CA1238578A

CA1238578A - Etoposide oral dosage form

Info

Publication number: CA1238578A
Application number: CA000476750A
Authority: CA
Inventors: Ismat Ullah; Selima Begum; Bernard C. Nunning
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 1984-03-19
Filing date: 1985-03-18
Publication date: 1988-06-28
Also published as: JPS60209516A; FI84023C; FR2561104A1; AU571308B2; DK164535C; YU42085A; NL8500739A; FI851040A0; FR2561104B1; ZA851935B; IE850686L; MY101916A; ES541370A0; GB2155789B; FI84023B; IT8519897A0; GB8506943D0; CH662731A5; IL74615A0; AT392904B

Abstract

Abstract of the Disclosure A liquid dosage form suitable for oral administration of etoposide which is sufficiently concentrated to be administrated in capsule form and which provides improved absorption of the drug relative to prior oral formulations.

Description

~ 5~8 Abstract of the Disclosure A liquid dosage form suitable ~or oral administration of etoposide whicb is suf~iciently concentrated to be administrated in capsule form an~ which provides improved absorption of the 5 drug rela~ive to prior oral formulations.

Field of t~e Invention . .
The present invention refers to a drug bio effecting and body treating composition having a glycosidic active ingredient (Class 424, subclass 180~.

Descrip~ion of the Prior Art Etoposide is a semi-synthetic product derived from podophyllotoxin. The material is identified by the chemical name 4'-demethylepipodophyllotoxin-9-(4,6-O(R)-ethylidene-beta-D-gluc-opyranoside). It is referred to in the literature as vP-16-213, VePesidRt Ethylidene-Lignan P, and EPEG. It has been evaluated for use in treatment of cancer under the auspicious of The National Cancer Institute under the number NSC-131540. It ~as recently been approved by the Federal ~ood and Drug Administration for use in the treatment of refractory testicular cancer and has been proposed for use in the treatment of small cell lung cancer.

In investigations conducted under the auspicious of the National Cancer Institute, the drug WAS supplied as a solution for injection having the following composition: etopo~ide, 100 mg; citric acid, anhydrous 10 mg; benzyl alcohol~ 150 mg;
polysorbate 80, puriied, 400 mg; polyethylene glycol 300, 3.25 ~; alcohol, absolute qs 5.12 9. Each ampule of the foregoing composition consis~ed of 5 ml of olution which was diluted 20 to

2.
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~ 85~3 50 times with 0.9~ sodium chloride or 5~ dextrose for injection before administration by slow intravenous infusion.

~hen the foregoing intravenous c~mposition w~s administered by ingestion rather than injection, the 5 ml ampule was either taken as a teaspoon dose ~orm or first diluted with water; it was found that the bioavailability by the oral route was approximately 90~ that by the intravenous route lM.D'Incalci et al., Cancer Chemoterapy and Pharmacology (1982) 7:141-145). A
similar dose taken by capsule in which 100 mg of actIve ingredient was contained in approximately 1.3 ml of encapsulated solution in which the vehicle consisted of polyethylene glycol 400, slycerine, water, and citric acid yielded only about one-balf the bioavailability of the intravenous sol~tion when taken by ingestion (M.D'Incalci et al., loc. cit.). ~be present invention addresses this problem of reduced bioavailabili~y of the capsule dosage form, and provides a liguid formulation of sufficiently high concentration for encapsulation which affords - bioavailability upon ingestion equal to the intravenous solution.

SummarY of the Invention The present invention takes advantage of our discovery that taurocholic acid when included in a solution dosage composition with etoposide results in markedly improved absorption of the drug follPwing ingestion of the composition. It is belived that this is due to the formation of a micellar solution of etoposide on dilution thereof with the gastric contents.

In investigating this problem, we have found that the capsule formulation referred to above when mixed with water in the proportion of about 10 ml of water per 100 mg of etoposide results in the immediate ~ormation of a heavy, milky white precipitate. When as little as an equal weight ~f taurocholic .
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acid relative to the etoposide is included in the liguid capsule formulation, precipitate formation is delayed ~or over an hour on mixing the îormulation with 10 ml of water. The ~ollowing t~bulation illustrates this effect of taurocholic acid and other bile acids.

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~385~l3 Surface tension measurements on the aqueous dilutions of ~he bile acid formulations referred to in the foregoing table have confirmed that, indeed, micellar s~luti~ns of etoposide are produced. This is reflected in tb~ failure for a further decrease in surface tension to occur as the concentration of taurocholic acid in the solution is increased. ~hat concentration where no further ~ecrease in surface tension occurs is referred to as critical micellar concentration.

The phenomenon of micellar solubilization of poorly water-soluble drugs mediated by bile acids, including taurocholic acid, has been previously reportsd with respect to griseofulvin, hexesterol, glutethimide (Bates et al., Journal of Pharmaceutical Sciences, 55, 191-199~, reserpine, Malone et al., ibid. 55, 972-974 (1966), fatty acids, and cholesterol (Westergaard et al., Journal of Clinical Investigation, 58, 97-108 (1976)~;

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DETAILED DESCRIPTION OF THE INVENTION

~ he present invention involves a pharmaceutical solution of etoposide which has the unique property of providing a stable apparent solution of the drug upon dilution thereof with from 1 ~ to 10D volumes ~f water. The solution is stable and fre~ ~
precipitate for a period of at least two hours sufficient to permit administration to and absorption by the mamm~lian organism.
It has been found that the bioavailability of etoposide following Of al administration of the present dosage form is substantially equivalent to that achieved by intravenous administ~ation of a solution of a drug. It is believed that ingestion of the present dosage form and resulting dilution thereof by the stomach contents results in the formation of a micellar solution of etoposide in the stomach which is readily absorbed by the ~astrointestinal ,15 tract. ~pplicants aO not wish to be bound, however, ~y any theoretical explanation of the mechanism by which the superior oral bioavailability of the present formulation is achieved.

Polyethylene glycol having a molecular weight of from 200 to 400 has been chosen as the vehicle for the present composition.
Polyethylene glycol has the necessary solvent capability for etoposide and exhibits acceptable viscosity and dispersibility in water to meet the requirements of the present invention. Poly-ethylene glycol having molecular weight of from 200 to 300 is preferred because i~ is less viscous than polyethylene glycol 400. The lower viscosity facilitates manufacturing manipu-lations, and increases the dispersibility of the composition on mixing with water or gastric contents. Other ingredients of the composition serve to improve dispersibility and to facilitate micelle formation on mixing thereof with water, or to improve compatibility of the solution with the oapsule shell when the ._ . ... ~ ., . , . ;

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' material is encapsulated in a soft gelatin c~psule according to a preferred embodiment of the invention.

From 5 to 9 parts by weight of polyethylene glycol 300 per par~ by weight of etoposide is preferably employed. Within this range the rate of solution of the etoposide is sufficient ~or manufacturing convenience, a sufficiently fluid mixtu~e is obtained for convenient handling,.and the solution is sufficiently concen~rated so tha~ a unit dosage form may be contained in a sufficiently small volume of solution to permit encapsulation within a soft gelatin capsule. More dilute solutions may, of course, be prepared for dropper or teaspoon dosage use. Such is also contemplated by the present invention.

The etoposide is preferably micronized prior to formulation into the present composition, but this is prima~ily a convenience 1~ and not a necessity since a true solution of etoposi~e in the polyethylene glycol is formed. Ordinarily when etoposide is dissolved in a water soluble organic solvent, and the resulting solution mixed with water, the etopocide precipitates because of its very low water solubility. ~ccording to the present invention, taurocholic acid is included in the composition and the presence of this ingredient results, presumably, in the formation of a micellar solution when the composition is mixed with water.

Other bile acids will similarly promote the formation o apparent micellar ~olutions on mixing of the polyethylene glycol solution with water, but they are unsuited for use in the present compositions since the so-produced micellar solutions are unstable or do not form at acid pH. Sodium deoxycholate or sodium cholate form micellar solutions with etoposide, but the micellar solutions have pH values of pH 10.9 and pH 11.0 respectively. ~pon ~cidifi-cation, the etoposide precipitates from such solutions. Such arenot therefor suitable for ingestion due to ~he acidic nature of .. .. ~ , 'I! ,. ~

~Z38~8 .
the gastric contents. Furthermore, for encapsulation within a soft gelatin capsule shell an acidic pH is preferred because the gelatin shell is disrupted by fill-solutions having pH values i~
excess of pH 8. O. It has been found by empirical experimentation that preferably bout 3.5 parts by wei~ht of taurocholic acid per part by weight o etoposide are desirable to provide a stable micellar solution on dilution of the composition with water.
Smaller amounts such as 2.0 parts-by weight, and larger amounts of taurocholic acid may be employed. No useful purpose is served 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 assure th~t an acidic pH value is obtained upon dilution ~o form the micellar solution. For purposes of pharmaceutical elegance and ease of handling in a manufacturing operation, we prefer t~
use a solid water-soluble organic carboxylic acid, but other acids may be employed. We prefer maleic, tartaric, citric, gluconic, or ascorbic acids which are water-soluble, non-toxic and convenient to handle in a pharmaceutical manufacturing operation. Most preferred is citric acid which we have found to be appropriate when used in from 0.1 to 0.5 parts by weight per part by weight of etoposide. The most preferred proportion is 0.2 parts by weight of citric acid per part by weight of etoposide.

Ethanol se~ves the important purpose in the composition o~
promoting rapid dispersion on mixing with water and facilitates formation of the micellar solution. Other water-soluble polar organic solvents such as methanol, propanol, acetone, etc. which are also effective are not suitable for ingestio~ and, accordingly, ethanol has been selected ~or this purpose. At least 5~ by weight of the composition of ethanol is necessary for this purpose, but higher amounts up to 20~ by weight may be used, particularly for purposes of a dropper or teaspoon dosage form.

.9 ~Z38~78 For encapsulation within a soft gelatin capsule, a maximum of 10 by weight ~f etbanol in the composi~ion may be used~ Solutions having higher concentrations of ethanol than 10~ by weight may cause dehydration of the gelatin capsule wall and hence may not be suitable for encapsulation with this type of a capsule.

Finally, for use of the present composition in a unit dose form contained within a soft gelatin capsule it is desirable to include up to about one part by weight of water per part by weight of etoposide to improve the compatibility of the composition with the soft gelatin capsule shell. ~he hydrophilic nature of polyethyleneglycol, ethanol, citric acid, and taurocholic acid causes the composition to abstract the water from the capsule shell and may cause it rupture on prolonged storage. Sufficient water is therefore included in the composition, preferably one part by weight of water per part by weight of etoposide, to render the composition compatible with the capsule shelI and prevent dehydration thereof. It is desirable to select an amount of water which will confer stability for a storage period of two years at room temperature when the capsules are stored in a : closed container The preferr~d embodiments of the present invention are stabie, liguid compositions in the form of true solutions having the following composition:

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~.23~3S7~

Ingred~ent Parts by Weight i polyethanol glycol 3D0 5 to 9 etoposide citric acid 0.1 to 0.5 taurocholio acid 2.0 to 10 ethanol 5 to 204 by weight of total solution weight The most preferred embodiment of the ~resent invention is the following composition:

Ingredient ~ 3_~Y~ 8 polyethylene glycol 300 6.8 . esoposide, micronized 1.0 citric acid 0.2 ethanol 1.0 taurocholic acid 3.5 water 1.0 The following example constitutes a description of the pr~ferred composition of the present invention.

Example The ~ollowing ingredient~ were weighed:

Etoposide 25.09 Citric Acid, Anhydrous, USP5;0g Polyethyle~e glycol 300170.09 Alcohol, USP 25.09 Taurocholic Acid . 87.5g Purified Water, USP 25~09 .,.,-~ , 11 ...... . . . .. ~

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~he taurocholic acid i. added p~rtionwise to the polyethylene glyrol 300 wi~h s~irring to form a suspension. The water is then added followed by the alcohol and citric acid. A solution forms which is warmed to 65~C, ~llowed to cool to 35C, and filtered (Millipore AP 25 29325). An atmosphere of nitrogen is main~ained over the solution during those steps. The filtrate is kept at 30-3SC, and the etoposide is then dissolved therein. The solution is then assayed (found 71.3 mg/g of e'coposide) and filled into soft gelatin capsules at 100 mg etoposide per capsule.

The foregoing capsule-fill solution has the following characteristics, and stability.

5YIo_o_-~LL __ 6 1~ Color Dark Brown 2. pH 4.6

3. Viscosity Satisfactory . Dispersibility Easily dispersible 5. Shell Compatibility~ Physical Compatible 6. Precipitation formation time on dilution with ~2 to ~3 hours 1:1, 1:5, 1:10 and 1:100 * A trademark ~`

~23~35'78 STABILITY

Storage TemperatureStorage I'ime4 Remaining tDays)

4 C ( Control ) 8 100 70~C 5 102 37~ 8 105 ' . ~

Claims

What is claimed is:

1. A pharmaceutical dosage form adapted for the oral administration of etoposide comprising etoposide, polyethylene glycol, taurocholic acid, ethanol, and a water soluble acid in such proportions as to form a homogeneous liquid.

2. The composition of Claim 1 in dosage unit form wherein said homogeneous liquid is contained within a soft gelatin capsule.

3. The composition of Claim 2 wherein said dosage unit contains from 10 mg. to 100 mg. of etoposide.

4. The composition of Claim 2 wherein said homogeneous liquid also contains water in an amount sufficient to prevent dehydration of the capsule shell and to render said shell stable during a storage period of at least 2 years at room temperature in a closed container.

5. The composition of Claim 1 wherein the molecular weight of the polyethylene glycol is within the range of about 200 to 400.

6. The composition of Claim 1 wherein the molecular weight of the polyethylene glycol is about 300.

7. The composition of Claim b wherein the weight of poly-ethylene glycol is from 5 to 9 times the weight of etoposide.

8. The composition of Claim 1 wherein said water soluble acid is a non-toxic organic carboxylic acid.

9. The composition of Claim 1 wherein said water soluble acid is citric acid.

10. The composition of Claim 1 wherein from 2.0 to 10 parts by weight of taurocholic acid per part by weight of etoposide is employed.

11. The composition of Claim 1 wherein 3.5 parts by weight of taurocholic acid per part by weight of etoposide is employed.

12. The composition of Claim 1 wherein the amount of ethanol is from 5 to 20% by weight.

13. A liquid pharmaceutical dosage form comprising a solution of the following composition:

14. The composition of Claim 13 comprising a solution adapted for encapsulation within a soft gelatin shell and having the following composition: