WO2001003702A1

WO2001003702A1 - Pharmaceutical formulations comprising a glucocorticosteroid and an antifungal azole, for increasing the local mucosal tissue concentration of glucocorticosteroids in the gi tract

Info

Publication number: WO2001003702A1
Application number: PCT/SE2000/001468
Authority: WO
Inventors: Janeric SEIDEGÅRD; Olof BORGÅ
Original assignee: Astrazeneca Ab
Priority date: 1999-07-12
Filing date: 2000-07-07
Publication date: 2001-01-18
Also published as: SE9902675D0; AU6194200A

Abstract

The invention relates to pharmaceutical formulations, doses and regimens comprising a glucocorticosteroid and an antifungal azole, which are adapted for administration to the GI mucosal tissue of a patient. The doses and regimens comprise 0.01 to 150 mg of the antifungal azole. The formulation comprises the glucocorticosteroid and antifungal azole in a ratio of 10000:1 to 1:1500 (glucocorticosteroid: antifungal azole). Formulations, doses and regimens of the present invention address the specific problem of increasing the bioavailability of glucocorticosteroids in the GI mucosa of a mammalian patient (e.g. a human), while minimising the potential for liver damage in the patient.

Description

CLAIMS;

1. A daily pharmaceutical dose formulated for administration to the GI mucosal tissue of a patient, wherein the dose comprises a glucocorticosteroid and from 0.01 to 150 mg of an antifungal azole.

2. A daily dose regimen comprising a glucocorticosteroid and from 0.01 to 150 mg of an antifungal azole formulated for simultaneous or sequential administration to the GI mucosal tissue of a patient.

3. The dose of claim 1, or the regimen of claim 2, comprising from 0. Img to lOOmg of the glucocorticosteroid.

4. A pharmaceutical formulation adapted for administration to the GI mucosal tissue of a patient, the formulation comprising a glucocorticosteroid and an antifungal azole in a ratio of 10000: 1 to 1 : 1500 (glucocorticosteroid : antifungal azole).

5. The dose of claim 1 or 3, or the regimen of claim 2 or 3, or the pharmaceutical formulation of claim 4, in a form selected from a suppository, an enema and a solid formulation comprising a core coated with an enteric coating, the core including the glucocorticosteroid and antifungal azole.

6. The dose of claim 1 , 3 or 5, or the regimen of claim 2, 3 or 5, or the formulation of claim 4 or 5, wherein the antifungal azole is an imidazole or triazole antifungal.

7. The dose, regimen or formulation according to claim 6, wherein the antifungal azole is etoconazole. 1 1

8. The dose of claim 1, 3, 5, 6 or 7, or the regimen of claim 2, 3, 5, 6 or 7, or the formulation of claim 4, 5, 6 or 7, wherein the glucocorticosteroid is budesonide.

9. The dose of claim 1, 3, 5, 6, 7 or 8, or the regimen of claim 2, 3, 5, 6, 7 or 8, or the formulation of claim 4, 5, 6, 7 or 8, when formulated for oral or rectal administration to the GI mucosal tissue of a patient.

10. Use in the manufacture of a daily pharmaceutical dose comprising a glucocorticosteroid, formulated for administration to the GI mucosal tissue of a patient, of from 0.01 to 150 mg of an antifungal azole to increase the bioavailability of the glucocorticosteroid in the GI mucosal tissue.

1 1. Use in the manufacture of a daily dose regimen comprising an antifungal azole and a glucocorticosteroid, formulated for simultaneous or sequential administration to the GI mucosal tissue of a patient, of from 0.01 to 150 mg of the antifungal azole to increase the bioavailability of the glucocorticosteroid in the GI mucosal tissue.

12. The use according to claim 10 or 1 1 , wherein the daily dose or regimen comprises from O. lmg to lOOmg of the glucocorticosteroid.

13. Use in the manufacture of a pharmaceutical formulation comprising a glucocorticosteroid, formulated for administration to the GI mucosal tissue of a patient, of an antifungal azole in a ratio of 10000: 1 to 1 : 1500 (glucocorticosteroid : antifungal azole) to increase the bioavailability of the glucocorticosteroid in the GI mucosal tissue.

14. The use according to any one of claims 10 to 13, wherein the dose, regimen or formulation is in a form selected from a suppository, an enema and a solid formulation comprising a core coated with an enteric coating, the core including the glucocorticosteroid and antifungal azole. 12

15. The use according to any one of claims 10 to 14, wherein the antifungal azole is an imidazole or triazole antifungal.

16. The use according to claim 15, wherein the antifungal azole is ketoconazole.

17. The use according to any one of claims 10 to 16, wherein the glucocorticosteroid is budesonide.

18. The use according to any one of claims 10 to 17 wherein the dose, regimen or formulation is adapted for oral or rectal administration to the GI mucosal tissue of a patient.

PHARMACEUTICAL FORMULATIONS COMPRISING A GLUCOCORTICOSTEROID AND AN ANTIFUNGAL AZOLE, FOR INCREASING THE LOCAL MUCOSAL TISSUE CONCENTRAΗON OF GLUCOCORΗCOSTEROIDS IN THE GI TRACT

The present invention concerns pharmaceutical formulations, doses and dose regimens, all of which comprise a glucocorticosteroid and an antifungal azole for administration to a patient to increase the local mucosal tissue concentrations of the glucocorticosteroid in the GI tract, while minimising damage to the liver. Glucocorticosteroids can be administered to patients (eg, humans) in order to treat disorders associated with the gastrointestinal (GI) tract. Reference is made to "The Functional Gastrointestinal Disorders", D Drossman ed., Little Brown & Co, 1994, which discloses GI disorders that are treatable with glucocorticosteroids.

BACKGROUND TO THE INVENTION

The major enzymes such as enzymes of the cytochrome P450 family and P-glycoprotein (P-gp) involved in drug metabolism are present in many types of cells, but are at the highest concentration in hepatocytes. The action of these enzymes plays an important role in determining the bioavailability of drugs in a patient. The liver has therefore been traditionally thought to be the primary site of drug metabolism, and previous efforts to affect drug metabolism have been focused on targeting the liver. This is acknowledged for example in WO 96/40192 (Avmax Inc.), which lists ketoconazole, troleandomycin, gestodene, flavones, erythromycin, ethynyl estradiol, and prednisolone as compounds that inhibit cytochrome P450. See also, "Drug Therapy Following Hearttranslplantation", W Schmitz et al, Transplantaionsmedizin, No. 4-4, Quartal 1994 also at http://www.pabst- publishers.de/txmed/1994-l/article-6.html, which discloses increasing the blood levels of cyclosporin A in heart transplant patients by administering ketoconazole in order to inhibit cyclosporin A metabolism specifically in the liver.

The literature reports dangerous side effects of substances, such as antifungal azoles, used to target the liver in order to increase drug bioavailability. At the levels of antifungal azoles conventionally used for this purpose, liver diseases can be a problem. For example, see http://www.aidsinfonyc.org/network/access/drugs/keto.html, which discloses that the conventional dose for ketoconazole is 200 to 400 mg/day. At these levels, this publication reports the occurrence of hepatitis as the most serious side effect. Additive liver toxicity is also a possibility when the antifungal azole is used in combination with other liver toxic agents such as alcohol.

The approach disclosed in WO 96/40192 is to increase systemic bioavailability by increasing net drug absorption and/or decreasing drug biotransformation in the gut wall by inhibiting cytochrome P450 3A-catalysed drug bioconversion and/or P-gp-mediated drug countertransport out of the gut epithelial cells and back into the GI lumen. These processes mediated by cytochrome P450 3A and P-gp in the GI tract have been developed by the human body for its protection, in order to hinder foreign compounds from being systemically available. The processes act at the cellular level of the mucosal tissue of the GI tract. P-gp is the product of the Multiple Drug Resistance- 1 (MDR-1) gene and is present on the apical membrane of the mature epithelial cells. Further discussion of cytochrome P450 3A and P-gp can be found in WO 96/40192. The latter document concentrates on the use of essential oils as inhibitors of cytochrome P450 3A and/or P-gp. The exemplary embodiment employs an essential oil in combination with cyclosporine as the drug; glucocorticosteroids are not disclosed by WO 96/40192 as a drug and this document does not address the specific problem of increasing local GI mucosal tissue concentrations of glucocorticosteroids.

WO 94/16710 deals with stable topical preparations having anti-inflammatory action combined with antifungal action to treat mycotic skin infections. Examples are given of preparations including ketoconazole and desonide (an acetonide glucocorticosteroid) in a ratio by weight of 40: 1 , which is the preferred ratio.

WO 92/18133 concerns the targeting of drugs specifically to the oral cavity to treat inflammatory conditions in the cavity. A mouthwash is disclosed for this purpose, while inhibiting the growth of Candida in the oral cavity (which is a perceived problem with other preparations for the oral cavity). The mouthwash contains a steroid and an antifungal agent, the latter for inhibiting Candida growth

US-5002938 discloses a gel formulation for topical administration. The gel is designed to treat skin fungal diseases and contains a 17-ester steroid and an agent having an imidazole functional group and possessing topical antifungal activity. The steroid is used to induce fungal spores to produce mycelia and as a vasoconstrictor at the site of topical application.

WO 96/1 1684 concerns the treatment of asthma by topically administering an inhibitor of cytochrome P450. Topical administration is achieved by inhalation of the inhibitor, in order to effect inhibition locally in the lungs and nasal passages. To this end, the inhibitor is provided as a powder in a hand-held inhaler, optionally together with an inhaled steroid. There is no disclosure of a form that is adapted for administration to the GI mucosal tissue. The application addresses the specific problem of achieving local pharmaceutical action in the lungs and nasal passages, while minimising the concentration of steroid away from the localised administration site.

SUMMARY OF THE INVENTION

The present invention provides formulations, doses and regimes that address the problem specifically of increasing the local mucosal tissue concentration of glucocorticosteroids in the GI tract of a mammalian patient (eg, a human), while minimising the potential for liver damage in the patient. By "GI" and "GI tract", we mean the system consisting of the stomach, small intestine and large intestine.

According to the invention, there is provided a daily pharmaceutical dose formulated for administration to the GI mucosal tissue of a patient, wherein the dose comprises a glucocorticosteroid and from 0.01 to 150 mg of an antifungal azole. The present invention also provides a daily dose regimen comprising a glucocorticosteroid and from 0.01 to 150 mg of an antifungal azole formulated for simultaneous or sequential administration to the GI mucosal tissue of a patient.

Furthermore, the present invention provides a pharmaceutical formulation adapted for administration to the GI mucosal tissue of a patient, the formulation comprising a glucocorticosteroid and an antifungal azole in a ratio of 10000: 1 to 1 : 1500 (glucocorticosteroid : antifungal azole).

Other aspects of the invention relate to the following:-

Use in the manufacture of a daily pharmaceutical dose comprising a glucocorticosteroid, formulated for administration to the GI mucosal tissue of a patient, of from 0.01 to 150 mg of an antifungal azole to increase the bioavailability of the glucocorticosteroid in the GI mucosal tissue.

Use in the manufacture of a daily dose regimen comprising an antifungal azole and a glucocorticosteroid, formulated for simultaneous or sequential administration to the GI mucosal tissue of a patient, of from 0.01 to 150 mg of the antifungal azole to increase the bioavailability of the glucocorticosteroid in the GI mucosal tissue.

Use in the manufacture of a pharmaceutical formulation comprising a glucocorticosteroid, formulated for administration to the GI mucosal tissue of a patient, of an antifungal azole in a ratio of 10000: 1 to 1: 1500 (glucocorticosteroid : antifungal azole) to increase the bioavailability of the glucocorticosteroid in the GI mucosal tissue.

Formulations, doses and regimens of the present invention achieve increases in the local mucosal tissue concentration of glucocorticosteroids in the GI tract of a mammalian patient, while minimising the potential for liver damage in the patient. FIGURE

Figure 1 shows the plasma concentrations of budesonide after administration of a fixed dose of budesonide to a human volunteer that has been administered with various doses of ketoconazole.

DETAILED DESCRIPTION OF THE INVENTION

We have now found that specifically the GI mucosal bioavailability of a glucocorticosteroid in a patient can be increased by administration to the patient of an antifungal azole simultaneously or sequentially with the glucocorticosteroid, by using much lower doses of antifungal azole than conventionally used for systemically increasing the bioavailability of drugs in general. The doses of antifungal azole used for the present invention therefore pose much less risk to the patient in terms of side effects, such as liver diseases discussed above.

An increase in GI mucosal bioavailability refers to an increase in the availability of the glucocorticosteroid over time in the mucosal tissue of the GI tract. An increase of the area under a curve representing plasma glucocorticosteroid concentration v. time, for example, is indicative of increased GI mucosal bioavailability. This is because an increase in glucocorticosteroid concentration in the GI mucosal tissue is achieved by the present invention, and a consequence of this is the release of a larger amount of the drug from the GI mucosal tissue into the body fluids, thereby leading to an accompanying increase in glucocorticosteroid concentration in the plasma over time.

In one embodiment a pharmaceutical formulation is provided which comprises the glucocorticosteroid pre-mixed with the antifungal azole, the glucocorticosteroid and antifungal azole being provided in a ratio of 10000: 1 to 1 : 1500 (glucocorticosteroid : antifungal azole). This is suitable for simultaneous administration (which is preferred to sequential administration). Preferably, the formulation comprises a ratio of glucocorticosteroid : antifungal azole of at least 1 : 1000, 1 :500, 1 :400, 1 :300, 1 :200, 1 : 100, 1 :50, 1 :25, 1: 10, 1 :5, 1 :2 or 1: 1. Preferably, the formulation comprises a ratio of glucocorticosteroid : antifungal azole of no more than 5000: 1 , 2500: 1 , 1000: 1 , 500: 1 , 400: 1 , 300: 1, 200: 1, 100: 1, 50: 1, 25: 1, 10: 1, 5;1 or 2: 1. An advantageous example is a ratio of 200: 1 to 1 : 1000. More advantageous is a ratio of 100: 1 to 1 :50.

A suitable daily dose (eg, an adult dose) of this formulation comprises glucocorticosteroid and from 0.01 to 150 mg of the antifungal azole. Preferably, the dose comprises at least 0.05 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg of antifungal azole. Preferably, the dose comprises no more than lOOmg, 75mg, 50mg, 35 mg, 25mg, 20mg, 16mg, lOmg, 8mg, 5mg or 4mg of antifungal azole. An advantageous example is 0.1 mg to 100 mg of antifungal azole, more advantageous is 0.1 mg to 50 mg of antifungal azole. Preferably, the dose comprises at least O. lmg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.75mg or Img of the glucocorticosteroid. Preferably, the dose comprises no more than lOOmg, 75mg, 50mg, 40mg, 30mg, 25mg, 20mg, 15mg, lOmg, 5mg or 3mg of glucocorticosteroid. In an advantageous example, the dose comprises from O. lmg to lOOmg, more preferably O. lmg to 20mg, more preferably O. lmg to lOmg, and even more preferably Img to lOmg of the glucocorticosteroid.

As an alternative to the pre-mixed formulation, a suitable daily dose regimen for simultaneous or sequential (ie, temporally spaced) administration of the glucocorticosteroid and antifungal azole comprises an amount of the glucocorticosteroid provided separate from (ie, not mixed with) the antifungal azole, the amounts of these substances being either (i) mixed and then administered to the patient, or (ii) one of the amounts being administered before the other such that the antifungal azole is present in the patient in an amount sufficient to bring about the increased GI mucosal bioavailability of the glucocorticosteroid. To this end, the daily dose regimen comprises the glucocorticosteroid and from 0.01 to 150mg of the antifungal azole. Preferably, the regimen comprises at least 0.05 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg of antifungal azole. Preferably, the regimen comprises no more than lOOmg, 75mg. 50mg, 35 mg, 25mg, 20mg, 16mg, lOmg, 8mg, 5mg or 4mg of antifungal azole. An advantageous example is 0.1 mg to 100 mg of antifungal azole, more advantageous is 0.1 mg to 50 mg of antifungal azole. Preferably, the regimen comprises at least O. lmg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.75mg or Img of the glucocorticosteroid. Preferably, the regimen comprises no more than lOOmg, 75mg, 50mg, 40mg, 30mg, 25mg, 20mg, 15mg, lOmg. 5mg or 3mg of glucocorticosteroid. In an advantageous example, the regimen comprises from O.lmg to lOOmg, more preferably O. lmg to 20mg, more preferably O. lmg to lOmg, and even more preferably Img to lOmg of the glucocorticosteroid. The regimen can be provided, for example, in the form of a blister pack in which the separate amounts are packaged in respective blisters.

For sequential administration, the administrations of the antifungal azole and the glucocorticosteroid are preferably spaced by up to 12 hours apart, more preferably up to 6 hours apart, and even more preferably up to 2 hours apart.

The formulation, dose or regimen described above can be in liquid or solid form that is adapted for administration of the antifungal azole and glucocorticosteroid to the GI mucosal tissue of a patient (eg, an adult human). For oral administration to the GI mucosal tissue, solid administration forms include tablets, pills, capsules, powders and granules. A preferred solid form is a core coated with an enteric coating, the core including the glucocorticosteroid and antifungal azole (by "core" we mean everything contained inside the enteric coating). The core can be solid (eg, crystalline), a gel or a liquid. When administered rectally to the GI mucosal tissue, suitable forms include suppositories and enemas, eg suspension enemas. It is preferable that the formulation is made so that the dissolution rate of the glucocorticosteroid and antifungal azole are proportional once administered to the patient.

Preferably, as can be readily determined by the skilled person, the antifungal azole is used in amounts that would lead to at least a doubling of the GI mucosal glucocorticosteroid bioavailability, as compared to administration of the glucocorticosteroid without an antifungal azole. This is provided that the maximum amounts indicated above are taken into account.

When reference is made to an antifungal azole, we intend that one or a mixture of such substances can be used. For example, a pharmaceutical dose or regimen can comprise the glucocorticosteroid and 0.01 to 150mg of a mixture of antifungal azoles.

Antifungal azoles are defined as antifungal compounds comprising an azole group and having cytochrome P450 and P-gp inhibitor activity. The definition therefore includes monocyclic, bicyclic and tricyclic azole compounds. Suitable antifungal azoles include imidazole and triazole antifungal compounds. Examples are ketoconazole, itraconazole, fluconazole and miconazole and derivatives of these. For other examples useable in the present invention, reference is made to US 5792780, EP- 122056, EP-332387 and EP- 122693, all of which are incorporated herein by reference and relate to the general field of antifungal azoles.

When reference is made to a glucocorticosteroid, we intend that one or a mixture of such substances can be used. Examples of glucocorticosteroids include the following, or salts or

® solvates thereof: budesonide (eg, provided as ENTOCORT capsules, eg 22R- budesonide), rofleponide (eg, as the palmitate), beclomethasone (eg, as the dipropionate or monopropionate), ciclesonide, tipredane, flunisolide, triamcinolone (eg, as the acetonide) and fluticasone (eg, as the propionate), prednisolone, mometasone (eg, as the furoate), fluocinolone (eg, as the acetonide), flumethasone, deflazacort, 6α,9α-difluoro-l l β- hydroxy-16α-methyl-17-spiro[androsta-l,4-diene-17,5'-[l,3]oxathiolane]-2',3,4'-trione,

6α,9 -difluoro- 1 1 β-hydroxy- 16α-methyl-3-oxo- 17α-propionyloxy-androsta- 1 ,4-diene-

17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-ylmethyl) ester, 6α,9α-difluoro-l l β- hydroxy-16α-methyl-3-oxo-17α-(2-oxo-tetrahydrofuran-4-ylsulfanyl-acetoxy)-androsta- l ,4-diene-17β-carbothioic acid methyl ester, 6α,9α-difluoro-l l β,21-dihydroxy-16α,17 - [2-(2-oxo-tertrahydrofuran-3-yl)suylfanyl]ethylidenedioxy-pregn-4-ene-3,20-dione, 9α- fluoro-1 lβ,17α,21-trihydroxy-3,20-dioxo-pregna-l ,4-diene-16 -acetic acid γ-lactone, 6α,9α-difluoro- 1 1 β-hydroxy- 16α-methyl-3-oxo- 17α-propionyloxy-androsta- 1 ,4-diene- 17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl)ester and other 17β-carbothioic lactone esters. Reference is made to the Merck Index, 12^th edition, S Budavari et al (ed.) for definitions and chemical names of these compounds. This is incorporated herein by reference.

EXPERIMENTAL

A healthy human volunteer received orally a dose of 0.25 mg ketoconazole together with

® ENTOCORT capsules providing a 3 mg dose of budesonide. The ketoconazole was administered as a bolus dose via a tube, connected with a plastic locomotive, at a predefined intraintestinal location, followed by the dose of budesonide. The volunteer's blood was repeatedly sampled over a 12 hour time period. Figure 1 shows the budesonide concentration in the samples over this period.

The experiment was repeated with the same volunteer separately with 0, 0.25, 1, 4, 8, 16, 32 and 200 mg of ketoconazole. The results of these trials are also shown in figure 1.

As the figure shows, at 4, 8 and 16mg of ketoconazole, the budesonide bioavailability increased 4 to 5 times as compared with the control (no ketoconazole). Furthermore, these results should be compared to an increase of 7 to 9 times with a dose of 200mg of ketoconazole. The increase in the plasma concentrations of glucocorticosteroid achievable as a consequence of the present invention is as a result of the inhibition of enzymes (eg, cytochrome P450 3A4, P-gp) in the GI mucosa by the relatively low levels of antifungal azole.