HK1016889B - Oral gel capsule formulation of 1,2,4-benzotriazine oxides - Google Patents

Description

Oral gel capsule formulation of 1, 2, 4-benzotriazine oxide

Background

Technical Field

The present invention relates to the field of cancer therapy. More particularly, the invention relates to the treatment of cancer with 1, 2, 4-benzotriazine oxide in an orally administered encapsulating suspension.

Progress of the report

Encapsulated suspensions and solutions as pharmaceutical carriers are known in the art. For example, U.S. patent No.4,701,327 discloses an etoposide soft capsule consisting of a soft gelatin shell in which an etoposide solution is wrapped; european patent specification publication No.0341,584B1 discloses a soft capsule formulation comprising sodium pyrifenoxasulfone in a polyethylene glycol solution; while British patent application No.2,229,094 discloses gelatin capsules consisting of fatty acid glycerides and/or mineral oil or liquid paraffin as a carrier for nitrofuranamine.

The liquid fill of soft or hard capsules provides a useful and advantageous means of formulating the drug so that the active can be added in a semi-solid, liquid or paste form. In most of the soft gel capsules provided by the prior art, the main objectives include shelf-life stability and effective absorption properties or bioavailability.

In the field of cancer treatment, rapid and efficient absorption of anticancer drugs is of paramount importance, so dosage/timing regimens are established for successful cancer cell challenge. For example, when preparing to increase the toxicity of a chemotherapeutic agent to a solid cancer tumor, a cytotoxicity-enhancing compound is administered to the patient, and the chemotherapeutic agent is administered over a subsequent time period to provide a synergistic effect. The rapid and complete absorption of these two drugs allows the physician to set the time interval between dosing for maximum efficacy. Parenteral administration is the most common for antineoplastic drugs. However, such administration is painful, inconvenient and costly to administer by a physician. In the treatment of cancer, the oral route of administration would eliminate this disadvantage.

It is an object of the present invention to provide capsules of 1, 2, 4-benzotriazine oxide formulations from which 1, 2, 4-benzotriazine oxide is rapidly and completely absorbed when the capsules are administered to a patient. Furthermore, the formulation is stable during storage.

1, 2, 4-benzotriazine oxides are known compounds. U.S. Pat. No.3,980,779 discloses 3-amino-1, 2, 4-benzotriazine-1, 4-dioxide compositions of the formulaAntibiotic composition for livestock growth

Wherein:

r and R¹One of which is hydrogen, halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl, sulfonamido. Carboxy or carbonyl lower alkoxy, and R¹Is halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl, sulfonamido, carboxy or carbonyl lower alkoxy.

U.S. patent 5,175,287 issued on 29.12.1992 discloses the use of 1, 2, 4-benzotriazine oxides in conjunction with radiation to treat tumors. 1, 2, 4-benzotriazine oxide sensitizes tumor cells to radiation, making them more suitable for this treatment modality.

Hall (Holden) et al (1992) in "enhancing the Activity of alkylating agents with SR-4233 in FSaIIC murine fibrosarcoma" (vector JNCI 84: 187-193) disclose the use of SR-4233, i.e., 3-amino-1, 2, 4-benzotriazine-1, 4-oxide, also known and sometimes referred to hereinafter as Tirapazamine, together with an anti-tumor alkylating agent. Cisplatin, cyclophosphamide, carmustine, and chloramphetamine four antitumor alkylating agents were each tested to examine the activity of Tirapazamine against hypoxic tumor cells in resisting the tolerance of antitumor alkylating agents. Tirapazamine was tested alone and in synergy with various amounts of anti-tumor alkylating agents. When SR-4233 was administered prior to treatment with a single dose of cyclophosphamide, carmustine or melphalan, a significant dose potentiation was observed which resulted in a synergistic cytotoxic effect on tumor cells.

International application No. pct/US89/01037 discloses 1, 2, 4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. Other related patents include: U.S. patents 3,868,372 and 4,001,410, which disclose methods for preparing 1, 2, 4-benzotriazine oxides, and U.S. patents 3,991,189 and 3,957,799, which disclose 1, 2, 4-benzotriazine oxide derivatives.

Summary of The Invention

The present invention provides a capsule preparation comprising a mixture of a compound of the formula (I) or a pharmaceutically acceptable salt of said compound, with an essential coconut oil preparation or a soybean oil preparation as a carrier

Wherein X is hydrogen, (1-4 carbon) hydrocarbyl, OH, NH₂NHR or NRR substituted (1-4 carbon) hydrocarbyl, halogen, hydroxy, (1-4 carbon) alkoxy, NH₂NHR or NRR where R is independently selected from (1-4 carbon) lower alkyl and (1-4 carbon) lower acyl, and substituted with hydroxy, NH₂Secondary and secondary ((1-4 carbon) alkyl) amino, (1-4 carbon) alkoxy or halogen-substituted (1-4 carbon) lower alkyl and (1-4 carbon) lower acyl; when X is NRR, two R together form a morpholine ring, a pyrrolidine ring or a piperidine ring, either directly or through an oxygen bridge;

n is 0 or 1; and

Y¹and Y²Independently H, nitro, halogen, (1-14 carbon) hydrocarbyl [ including cyclic and unsaturated hydrocarbyl, optionally substituted with one or two groups selected from halogen, hydroxy, epoxy, (1-4 carbon) alkoxy, (1-4 carbon) alkylthio, primary amino (NH)₂) (1-4 carbon) alkyl secondary amino, di ((1-4 carbon) alkyl) tertiary amino in which two alkyl groups are connected together to form a morpholine ring, a pyrrolidine ring or a piperidine ring, (1-4 carbon) acyloxy, (1-4 carbon) acylamino and thio analogs thereof, (1-4 carbon) acetamidoalkyl, carboxyl, (1-4 carbon) alkoxycarbonyl, carbamoyl, (1-4 carbon) alkylcarbamoyl, (1-4 carbon) alkylsulfonyl or (1-4 carbon) alkylphosphoryl]Wherein the hydrocarbon group may be optionally inserted with a single ether bond (-O-); or Y1 and Y2 may also be independently morpholino, pyrrolidinyl, piperidinyl, NH2, NHR ', NR ' R ' O (CO) R ', NH (CO) R ', O (SO) R ' or O (POR ') R ', wherein R ' is optionally hydroxylatedA group, an amino group, a (1-4 carbon) alkyl secondary amino group, a di ((1-4 carbon) alkyl) tertiary amino group, a morpholino group, a pyrrolidinyl group, a piperidinyl group, a (1-4 carbon) alkoxy group, or a halogen-substituted (1-4 carbon) hydrocarbon group.

The preferred compound for use in the present invention is 3-amino-1, 2, 4-benzotriazine oxide (Tirapazamine).

The present invention also relates to a method of treating cancer, the method comprising: administering to a mammal in need of such treatment an effective amount of an oral formulation as defined herein.

The oral formulation is contained in soft or hard gelatin capsules. The total weight content of the capsule is 200-2000 mg, and the capsule comprises:

5-50% (w/w) of a compound of formula (I);

50-95% (w/w) oily vehicle of refined coconut oil or soybean oil;

0 to 30% (w/w), preferably 10 to 20% (w/w), of a single or mixed viscosity modifier, examples of which are hydrogenated vegetable oil, yellow wax and glyceryl monostearate; and

0 to 10% (w/w), preferably 2 to 8% (w/w), of a single or mixed pharmaceutically acceptable surfactant, examples of which are sorbitan monolaurate, polysorbates 20, 40, 60 and 80, lecithin and Potoxamers 124, 188, 237, 338 and 407.

Preferably, the anti-cancer tumor compound is present in an amount of about 10% to about 25% (w/w) of the formulation, and the oleaginous excipient is present in an amount of about 60% to about 80% (w/w) of the formulation.

Detailed description of the invention

Antitumor agent

The present invention provides compositions and methods for treating mammalian, including human, cancers, particularly solid cancers. In this aspect of the invention, an effective amount of a compound of formula (I) as defined herein is administered in a soft gel capsule about half an hour to about 24 hours prior to the administration of an effective amount of a cancer-sensitive chemotherapeutic agent to a mammal in need of such treatment. The testing of compounds of formula (I) and (la) is described in U.S. patent application Ser. No.125,609, filed 9/22 1993, the contents of which are incorporated herein by reference in their entirety.

As used herein, the sensitivity of a tumor to a chemotherapeutic agent is considered to be the therapeutic effect that a chemotherapeutic agent can exert by any mechanism, such as killing tumor cells, reducing cell proliferation, or reducing tumor size. Also as used herein, an effective amount of a compound of formula (I) as defined herein refers to an amount that is capable of killing tumor cells or is capable of killing tumor cells in conjunction with a chemotherapeutic agent. An effective amount of a chemotherapeutic agent refers to an amount of a chemotherapeutic agent that is capable of killing cancer cells or producing an otherwise therapeutic effect, such as reducing the size of a tumor or slowing the growth and proliferation of tumor cells.

Gel capsule carrier of antineoplastic agent

In preparing the softgel capsules of the present invention, extensive research has been conducted to provide characteristics of softgel capsules that will give the same stability and rapid absorption. Suitable carriers include:

refined coconut oil

Peanut oil

Soybean oil

PEG400

The initial preparation was carried out as follows:

1.0g of Tirapazine was added to each of 9.0g of the carriers and placed in a glass vial with a screw top for evaluation of physical and chemical stability.

Physical stability drug/carrier mixture (in glass

5mL in a bottle) was run at a temperature per 24 hours

Circulating at 5-40 deg.C, at 0,

1. Particle size monitoring was performed at 2 and 4 weeks.

Chemical stability drug/carrier mixture (in glass frit)

5mL in a bottle) was stored at 70 ℃ for 4 weeks, and

physical stability (increased particle size)

Test with little or no change

Samples were analyzed for chemical stability.

Physical/chemical studies showed that refined coconut oil and soybean oil would be suitable for further experiments, while peanut oil and PEG400 were found to be unacceptable. The chemical stability data are shown in table 1. Thus, surfactant-containing refined coconut oil and soybean oil formulations (examples 1 and 2) were prepared using the theoretically determined effective pharmaceutical amounts:

1. the required amount of drug is weighed.

2. The oil and emulsifier mixture is added to the drug.

3. Melting the mixed fat (20% yellow wax + 80% w/w hydrogenated vegetable) at about 40 deg.C

Oil) and added to step 2.

4. The mixture was homogenized in an Ultra Turrax homogenizer for 3x1 minutes.

Table I: total percent heterogeneity (ETI) by weight determination of Tirapazamine/support using liquid chromatography after 6 weeks at 70 deg.C

70 deg.C/4 weeks
	Carrier initiation A B
Refined coconut oil 0.300.260.21 peanut oil 0.241.921.94 Soybean oil 0.271.911.90 PEG 4000.2419.1119.13

Example 1

Tirapazamine 50mg

Refined coconut oil 269mg

Sorbitan monolaurate 13mg

Yellow wax 25.8mg

Hydrogenated vegetable oil 103.2mg

A total of 441mg

Example 2

Tirapazamine ng

Soybean oil 245mg

Lecithin 5mg

Yellow wax 25.2mg

Hydrogenated vegetable oil 101.8mg

A total of 427mg the particle size and chemical analysis of formulation examples 1 and 2 were performed and the results are listed in tables II and III.

Table II: formulation examples 1 and 2 were stored at 70 ℃ for 4 weeks to determine the mean particle size (. mu.m) by laser diffraction

Particle size of μm

Time points (weeks) example 4 example 5

0 90.8 143.1

1 113.2 120.2

2 133.9 147.1

4 136.7 149.7

Both formulations were stable against ETI at 5 ℃/40 ℃ cycle for 4 weeks.

Table III: the percentage of total heterogeneity (ETI) determined by liquid chromatography after storage at a temperature cycle of between 70 ℃ and 5 ℃/40 ℃ for formulations example 1 and example 2 after 4 weeks

70 5-40℃

Formulation initial 4 weeks

Example 10.273.410.15

Example 20.203.110.16

There was no significant change in the drug particle size within 4 weeks, either with the refined coconut oil or the soybean oil formulation. Although significant degradation was observed after 70 ℃/4 weeks. Both formulations were chemically stable when stored at 5 ℃/40 ℃.

The prepared capsules had a target fill weight of 280mg (+/-10%), so formulation examples 1 and 2 had to be adjusted. The resulting formulations are shown in examples 3 and 4.

Example 3

Tirapazamine 50mg

Refined coconut oil 175.9mg

Sorbitan monolaurate 9.30mg

Yellow wax 8.96mg

Hydrogenated vegetable oil 35.84mg

A total of 280mg

Example 4

Tirapazamine 50mg

Soybean oil 178.5mg

Lecithin 3.68mg

Yellow wax 7.56mg

Hydrogenated vegetable oil 30.26mg

A total of 270mg

The chemical analyses of formulation examples 3 and 4 were carried out over a period of 17 weeks, and under different storage conditions. The results are shown in Table IV.

Table IV: formulations of Tirapazamine examples 3 and 4 were tested for percent estimated Total heterogeneity (ETI) by liquid chromatography after 17 weeks of storage

ETI results of refined coconut oil formulations after 17 weeks of storage

Initially: 0.41

1 week, 4 weeks, 17 weeks

Condition A B A B A B

5℃ 0.28 0.32

30℃ 0.37 0.27 0.38 0.22 0.50 0.47

30℃/75％ 0.22 0.18 0.24 0.32 0.46 0.49

RH

40℃ 0.21 0.25 0.38 0.48 1.15 2.87

ETI results for Soybean oil formulations after 17 weeks of storage

Initially: 2.39

17 weeks

Condition A B

30℃ 0.94 1.02

30℃/75％RH 0.84 0.74

40℃ 4.52 4.06

A and B represent duplicate analysis

Both formulation examples 3 and 4 showed significant degradation after 17 weeks at 40 ℃. The example of the soybean oil formulation showed some degradation at 30 ℃ while the formulation of refined coconut oil did not.

The preferred formulation and physical/chemical stability of the unit dose/mg is shown in formulation example 5.

Example 5

Tirapazamine 50mg

Refined coconut oil 175.9mg

Sorbitan monolaurate 9.26mg

Hydrogenated vegetable oil 37mg

Yellow wax 7.4mg

A total of 280mg

Formulation example 5 was manufactured on a 2.1Kg scale. The hydrogenated vegetable oil and yellow wax were weighed into a container. The vessel was heated and the contents were stirred until molten. The essential coconut oil and sorbitan monolaurate are mixed thoroughly and then added to the molten hydrogenated vegetable oil/yellow wax mixture. The resulting mixture was warmed and stirred until a homogeneous mixture was obtained. The Tirapazamine was then added to the mixture with stirring. The resulting suspension was homogenized.

Formulation example 5 showed good physical properties for filling capsules. This paste exhibited good shear thinning flow characteristics and did not separate after 18 hours of standing. It was found that this formulation could be processed on a soft gelatin capsule filling machine. Table V shows the "on-line" data taken during the manufacture of a 2.1Kg batch of formulation example 5. Table VI shows the "on-line" data taken during the filling of this suspension into soft gelatin capsules.

Table V: on-line analysis (detection by UV) in the preparation of Tirapazamine Soft gelatin Capsule suspensions

Sample points Mg/280% of the claims%

50mg/280mg

Roof 47.6295.24

46.71 93.42

Bottom 48.2296.44

48.65 97.30

Middle 47.8095.60

Table VI: analysis of on-line samples taken while filling softgel capsules

The liquid chromatography tests were carried out on the capsules taken at the beginning, at the middle and at the end of the filling (average of 5 capsules)

% relative standard deviation of Mg/Capsule theoretical value at sample point

Start 50.12100.22.18

Middle 50.67101.30.70

End 48.7797.50.98

Uniformity of weight of capsules (average of 5 capsules) taken at the beginning, middle and end of filling

Sample point mg range/mg

Onset 284.97278.09-288.19

Middle 286.09285.14-286.87

Tail 282.03278.71-284.41

The invention has been described with reference to preferred embodiments, it being understood that any variation within the scope of the invention will be apparent to those skilled in the art.

Claims (9)

1. A gelatin capsule comprises the following components in a total content weight of 200-2000 mg encapsulated in a gelatin shell:

5-50% (w/w) of an anticancer compound of the formula or a pharmaceutically acceptable salt of said compound

Wherein X is hydrogen; C1-C4 hydrocarbyl; OH, NH₂NHR or NRR substituted C1-C4 hydrocarbyl; halogen; a hydroxyl group; C1-C4 alkoxy; NH (NH)₂(ii) a NHR or NRR where R is independently selected from the group consisting of C1-C4 lower alkyl and C1-C4 lower acylAnd by hydroxy, NH₂Secondary and secondary amino groups of C1-C4 alkyl groups, and tertiary di (C1-C4 alkyl) amino groups, C1-C4 alkoxy groups, or halogen-substituted C1-C4 lower alkyl groups and C1-C4 lower acyl groups; when X is NRR, two R together form a morpholine ring, a pyrrolidine ring or a piperidine ring, either directly or through an oxygen bridge;

n is 0 or 1; and

Y¹and Y²Independently H, nitro, halogen, C1-C14 hydrocarbyl groups including cyclic hydrocarbons and unsaturated hydrocarbons, optionally substituted with one or two substituents selected from halogen, hydroxy, epoxy, C1-C4 alkoxy, C1-C4 alkylthio, primary amino, C1-C4 alkyl secondary amino, di (C1-C4 alkyl) tertiary amino, di (C1-C4 alkyl) tertiary amino in which two alkyl groups are linked together to form a morpholine ring, a pyrrolidine ring or a piperidine ring, C1-C4 acyloxy, C1-C4 acylamino and thio analogues thereof, C1-C4 acetamidoalkyl, carboxy, C1-C4 alkoxycarbonyl, carbamoyl, C1-C4 alkylcarbamoyl, C1-C4 alkylsulfonyl or C1-C4 alkylphosphoryl, wherein the hydrocarbyl group may optionally be interrupted by a single ether linkage; or Y1 and Y2 can also be, independently, morpholino, pyrrolidinyl, piperidinyl, NH₂NHR ', NR ' R ' O (CO) R ', NH (CO) R ', O (SO) R ' or O (POR ') R ', wherein R ' is a C1-C4 hydrocarbon group which may be substituted by hydroxy, amino, C1-C4 alkyl secondary amino, di (C1-C4 alkyl) tertiary amino, morpholinyl, pyrrolidinyl, piperidinyl, C1-C4 alkoxy or halogen;

50-95% (w/w) of an oily vehicle selected from soybean oil and refined coconut oil;

0-30% (w/w) of viscosity modifier;

0-10% (w/w) of a pharmaceutically acceptable surfactant.

2. The gelatin capsule of claim 1, wherein the anticancer tumor compound is 3-amino-1, 2, 4-benzotriazine oxide.

3. The gelatin capsule of claim 1, wherein said anticancer tumor compound is present in an amount of 10% to 25% (w/w) of said formulation.

4. The gelatin capsule of claim 1, wherein said oleaginous excipient comprises 60% to 80% (w/w) of said formulation.

5. The gelatin capsule of claim 1, wherein said viscosity modifying agent is selected from the group consisting of hydrogenated vegetable oils and beeswax and glyceryl monostearate.

6. The gelatin capsule of claim 1 wherein said pharmaceutically acceptable surfactant is selected from the group consisting of sorbitan monolaurate and lecithin.

7. The gelatin capsule of claim 1, wherein said viscosity modifying agent is present in an amount of 10% to 20% (w/w) of said formulation.

8. The gelatin capsule of claim 1, wherein said surfactant is present in an amount of 2% to 8% (w/w) of said formulation.

9. The gelatin capsule of claim 1, wherein said gelatin capsule is a soft gelatin capsule.