
The formulation described in (3) or (4). (6) Claims (1), (2), (3), in which the concentration of the acetate buffer is 00005-002M,
The formulation described in (4) or (5). (7) Claims (1), (2), (3) in which the polyol is mannitol or lactose.
, (4), (5) or (6). (8) About 1 vincristine sulfate per final solution/ml
, mannitol or lactose θ~10θ~, methylparaben and propylparaben alone or together in l~2q and the total amount/ml
The pH was maintained at approximately 1A to 1A with a θθθ2 to θθ/M acetate buffer. Claims (1), (2), (3), (4)
), (5). The formulation described in (6) or (7). (9) Per 1IIIt of final solution, about 1 vincristine sulfate, mannitol lθθ da, methylparaben/, 3I
The formulation according to claim (8), containing IIg and propylparaben 02115. 0I final solution/1gt, about vinblastine sulfate/IR9, mannitol or lactose lθ~lθθ
~, preservatives selected from methylparaben and propylparaben, singly or in combination, containing two and enough water to make the total amount /ml, 00~θ0θ2M
PL was maintained at approximately 3 to 1A2 with acetate buffer. Claims (1), (2), (5)
, (6) or (7). 01) Per final solution/ml, vinblastine sulfate approx.
, mannitol lθθ~, methylparaben/3~ and propylparaben θ2~
The formulation described. a-bu Final solution/per ml, about 1q of vindesine sulfate
. Mannitol or lactose/θ~lθθ~. Preservatives selected from methylparaben and propylparaben, singly or together, from l to 2■ and the total amount to lπ
1 of water to maintain the pH at approximately 3θ to 3O. Claims (1) and (2). The formulation described in (5), (6) or (7). 0. Approximately pinchin sulfate/ml per final solution/ml. Contains mannitol lθθ~, methylparaben/3~ and propylparaben 02~, and has a pH of about 3.2~
I kept it at 3g. The formulation according to claim 02.