JPH08301762A - Agent for treatment of lung cancer - Google Patents

Abstract

PURPOSE: To obtain an agent for the treatment of lung cancer, containing a camptothecin compound or its salt as an active component and capable of selectively accumulating the active component at the morbid region of the lung in high concentration and decreasing the migration to the normal tissue to remarkably lower the side effects. CONSTITUTION: This agent contains a camptothecin compound or its salt (preferably camptothecin or camptothecin Na salt) as an active component. The administration dose of the active component is preferably 0.5-5mg per dose for camptothecin Na salt. The objective agent is used as a pharmaceutical composition containing the camptothecin compound or its salt as the sole component or in combination with a carrier and applied in the form of inhalation powder or inhalation liquid. The particle diameter of the camptothecin compound or its salt and the carrier is preferably 0.5-5μm each in the case of inhalation powder. The inhalation liquid is preferably administered by using a nebulizer for the treatment of asthma under a condition to generate liquid droplets having particle diameter of 0.5-5μm.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel therapeutic agent for lung cancer. More specifically, it relates to a novel lung cancer therapeutic agent for intrapulmonary administration containing captothecins as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Camptothecin, a natural cytotoxic alkaloid, is a topoisomerase I inhibitor and a potent antitumor agent. This is described by Wall et al. (J. Am. Chem. S.
oc., 88, 3888, (1966)), the Chinese plant Camptoteca acumi
nata) leaf and bark.

Camptothecin has been shown to be effective in the treatment of solid tumors (eg Chem. Rev., 23 ,.
385 (1973) and Cancer. Treat. Rep., 6
0, 1007 (1967)). However, as a result of a phase II clinical trial conducted in the United States, in addition to having no remarkable therapeutic effect, myelosuppression and hemorrhagic cystitis frequently occur as side effects, and development as a drug has been discontinued. In addition, this product is extremely insoluble in water as a basic physical property,
Significant formulation and clinical use constraints (PM Mug
gia et al., Cancer Chemother. Rep., 56,515
(1972) and CR Hutchinson, Tetrahedron,
37, 1047 (1981)).

Various modified camptothecins or derivatives have been provided for the purpose of improving water solubility, reducing side effects, and enhancing activity (for example, JP-A-56-158786,
US Pat. No. 4,399,282, US Pat.
73,672 specification). As an example, irinotecan hydrochloride has improved water solubility and can be administered by a parenteral route. Further, its metabolite has an activity equal to or higher than that of camptothecin, and is effective for solid cancers such as colon cancer and lung cancer. In particular, the response rate for non-small cell lung cancer, for which there has been no effective drug until now, is as high as 30%. However, as for side effects, although hemorrhagic cystitis, which is a side effect of camptothecin, does not appear, severe leukopenia, diarrhea, etc. appear at a high rate as a single agent, and its clinical use is extremely limited.

[0005]

As described above, although the effectiveness of camptothecins against solid tumors including lung cancer has been clarified, the frequency of serious side effects such as leukopenia is high and overcome. The current situation is that an appropriate drug delivery system that does not provide is not provided.

That is, an object of the present invention is to provide a therapeutic agent for lung cancer which contains camptothecins or salts thereof as an active ingredient and has few side effects.

Further, the object of the present invention is to selectively present a high concentration of camptothecins or salts thereof in lung tissue which is a disease site, and to reduce migration to other tissues which are not disease sites. Another object of the present invention is to provide a novel therapeutic agent for lung cancer containing camptothecin or a salt thereof as an active ingredient, which has extremely reduced side effects.

[0008]

Means for Solving the Problems As a result of intensive studies in view of the above circumstances, the present inventors have found that when a camptocin is administered to the pulmonary airways to achieve a high concentration and a high dose only in the lung local area where lung cancer occurs. The present inventors have found that a relatively low dose exerts a drug effect on lung cancer, and in this case, the side effect of leukopenia and the like is suppressed, and the present invention was reached.

That is, the present invention is a lung cancer therapeutic agent for pulmonary administration, which comprises camptothecins or salts thereof as an active ingredient. Among them, the present invention is a therapeutic agent for lung cancer for pulmonary administration, which comprises a camptothecin or a salt thereof and a pharmaceutically inert carrier as a pharmaceutical composition, and the camptothecin or a salt thereof is an active ingredient.

Conventionally, intravenous administration, oral administration and the like are known as administration routes for camptothecins or salts thereof.
Surprisingly, no administration into the respiratory tract is known.

As the camptothecins used in the present invention, there are known camptothecins such as camptothecin, 10-hydroxycamptothecin, topotecan, irinotecan and the like, which are known in the prior art such as JP-A-56-158786, and modified forms thereof. Examples thereof include derivatives thereof and salts thereof.

The camptothecin salts of the present invention include:
Examples thereof include camptothecin sodium salt, alkali metal salts such as irinotecan hydrochloride, organic acid salts, inorganic acid salts and the like.

Of the above-mentioned compounds, the camptothecins and salts thereof of the present invention are preferably camptothecin, camptothecin sodium salt, topotecan, and irinotecan hydrochloride, and more preferably camptothecin and camptothecin sodium salt. These camptothecins of the present invention or salts thereof are conventionally known substances, for example,
Irinotecan can be produced by the method described in JP-A-56-158786.

The amount of camptothecins or salts thereof used in the present invention varies depending on the activity of each camptothecin derivative, and cannot be generally stated. It is effective for lung cancer by intrapulmonary administration and is effective from lung tissue. This is a so-called therapeutically effective amount that does not cause serious side effects such as leukopenia due to absorption. As an example, the single dose of camptothecin sodium salt is 0.1-10 mg, more preferably 0.5-5 mg.

The therapeutic agent for lung cancer for pulmonary administration of the present invention containing camptothecin or a salt thereof as an active ingredient is in the form of an inhalable powder or inhalant solution of camptothecin or a salt thereof as an active ingredient, or camptothecin. As a pharmaceutical composition comprising a salt or a salt thereof and a pharmaceutically inert carrier, it is administered into the respiratory tract, for example, in the form of inhalation powder or inhalation liquid.

The inhalable powder in such a case means a camptothecin or its salt as an active ingredient and a pharmaceutically inert carrier such as a base having a dispersion assisting function and / or a diluting function and / or a sustained release function. It shows a form in which it is dispersed in the air by a mixture with or a propellant such as gas or a propellant.

Specific examples of the former base include, for example, water-soluble monosaccharides or oligosaccharides or polysaccharides such as mannitol, lactose and dextran; gel formation such as hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Water-soluble or water-insoluble celluloses such as crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, and derivatives thereof; for example, hydroxypropyl starch, carboxymethyl starch, crosslinked starch , Amylose, amylopectin,
Water-absorbing and poorly water-soluble polysaccharides such as pectin and derivatives thereof; eg gum arabic, tragacanth gum,
Water-absorbing and sparingly water-soluble gums such as glycomannan and derivatives thereof; for example, polyvinylpyrrolidone, crosslinked polyacrylic acid and its salts, crosslinked polyvinyl alcohol, crosslinked vinyl polymers such as polyhydroxyethylmethacrylate and their derivatives. Examples thereof include biodegradable polymers such as polylactic acid, polyglycolic acid, albumin, gelatin, and collagen; and lipid sugars that form molecular aggregates such as liposomes such as phospholipids and cholesterol.

Here, examples of the base having a dispersion assisting function include mannitol, lactose, glucose, dextran and the like, and examples of the base having a diluting function include mannitol, lactose, glucose, dextran and the like. Examples of the base having a sustained release function include polylactic acid, polyglycolic acid, albumin, gelatin, collagen and the like.

Examples of the propellant and propellant include chlorofluorocarbons, hydrofluorocarbons, hydrocarbons, dimethyl ether, nitrogen gas and the like.

The inhalation powder containing the camptothecins or salts thereof of the present invention as an active ingredient may be, for example, in a form in which a single dose is filled in a capsule or the like and the contents are taken out at the time of use. It may be in the form of multidose to be dispensed / administered. Both can be administered by a powder inhaler in which the active ingredient camptothecin or its salt is dispersed in the air by inhalation. In addition, soybean lecithin, sorbitan trioleate, and other surfactants are mixed in an appropriate amount, and suspended in an aerosol propellant such as CFC and a propellant, whereby a camptothecin or a salt thereof is dispersed in the air in a quantitative spray formula ( It can also be administered by powder) inhaler.

The camptothecins or salts thereof of the present invention preferably have a particle size smaller than 10 μm, which enables pulmonary administration. More preferably, the particle size is 0.5 to 5 μm. The most important factor for delivering a drug to the lungs is the particle size. Usually, particles of 10 μm or more are trapped and deposited in the oral cavity and nasal cavity, so 0.5 is required for deposition from the bronchi into the lungs. It is desirable that it is ˜5 μm.

The inhalation powder containing camptothecins or salts thereof of the present invention as an active ingredient is used for preventing aggregation of particles between capsules and inhalers (dispersion assisting function), or filling a small amount of camptothecins or salts thereof in capsules, etc. In order to prevent the weight deviation from increasing in the process of (dilution function),
It can be used as a mixture with a base such as mannitol.
At this time, the particles serving as a base preferably have a size of 30 to 150 μm, and the mixing ratio with camptothecins or salts thereof is determined by the required amount of the drug. The mixing of camptothecins or salts thereof with these bases can be carried out by a container rotating type or mechanical stirring type mixing machine. In addition, a lubricant and the like can be mixed to improve dispersibility and container adhesion.

The base having a sustained release function preferably has a particle size of 0.5 to 5 μm so that the base particles are deposited in the lungs from the bronchi together with the active ingredient camptothecins or salts thereof. Furthermore, it is desirable that the active ingredient camptothecin or a salt thereof and a base material having a sustained release function are complexed.

The term "composite of the camptothecins or salts thereof of the present invention with a base having a sustained-release function" means that the camptothecins or salts thereof are dispersed or dissolved in the base. In particular, in the case of powder, a state in which a base and camptothecin or a salt thereof are present in a certain ratio in one particle, and the camptothecin or a salt thereof is dispersed or dissolved in the base. Say.
Particles in which camptothecins or salts thereof and a base having a sustained release function are complexed can be produced by, for example, a spray drying method.

Furthermore, although we have disclosed fine particles for inhalation containing specific cellulose lower alkyl ethers and a drug and a method for producing the same (WO93 / 25198), those techniques are also inhalation powders of the present invention. It can also be applied as.

The inhalation liquid refers to a form in which camptothecin or its salt as an active ingredient is solubilized or suspended in water alone or with an appropriate additive, and is dispersed in the air as droplets by using a nebulizer or the like. . In addition to camptothecins or salts thereof, surfactants, preservatives, stabilizers, odorants, buffers, isotonic agents and the like may be added to the liquid preparation. Therefore, the camptothecins of the present invention are conventionally known methods for producing fat emulsions (for example, WO89 / 02265).
No.) in the form of lipid microspheres in an aqueous medium.

Examples of such a surfactant include nonionic, cationic and anionic surfactants such as soybean lecithin, sorbitan trioleate and polysorbate 80. That is, as the additive, specifically, as the surfactant, for example, sorbitan trioleate, polysorbate 80 and the like; as the preservative,
For example, quaternary ammonium compounds such as benzalkonium chloride, paraoxybenzoic acid esters, phenol, chlorobutanol and the like; preservatives such as menthol and citrus flavors; buffering agents such as phosphates and citrates. Acid salts, acetates and the like; isotonic agents include, for example, salt, grape and the like.

The inhalation liquid of the camptothecins or salts thereof of the present invention usually has a particle diameter of 0.5 to 5.0.
It is desirable to administer using a nebulizer for treating asthma as small as about μm.

[0029]

The present invention will be described in detail below with reference to examples.
It is provided to illustrate the present invention, but not to limit the present invention.

Example 1 <0.2 mg / 5 mg / capsule DPI (inhalation powder)
> 2.0 g of camptothecin sodium salt finely pulverized to have a particle size of 0.5 to 5.0 μm is uniformly mixed with 50 g of Japanese Pharmacopoeia lactose (particle size 37 to 140 μm: 100 to 400 mesh) and hardened. Filled into capsules. This gave 10,000 capsules of the formulation, corresponding to 0.2 mg / 5 mg / 1 capsule. The capsule can be punctured using a powder inhaler so that the capsule contents can be inhaled.

[Example 2] <0.2 mg / 250 μl / 1 injection MDI (inhalation CFC preparation)> Finely pulverized to a particle size of 0.5 to 5.0 μm
m camptothecin sodium salt (600 mg), sorbitan triolate (4.0 g) and Freon (Freo)
n (registered trademark 11) (300 g) was mixed at about 10 ° C. and suspended so as not to agglomerate. The suspension thus obtained is subsequently added to 1.36 kg of a safe jet mixture (Freon® 11, 114) at a temperature of −50 ° C.,
The mixture was homogenized. While still cooling, it was filled in an aluminum can and immediately sealed with a fixed amount of a valve. This allows
100 cans of 300 injections of 0.2 mg / 250 μl / 1 injection were obtained.

[Example 3] <0.2 mg / 2 μl of inhalation liquid> 50 g of camptothecin sodium salt, 15 g of egg yolk lecithin, and 120 g of soybean oil
Was added and dissolved by heating with stirring at 40 to 75 ° C. To this, 900 ml of distilled water for injection was added, and then 24 g of glycerin in the Japanese Pharmacopoeia was added to make 1,000 ml with distilled water for injection at 20 to 40 ° C., and the mixture was roughly emulsified with a homomixer. Using a Menton-Gaurin type homogenizer, this was 120 kg / cm ^{2 in} the first stage and the total pressure was 500 kg /
cm ² under pressure, pass 10 times, emulsify into lipid microspheres and finally p with sodium hydroxide.
H was adjusted to 5-7. An injection ampoule was filled with 2.0 ml of each under nitrogen to prepare a liquid agent for inhalation. As a result, 500 inhalation solutions corresponding to 0.2 mg / 2 mg of camptothecin sodium salt were obtained.

Example 4 In Vivo Antitumor Activity in Lewis Lung Cancer Transplanted Mice
A 7-week-old C57BL / 6 mouse (male) was subcutaneously injected with 10 ⁶ viable Lewis lung cancer cell suspension to prepare a lung cancer model mouse. After intraperitoneal administration of camptothecin sodium salt (camptothecin Na salt) (first group) and inhalation administration group of camptothecin sodium salt (second group) by the preparation of Example 1, after subcutaneously transplanting Lewis lung cancer,
It was administered on days 1, 5, and 9. Tumor weight was measured after 21 days.

The drug was administered in three doses with a total dose of 0, 50,
Each dose was approximately averaged to give 100, 200, and 400 mg / kg. Six mice were used per dose for each dose group. The first group was prepared by dissolving camptothecin sodium salt in physiological saline at a dose. In the second group, camptothecin sodium salt was finely pulverized and used as a powder having a particle diameter of 0.5 to 5 μm. In addition, in the administration of the second group, particles of camptothecin sodium salt were aerosolized and inhaled in a predetermined amount.

The results were evaluated as follows. The tumor weight represents the average tumor weight of each dose group as a percentage based on the average tumor weight of the 0 mg / kg administration group after 21 days in each group, and the value is 75 to 10
0% is 0 point, 50-74% is 1 point, 25-49% is 2 points
A score of 0 to 24% was scored as 3 points. In addition, the number of deaths as an index of toxicity, when 3 or more out of 6 died, x,
The case where 2 or less of 6 died is represented by ◯. The results are shown in Table 1.

[0036]

[Table 1]

From these results, it is understood that the camptothecin sodium salt inhalation administration group is more effective in reducing the tumor weight of Lewis transplanted lung cancer tumor and the number of deaths due to toxicity is lower than the intraperitoneal administration group of camptothecin sodium salt.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 9/14 A61K 9/72 9/72 9271-4C C07D 491/22 // C07D 491/22 A61K 9/14 L U (72) Inventor Takao Fujii 4-3 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center

Claims (9)

[Claims] 1. A therapeutic agent for lung cancer for pulmonary administration, which comprises camptothecins or salts thereof as an active ingredient. 2. The therapeutic agent for lung cancer for intrapulmonary administration according to claim 1, which is in the form of an inhalation powder or an inhalation liquid. 3. The therapeutic agent for lung cancer for intrapulmonary administration according to claim 1, which is a pharmaceutical composition comprising camptothecin or a salt thereof and a pharmaceutically inactive carrier. 4. The therapeutic agent for lung cancer for intrapulmonary administration according to claim 3, wherein the pharmaceutical composition is in the form of inhalation powder. 5. A camptothecin compound or a salt thereof is 0.
The lung cancer therapeutic agent for intrapulmonary administration according to any one of claims 3 to 4, which is a granular material having a particle diameter of 2 to 5 µm. 6. An inert carrier is a base having a dispersion assisting function and / or a diluting function, and the base is 30 to 15
The lung cancer therapeutic agent for intrapulmonary administration according to any one of claims 3 to 5, which is a granular material having a particle size of 0 µm. 7. The inert carrier is a base material having a sustained release function, and the base material is a granular material having a particle size of 0.5 to 5 μm. A lung cancer therapeutic agent for intrapulmonary administration according to the item. 8. The therapeutic agent for lung cancer for intrapulmonary administration according to claim 3, wherein the pharmaceutical composition is in the form of an inhalation solution. 9. The therapeutic agent for lung cancer for intrapulmonary administration according to claim 8, wherein the inhalation liquid is a solution or suspension in an aqueous medium.