JPS60209516A - Epoxide oral administration composition - 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 Field of the Invention The present invention relates to medicaments with biological effects having glycosidic active ingredients and for the treatment of medicinal diseases (class 4.24,
subclass 180).

Description of the Prior Art Etoposide (etopo, 5jde) is a semisynthetic product derived from podophyllotoxin. The substance has the chemical name 4'-demethylepipodophyllotoxin-9-(
4,6-0(R)-ethyrythene-β-D-gelcopi? Noside). It is VP-1621 in the literature
3, designated as VePesid®, enalidene-lignan P, and EPEG. That's N'5
The National Cancer Institute under C-131540.
It was evaluated for use in the treatment of cancer under the auspices of Institute 1-.

It was recently approved by the Federal Food and Drug Administration for use in the treatment of refractory green cancer, and has also been proposed for use in the treatment of small cell lung cancer.

In a study conducted under the auspices of the National Cancer Institute, the drug was supplied as an injectable solution with the following composition:
Company M; Quen # (anhydrous), 100mg; Hensyl alcohol, 150mg; Borisolhate 80 (purified product)
, 4oomg; polyethylene glycol 300.3.2
5g; alcohol (anhydrous qs), 5.12g. Each ampoule of said composition consisted of 5 ml of solution and was diluted 20-50 times with 0.9% thorium chloride or 5% dextrose for injection before administration by slow intravenous infusion.

When the intravenous composition is administered by ingestion rather than by injection, and the 5 mA ampoule is taken as a teacup dosage form or first diluted with water, the bioavailability by the oral route is lower than by the intravenous route. Approximately 90% of the
ancer chemotherapy and Phar
macology (] 982) 7: 141~
I45).

Excipients include polyethylene glycol 400, glycerin,
A similar drug taken by capsules containing 100 mg of active ingredient in approximately 1.3 ml of an encapsulated solution consisting of water and citric acid demonstrated the bioavailability of the intravenous solution when taken by ingestion. (M, D' Incalci et al., ibid.). The present invention addresses this problem of low bioavailability of capsule dosage forms and provides liquid formulations that are sufficiently concentrated for encapsulation to provide bioavailability on ingestion equivalent to intravenous solutions.

SUMMARY OF THE INVENTION The present invention takes advantage of the discovery that when taurocholic acid is included with etopodi 1-' in a solution dosage composition, it results in significantly improved absorption of the drug after ingestion of the composition. This is thought to be due to the micellar solution of etoposide being diluted by the gastric contents.

In a study of this problem, it was observed that when mixed with water at a ratio of about 10 ml of water per 100 mg of etoposide, the capsule formulation described above readily formed a heavy milky white precipitate. A liquid cuff containing a small amount of taurocholic acid of about the same weight as Etopozi 1.

When included in the cell formulation, the formation of a precipitate is delayed by more than an hour when the formulation is mixed with 10 ml of water. The following table shows this effect of taurocholic acid and other bile acids.

The surface tension of the aqueous dilution of the bile acid formulation shown in the previous table was measured, and it was confirmed that a micellar solution of etoposide was actually formed. This is reflected in the inability of increasing the concentration of taurocholic acid in solution to cause a further decrease in surface tension. The concentration at which no further decrease in surface tension occurs is designated as the critical micelle concentration.

The phenomenon of micellar solubilization of poorly water-soluble drugs mediated by bile acids, including taurocholic acid, has previously been demonstrated in griseofulpine, xestrol, and glutethimit.
mes et al., Journal of Pharmaceu
ticalScience, 55.191-199)
, reserpine (Ma 1one et al., ibid. 55.972~
974 (1966, )), fatty acids and cholesterol (Westergaard et al., Journal of'
clinicalInvestiga, tion, 5
8.97-108 (1,976').

DESCRIPTION OF THE INVENTION The present invention includes a drug solution of a drug that has the unique property of providing a stable apparent solution of the drug upon dilution with 1 to 100 volumes of water. The solution is stable and non-precipitating for at least two hours long enough to permit administration to and absorption by the mammalian organism. The bioavailability of etoposide following oral administration of this dosage form was found to be substantially equivalent to that achieved by intravenous administration of a solution of the drug. Ingestion of this dosage form and its resulting dilution by gastric contents appears to form a micellar solution of etoposide in the stomach, which is more readily absorbed from the gastrointestinal tract. However, applicants do not intend to be bound by any theoretical explanation of the mechanism by which the superior oral bioavailability of this formulation is achieved.

Polyethylene glycol with a molecular weight of 200-400 was chosen as the excipient for this composition.

B1) Ethylene glycol has the necessary solubility capacity for etoposide and exhibits an acceptable viscosity and dispersibility in water that meets the requirements of the present invention. Polyethylene glycol having a molecular weight of 200-300 is preferred because it has a lower viscosity than polyethylene glycol 400. Low viscosity facilitates manufacturing operations and also increases the dispersibility of the composition in mixing with water or stomach contents. Other components of the composition may improve paternity and promote micelle formation when mixed with water, or when the substance is encapsulated in soft gelatin capsules according to a preferred embodiment of the present invention. Useful for improving compatibility with the outer skin.

Preferably, 5 to 9 parts by weight of polyethylene glycol 300 are used per part by weight of etoposide. Within this range, the proportion of solution of etoposide is sufficient to provide convenient manufacturing and a liquid mixture that is convenient enough to handle? The 8-liquid solution reaches a satisfactory concentration overnight (in a volume small enough to allow the unit dosage form to be encapsulated in a soft gelatin capsule). Thinner liquids can of course be manufactured for dropper or teacup dosing, which are also contemplated by the present invention.

It is preferred to micronize the etoposide prior to incorporation into the composition;
- This is of secondary convenience and not essential, as a true 18 liquid of Boll is formed.

Normally, when etoposide is dissolved in a water-soluble (1 m solvent) and the resulting solution is mixed with water, the compound precipitates due to its very low water solubility.According to the present invention, taurocholic acid is included in the composition, and the presence of this component likely results in the formation of micelles when the composition is mixed with water.

Other bile acids similarly promote the formation of apparent micellar solutions in mixing polyethylene glycol solutions with water, but they are known to cause micellar solutions to be unstable and
Or, since micelles are not formed at acidic pH,
Not suitable for use in this composition. Is thorium deoxycholate or thorium cholate acceptable? (it forms, but the micellar solutions have pH 10.9 and pH 11.0, respectively).
Set the H value to h.

Upon acidification, etoposide precipitates from such solutions. They are therefore unsuitable for ingestion due to the acidic nature of the stomach contents. Furthermore, the encapsulation within the soft Seratin capsule shell preferably has an acidic pH since the Piratin shell will be disrupted by the filling solution having a pH value above pH 8.0. Through experimental experience, it has been found that preferably about 3.5 parts by weight of taurocholic acid for each part by weight of etoposide is preferred to provide a stable micellar solution upon dilution of the composition with water. Smaller amounts, such as 2.0 parts by weight, and larger amounts of taurocholic acid can be used. No useful purpose is promoted by using more than about 10 parts by weight of taurocholic acid per part by weight of etoposide.

A water-soluble acid is included in the composition to ensure that an acidic pH value is obtained upon dilution to form a micellar solution.

The use of solid, water-soluble organic carboxylic acids is preferred because of their pharmaceutical quality and ease of handling during manufacturing operations, but other acids may also be used. Preferred are maleic, tartaric, citric, gluconic, or ascorbic acids, which are water-soluble, non-toxic, and convenient to handle in drug manufacturing operations. Citric acid is most preferred and has been found to be suitable when used at 0.1' to 0.5 parts by weight per part by weight of etoposide. The most preferred ratio is 0.2 parts by weight of citric acid per part by weight of etovod.

Ethanol serves an important purpose in the composition of promoting rapid dispersion when mixed with water, facilitating the formation of micellar solutions. Other water-soluble polar organic solvents, such as methanol, propatool, acetone, etc., are also effective but not suitable for ingestion, so ethanol was chosen for this purpose. At least 5% by weight of ethanol in the composition is necessary for this purpose, but higher amounts up to 20% by weight may be used, especially for purposes of dropper or teacup dosage forms.
can be used. Up to 10% by weight of ethanol can be used in the composition for encapsulation within soft dolatin capsules. Solutions with concentrations of ethanol higher than 10% by weight will result in dehydration of the gelatin capsule walls and may therefore be unsuitable for encapsulation with this type of capsule.

Finally, to use this composition in a unit dosage form contained within a soft gelatin capsule, it is necessary to use an etoposite to improve the compatibility of the composition with the soft gelatin capsule shell.
Preferably, each part by weight contains up to about 1 part by weight of water. The hydrophilic nature of polyethylene glycol, ethanol, citric acid and taurocholic acid allows the composition to extract water from the capsule shell, which may be destroyed on prolonged storage. Accordingly, sufficient water is included in the composition to render the composition compatible with the capsule shell and to prevent its dehydration, preferably 1 part water per part by weight of etovod. The capsule is sealed! It is desirable to choose an amount of water which, when stored in P, - gives room quality for a storage period of two years at room temperature.

A preferred embodiment of the invention is a stable liquid composition in the form of a true solution having the following composition: □-min parts by weight polyethylene glycol 300 5-9 engineering I/positive 11 citric acid 0.1-0.5 Qurocol #2.0-10 Ethanol 15-20% by weight of the total solution weight The most preferred embodiment of the present invention is the following composition.

2-iM', -73 parts polyethylene glycol 300 6.8 Etoposide, ultrafine particles 1.0 Citric acid 0.2 Ethanol 1.0 Taurocholic acid 3.5 Water 1.0 The following examples show preferred compositions of the present invention. Construct a description of a thing.

Example The following ingredients were weighed.

Polyethylene glycol 300 110.0g Alcohol, USP 25.0g Taurocholic acid 87.5g Purified water, USP 25.0g Add some taurocholic acid to polyethylene glycol 300 while stirring. Add in portions to form a suspension. Then add water, then alcohol and citric acid. A solution is formed, which is warmed to 65°C, cooled to 35°C and filtered (Millipore A P25 29 325)
. These steps are performed under a nitrogen atmosphere. 3 of the filtrate
The temperature is kept at 0-35°C, and then the etoposide is dissolved therein. Next, the solution was assayed and Etopoposi I'71.3 mg/g.
was observed), each capsule was filled with OOmg of Etoposi 1' into soft gelatin capsules.

The capsule filling solution has the following properties and stability:

Characteristics 1, Color Dark brown 2, pH 4,6 3, Viscosity Satisfactory 4, Dispersibility Easy dispersibility 5, Shell compatibility, Physical compatibility 6, HzO l: 1.1:5, 〉3 hours 1: 10
, and precipitate formation time W at dilution to 1:10o Storage temperature Storage time Survival rate (days) (%) 4°C (control) 8 100 70°C 5 102 70°C 8 102 56°C 8 102 37°C 8 105 25 ℃ 8 99

Claims (9)

[Claims] (1) An orally administered heart containing 1-151 methylene glycol, taurocholic acid, ethanol and 1 volume of water in proportions to form a homogeneous liquid. Compositions of Compatible Pharmaceutical Dosage Forms. (2) The composition of claim 1+ in the form of a 1° dosage unit contained within a homogeneous liquid or soft Seratin capsule. (3) Medication car glossy etoboc I” 10-100 mg
The composition according to claim (2), comprising: (4) To prevent dehydration of the capsule outer shell and to create a homogeneous liquid, hiJ
3. The composition of claim 2, further comprising sufficient water to stabilize the shell in a sealed container at room temperature for a storage period of at least two years. (5) The molecular weight of polyethylene glycol is approximately 200-4
00. (6) The composition according to claim 8'1, wherein the molecular weight of the polyethylene glycol is about 300. (7) The weight of polyethylene Grini I-/Shi is: 1-1
The composition according to item f6+ of claim '11, which is 5 to 9 times the weight of .j'-'1''. (8) Water? The composition of claim fi1, which is a soluble acid or a non-toxic 4-carboxylic acid. (9) Water? Volume 1 raw acid caffein 1y, '1 buttocks'
1. The composition according to item (1) of the scope of the invention. Claim No. 1, wherein 2.0-10 parts by weight of taurocholic acid is used per part by weight of etovone.
Compositions as described in Section. A composition according to claim 1, wherein 3.5 parts by weight of taurocholic acid are used per part by weight of OD. (121) The composition according to claim (1), wherein the amount of ethanol is 5 to 20 kg by weight. A composition in a liquid pharmaceutical dosage form comprising a 5-20M volume % solution of the composition. , the following composition: Ingredients xm, i Polyethylene glycol 300 6.8 etopodi 1-1
The composition according to claim 01, comprising a solution having: ultrafine particles 1.0 citric acid 0.2 ethanol 1.0 taurocholic acid 3.5 water 1.0.