WO2000037083A1

WO2000037083A1 - Oral antiestrogen pharmaceutical composition

Info

Publication number: WO2000037083A1
Application number: PCT/US1999/027933
Authority: WO
Inventors: Frank Everett Bowen
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme LLC
Priority date: 1998-12-18
Filing date: 1999-12-16
Publication date: 2000-06-29
Anticipated expiration: 2001-06-18
Also published as: AU2156800A; AR021719A1

Abstract

An oral dosage form of the antiestrogen of formula (I) which is administrable to a female mammal that has fasted or eaten which comprises the antiestrogen of formula (I), an effective amount of at least one disintegrant and an effective amount of a surfactant sufficient to achieve an AUCfed/AUCfasted ratio of less than about 15 is disclosed.

Description

ORAL ANTIESTROGEN PHARMACEUTICAL COMPOSITION

Background of the Invention

The present invention relates to an improved pharmaceutical composition of the orally active antiestrogen of the formula I.

The synthesis and the antiestrogenic activity of the compound of formula I, i.e., (S)-7- hydroxy-3-(4'-hydroxyphenyl)-4-methyl-2-(4"-[2'"-(l-piperidino)ethoxy]phenyl)-2H- benzopyran 4',7-bistrimethylacetate, is disclosed in J Med Chem. 1997, 40, 2117-2122. See also US Patent Nos. 5,395,842 and 5,407,947 and J Med Chem. 1990, 33, 3216-3222. The compound of formula I has shown in-vitro and in-vivo activity for treating female breast cancer. However, the compound is lipophilic and exhibits a food effect, and exhibits higher absorption in patients after ingestion of food compared to fasted conditions.

In general, it is known that the absorption and bioavailability of any particular therapeutic agent can be affected by numerous factors when dosed orally. Such factors include the presence of food in the gastrointestinal (GI) tract because, in general, the gastric residence time of a drug is usually significantly longer in the presence of food than in the fasted state. If the bioavailability of a drug is affected beyond a certain point due to the presence of food in the GI tract, the drug is said to exhibit a "food effect". Food effects are important inasmuch as, when a drug exhibits an adverse food effect, there is risk associated with administering it to a patient who has not eaten recently. The risk derives from the potential that absorption into the bloodstream may be adversely affected to the point that the patient risks insufficient absorption to remediate the condition for which the drug was administered. In the course of the development of a suitable oral dosage form for the antiestrogen compound of formula I, a formulation was produced which exhibited an AUCf_e /AUCt_asted ratio of about 100 This adverse food effect is undesirable particularly for compounds such as the antiestrogen compound of formula I which is targeted to treat female breast cancer patients who would be adversely affected by this food effect.

There is a need for an improved oral pharmaceutical composition of the compound of formula I that has a lower food effect and produces increased bioavailability for the antiestrogen of formula I.

Summary of the Invention

We have discovered that the AUC_(ccι/AUC|_c,_sled ιatιo is dramatically lowered to a value less than about 15 by incorporation of a combination of the antiestrogen compound of formula I and an amount of at least one of selected disintegrant and an amount of a nonionic surfactant sufficient to achieve this dramatically improved ratio.

This invention provides an oral dosage form of the antiestrogen of formula I which is administrate to a female mammal that has fasted or eaten which comprises the antiestrogen of formula I,

an effective amount of at least one disintegrant and an effective amount of a surfactant sufficient to achieve an AUCf_ed/AUCf_asted ratio of less than about 15.

This invention also provides an oral pharmaceutical composition compπsing the antiestrogen of formula I, an effective amount of a disintegrant selected from croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch and microcrystalhne cellulose and an effective amount of a nonionic surfactant selected from sodium lauryl sulfate, stearyl alcohol and solid polyethylene glycols and pharmaceutically acceptable excipients. This invention also provides an oral antiestrogen pharmaceutical composition comprising:

Amount

Ingredient (parts by weight)

Compound of formula I, micronized about 5-20

Lactose (monohydrate) about 160-240

Microcrystalhne Cellulose about 20-60

Croscarmellose Sodium about 20-60

Sodium lauryl sulfate about 10-20

Magnesium stearate about 0.5-2.0

This invention also provides an oral antiestrogen composition comprising:

Weight

Ingredient (parts by wen ght)

Compound of formula I, micronized about 20

Lactose, monohydrate NF about 200

Microcrystalhne Cellulose NF about 34

Croscarmellose Sodium NF about 30

Sodium lauryl sulfate NF about 15

Magnesium stearate about 1 Total: about 300

This invention also provides an oral dosage form of the antiestrogen of formula I which comprises the antiestrogen of formula I,

which upon administration of an effective amount of said oral dosage form to a female mammal that has fasted or eaten results in an AUCf_ec./AUCtaste-ι ratio of less than about 15.

This invention also provides a method of treating estrogen-sensitive diseases in a female which comprises administering to such a female an antiestrogen effective amount of the oral compositions of this invention

DETAILED DESCRIPTION OF THE INVENTION

The antiestrogen compound formula I metabolizes in vivo into the antiestrogen compound of formula II

π

During the course of development of the compound of formula I, a formulation (the composition of Example 3) was prepared but the AUCf_ed/AUCf_asted ratio was approximately 100 after administration of a 20 mg dose of the compound of formula I in the composition of Example 3 The oral dosage pharmaceutical composition of this invention dramatically reduced the magnitude of the food effect, by loweπng the AUCfed/AUCf_asted ration from 100 to about 12 fold after administration of a single 20 mg dose of the compound of formula I in the composition of Example 2. The bioavailability of the compounds of formulas I and II under fasted conditions was also improved by administration of the composition of Example 2 compared to that of the composition of Example 3. More importantly, there was a reduction in the coefficient of vaπation of the AUC values from about 39% to 28% The bioavailability of the compound of formula I was increased four fold as measured by AUC_{0 2} using the composition of Example 2. The oral pharmaceutical composition of present invention should be administered orally to postmenopausal or ovanectomized females having estrogen-sensitive diseases, alone or as an adjuvant to surgery or other anticancer therapies in 20 or 40 mg in single or divided doses in capsule or tablet form, daily. The terms "an effective amount of at least one of selected disintegrant and an amount of a surfactant sufficient to achieve an AUC|_ed/AUCf_asted ratio of less than about 15" as used herein means an amount of disintegrant, e.g., croscarmellose sodium or crospovidone and microcrystalhne cellulose, relative to an amount of the antiestrogen of formula in the range of about 8: 1 to 6: 1 ; and an amount of a nonionic surfactant relative to an amount of the antiestrogen of formula in the range of about 2: 1 to 1: 1.

Suitable disintegrants are selected from the group consisting of at least one of croscarmellose sodium (a cross linked polymer of carboxymethylcellulose sodium, see NF XVII page 1922 ( 1990)), crospovidone, sodium starch glycolate, pregelatinized starch and microcrystalhne cellulose. Preferably, the disintegrants are selected from croscarmellose sodium or crospovidone. Preferably, croscarmellose sodium and microcrystalhne cellulose are used as the disintegrants in compositions of this invention for capsules. Crospovidone may be used as the disintegrant in compressible tablets. Those skilled in the art will appreciate that it is desirable for compressible tablets to disintegrate within 30 minutes; therefore, the disintegrant used preferably results in the disintegration of the tablet within 30 minutes.

Typically suitable pharmaceutically acceptable excipients include lubricants, ghdants, and bulking agents.

Suitable lubricants include, talc, magnesium stearate, calcium stearate, steaπc acid, hydrogenated vegetable oils and the like Preferably, magnesium stearate is used.

Suitable nonionic surfactants include sodium lauryl sulfate, stearyl alcohol and solid polyethene glycols (PEG) such as PEG-3350, PEG-4000, PEG-600 or PEG-8000. Preferably, the nonionic surfactant is sodium lauryl sulfate.

Suitable ghdants, if used, include silicon dioxide and talc. Preferably, silicon dioxide is used. Suitable bulking agents include xylitol, mannitol, compressible sugars, lactose, and microcrystalline celluloses. Preferably, lactose or lactose monohydrate is used for capsules.

General Experiment The antiestrogen compound of formula I was micronized to produce a drug substance with the following range of particle sizes: 95% < 20 micrometers; 85% < 10 mocrometers; and 60% < micrometers. Micronization was conducted using a Jet Pulverizer fluid energy mill with 100 psi nitrogen gas, but any other suitable micronizer may be used.

General Method of Manufacture of the compositions of Examples 1-5

(1) Charge the antiestrogen of formula I and a portion of the lactose monohydrate to a suitably sized mixer and blend for 5 minutes or until homogeneous.

(2) Pass the blend from step 1 through a 30 mesh screen.

(3) Return the screened blend from step 2 to the mixer of step 1 and add the remainder of the lactose monohydrate. Blend for 5 minutes or until homogeneous.

(4) Add to the mixer, the microcrystalline cellulose, croscarmellose sodium and the sodium lauryl sulfate and magnesium stearate and blend until homogeneous.

(5) Fill the powder from step 4 into No. 2 capsule shells. The powder from step 4 may also be compressed into tablets using standard equipment.

Example 1

Ingredient Amount (parts by weight)

Compound of formula I, micronized about 5-20 Lactose (monohydrate) about 160-240 Microcrystalline Cellulose about 20-60 Croscarmellose Sodium about 20-60 Sodium lauryl sulfate about 10-20 Magnesium stearate about 0.5-2.0

Example 2

Ingredient Weight (parts bv weight)

Compound of formula I, micronized 20.0

Lactose, monohydrate NF 200.0

Microcrystalline Cellulose NF 34.0

Croscarmellose Sodium NF 30.0

Sodium lauryl sulfate NF 15.0

Magnesium stearate 1.0

Total: 300.0 Example 3

Ingredient Weight (parts bv weight)

Compound of formula I, micronized 20.0

Lactose, Monohydrate NF 235.0

Microcrystalline Cellulose 32.0

Corn Starch NF 12.0

Magnesium Stearate NF 1.0

Total: 300.0

* Filled into No. 2, white opaque, two-piece hard gelatin capsule.

Example 4

Ingredient Weight (parts bv weight)

Compound of formula I, micronized about 5 Lactose, monohydrate NF about 215 Microcrystalline Cellulose NF about 34 Croscarmellose Sodium NF about 30 Sodium lauryl sulfate NF about 15 Magnesium stearate about 1 about 300

Example 5

Ingredient Weight (parts bv weight)

Compound of formula I, micronized about 10 Lactose, monohydrate NF about 210 Microcrystalline Cellulose NF about 34 Croscarmellose Sodium NF about 30 Sodium lauryl sulfate NF about 15 Magnesium stearate about 1 about 300

Two three-way crossover studies conducted in 18 normal postmenopausal female volunteers were conducted-using the compositions of Example 2 & 3 to evaluate the effect of food on the oral bioavailability of the antiestrogen of formula I and its active metabolite, the antiestrogen compound of formula II. The arithmetic means of the pharmacokinetic parameters of these two crossover studies are summarized in Tables I to IV hereinbelow. TABLE 1 Mean Pharmacokinetic Parameters of Human Plasma of the Compound of Formula I following administration single oral dose of 20 mg of composition of Example 3.

TABLE II Mean Pharmacokinetic Parameters of Human plasma of the Compound of Formula II following a single oral dose of 20 mg of the Compound of Formula I in Composition of Example 3.

% CV = Coefficient of vaπation. expressed as percentage

AUCo-₂ = Area under the plasma concentration - time curve from time 0 to 24 hrs., expressed in ng hr/ml C ax = Maximum measured plasma concentration in ng/ml Tmax = Time in hrs at maximum measured plasma concentration

TABLE III Mean Pharmacokinetic Parameters of Human Plasma of the Compound of Formula II following administration of a single dose of 20 mg of the Composition of Examples 2 or of the Composition of Example 3.

TABLE IV Mean Pharmacokinetic Parameters of Human Plasma of the Compound of Formula I following a single dose of 20 mg of the Compound I in the compositions of Example 2 or of Example 3.

% CV = Coefficient of variation, expressed as percentage

² AUC₀-₂₄ = A Arreeaa uunnddeerr 1 the plasma concentration - time curve from time 0 to 24 hrs., expressed in ng hr/ml Cmax = Ma ixx ii mmuumm mmeea. sured plasma concentration in ng/ml ⁴ Tmax = Time in hrs at maximum measured plasma concentration

Based on the pharmacokinetic parameters listed in Tables I-IV, the plasma levels of the compound of formula II was absorbed after administration of the oral composition of this invention of Example 2 under fasted conditions to a greater extent than after the administration on the composition of Example 3. Under fed conditions, the pharmacokinetics of the compositions of Examples 2 and 3 were essentially the same. Table 3 illustrates that food increased the plasma concentrations of the compound of formula II after administration of the oral composition of Example 2 by 70% compared to fasted conditions (AUC₀-₂ fed = 74J; AUC₀-₂₄ fasted = 44.32).

Based on the pharmacokinetic parameters listed in Tables I-IV, the amount of the compound of formula I absorbed (as measured by AUCo-₂ fasted) was four times greater after administration of a single 20 mg dose of the compound of formula I in the composition of Example 2 compared to the same dose of the compound I in the composition of Example 3. Under fed conditions, the plasma levels of the compound of formula I were about 20% greater after administration of 20% of the compound of formula I in the composition of Example 2 compared to the same dose from administration of the composition of Example 3.

Unexpectedly, the coefficient of variation for the plasma levels of the compound of formula I was dramatically reduced to 28% (after administration of the composition of Example 2) compared to 39% after administration of the composition of Example 3.

The magnitude of the food effect (AUCf_ed/AUCf_asted) is reduced from about 100 (after administration of the composition of Example 3) to about 13 (after administration of the composition of Example 2).

Claims

What is claimed is:

1. An oral dosage form of the antiestrogen of formula I which is administrable to a female mammal that has fasted or eaten which comprises the antiestrogen of formula I,

an effective amount of at least one disinte '&grant and an effective amount of a surfactant sufficient to achieve an AUCfcd/AUCι_asted ratio of less than about 15.

2. The oral dosage form of claim 1 wherein the disintegrant is at least one selected from croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch and microcrystalline cellulose.

3. The oral dosage form of claim 1 wherein the disintegrant is a mixture of croscarmellose sodium and microcrystalline cellulose.

4. The oral dosage form of claim 1 wherein the surfactant is sodium lauryl sulfate or a solid polyethylene glycol.

5. The oral dosage form of claim 1 in the form of a capsule.

6. The oral dosage form of claim 1 in the form of a tablet.

7. An oral pharmaceutical composition comprising the antiestrogen of formula I of claim 1, an effective amount of at least one disintegrant selected from croscarmellose sodium, crospovidone, sodium starch glycolate pregelatinized starch and microcrystalline cellulose and an effective amount of a nonionic surfactant selected from sodium lauryl sulfate, stearyl alcohol and solid polyethylene glycols and pharmaceutically acceptable excipients. An oral antiestrogen pharmaceutical composition comprising:

Amount

Ingredient (parts by weight)

Compound of formula I micronized about 5-20 Lactose (monohydrate) about 160-240 Microcrystalline Cellulose about 20-60 Croscarmellose Sodium about 20-60 Sodium lauryl sulfate about 10-20 Magnesium stearate about 0.5-2.0

9. A method of treating estrogen-sensitive diseases in a female which comprises administering to such a female an antiestrogenic effective amount of the oral composition of claim 8.

10. An oral antiestrogen composition comprising:

Weight

Ingredient (parts bv weight)

Compound of formula I, micronized about 20

Lactose, monohydrate NF about 200

Microcrystalline cellulose NF about 34

Croscarmellose sodium NF about 30

Sodium lauryl sulfate NF about 15 Magnesium stearate about 1 about 300

11. The method of treating an estrogen-sensitive disease in a female which comprises administering to such a female an antiestrogenic amount of the oral antiestrogen composition of claim 10.

12. The oral dosage form of claim 10 in the form of a capsule.

13. The oral dosage form of claim 10 in the form of a tablet.

14 An oral dosage form of the antiestrogen of formula I which comprises the antiestrogen of formula I,

which upon administration of an effective amount of said oral dosage form to a female mammal that has fasted or eaten results in an AUCfe_d/AUCf_aslCd ratio of less than about 15.