WO1996013254A1

WO1996013254A1 - Pharmaceutical composition comprising atovaquone

Info

Publication number: WO1996013254A1
Application number: PCT/GB1995/002523
Authority: WO
Inventors: Walker Anderson Long; Craig William Davis; Kevin Alexander Miller; Jeffrey Scott Staton
Original assignee: Glaxo Wellcome House
Priority date: 1994-10-26
Filing date: 1995-10-25
Publication date: 1996-05-09
Also published as: AU3705695A

Abstract

The present invention provides a pharmaceutical composition comprising atovaquone and a non-protein pulmonary surfactant. Suitably the composition comprises 10 to 30 % atovaquone by weight and 70 to 90 % non-protein pulmonary surfactant. The composition is suitable for oral or pulmonary administration and provides atovaquone having improved bioavailability.

Description

PHARMACEUTICAL COMPOSITION COMPRISING ATOVAQUONE

The present invention relates to a pharmaceutical formulation containing a non-protein pulmonary surfactant and atovaquone and its use, particularly for lung infections.

Atovaquone (2-[4-(4-chlorophenyI)cyclohexyl]-3-hydroxy- 1 ,4-naphthoquinone) is described in US Patent No. 5053432. It has been described as being useful in the treatment of Pneumocystis carinii, malaria and a number of other protozoal infections. Unfortunately, atovaquone is poorly soluble and poorly bioavailable and its efficacy is limited by its bioavailability. This makes formulation using standard formulatory techniques difficult, particularly for the treatment of Pneumocystis carinii which requires relatively high plasma concentrations of atovaquone.

It is therefore an object of the present invention to provide a pharmaceutical formulation containing atovaquone which improves atovaquone bioavailability and which gives good plasma concentrations of atovaquone.

It has now been discovered that improved atovaquone bioavailability and good plasma levels of atovaquone can be achieved by formulating atovaquone with a non-protein pulmonary surfactant and administering the formulation via the pulmonary or oral route.

Accordingly, the present invention provides a pharmaceutical composition for use in the preparation of pharmaceutical formulations which comprises 2 to 50% of atovaquone by weight and 50 to 98% of a non-protein pulmonary surfactant. Suitably the composition comprises 10 to 30% atovaquone by weight and 70 to 90% non-protein pulmonary surfactant by weight. A preferred composition comprises 17.4% atovaquone by weight and 82.6% non protein pulmonary surfactant.

By the term non-protein pulmonary surfactant is meant a synthetic material useful for assisting respiration when natural pulmonary surfactant is deficient or dysfunctional. Suitably, non-protein pulmonary surfactants include a phospholipid such as dipalmitoylphosphatidylcholine DPPC. A preferred synthetic pulmonary surfactant contains 50-60% of a phospholipid, such as DPPC, 20-40% sodium chloride, and 4-10% of an agent that provides mobility for the phospholipid film such as cetyl alcohol and optionally 4-10% tyloxapol. Phospholipids that may be substituted for DPPC include phoshatidylglycerols. phosphatidylinositols, phosphatidylserines. phosphatidylethanolamines, sphingomyelins, and other phosphatidylcholines. Examples of mobility enhancing agents other than cetyl alcohol include C 14.13 fatty acid type alcohols such as stearyl alcohol or myristyl alcohol. Other formulation agents that can be incorporated in the compositions of the present invention include non-ionic surfactants such as polyoxyethylene stearates; and other typical tonicity adjusters such as dextrose, mannitol and calcium salts. Such a synthetic pulmonary surfactant is marketed by the Wellcome Foundation Limited under the trade mark EXOSURF.

The composition is suitably manufactured to a median particle size of 1-5 microns and preferably to a median particle size of 2 microns. This particle size enables administration of respirable particles via nebulization or aerosolization without additional energy input to obtain the desired particle size. This small particle size also facilitates administration by instillation in minimizing the potential for airway obstruction. Thus, by using this particle size for the composition, the need for additional mechanical energy during pulmonary administration to reduce particle size can be eliminated. Manufacturing techniques utilized to obtain this particle size include, but are not limited to, homogenization, microfluidization, micronization, milling, re-crystallization, spray-drying, etc. It is recognized that those skilled in the art may be aware of additional techniques to obtain this particle size and these techniques are therefore included within this embodiment. The compositions of the present invention are also particularly suitable for dilution with water to give aqueous pharmaceutical formulations.

Spray drying followed by microfluidization has been found to be particularly advantageous in preparing compositions of the present invention having the required particle size and a sufficient concentration of atovaquone. Accordingly, there is also provided a method for preparing compositions of the present invention which method comprises spray drying atovaquone with the non-protein pulmonary surfactant followed by microfluidizing a suspension of the spray dried material. Preferably, atovaquone and the non-protein pulmonary surfactant are dissolved in tetrafuran prior to spray drying. Suitably the spray dried atovaquone and surfactant are added to a saline solution at a non-extreme elevated temperature, for example 65-70°C, prior to microfluidizing.

In a further aspect, the present invention provides a method for the treatment and/or prophylaxis of a parasitic infection in mammals, including humans, which comprises administering an effective amount of a composition of the present invention. Preferably, the composition is administered by the pulmonary route or orally. Parasitic infections that can be treated by compositions of the present invention include malaria, toxoplasmosis and other protozoal infections and pneumocystis carinii. The amount of atovaquone and non-protein pulmonary surfactant required to be effective as an anti-parasitic agent will, of course, vary and is ultimately at the discretion of the medical practitioner. The factors to be considered include the nature of the formulation, the mammal's bodyweight, age and general condition and the nature and severity of the disease to be treated. In general, a suitable effective dose for administration to man for treatment of a protozoal parasitic disease is in the range of 0.5 mg to 30 mg of atovaquone per kilogram bodyweight per day, and 0.5 to 1500 mg of DPPC per kilogram bodyweight per day, for example 1 to 20 mg/kg/day of atovaquone and 1 to 1000 mg/kg/day of DPPC, particularly 3 to 15mg/kg/day of atovaquone and 3 to 750 mg kg/day of DPPC.

A suitable effective dose for administration to man for prophylaxis of parasitic diseases is in the range of from 3 to 20 mg kg/week of atovaquone and 3 to 1000 of DPPC, for example from 6 to lOmg/kg/week of atovaquone and 6 to 500 of DPPC.

The compositions of the present invention may conveniently be presented as pharmaceutical formulations in unit dosage form. A convenient unit-dose formulation contains the active ingredients in amounts of 200 mg to 1000 mg atovaquone and 200 to 10000 mg DPPC.

Suitable formulations within the scope of the present invention include, for example, solid dosage forms such as tablets and liquid dosage forms, such as suspensions. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared using methods known in the art of pharmacy.

The compositions of the present invention may be administered to the lungs of a patient by any suitable means, but are preferably administered by generating an aerosol comprised of respirable particles containing atovaquone, which particles are inhaled by the patient. The particles may optionally contain other therapeutic ingredients. Aerosols of liquid particles comprising atovaquone may be produced by any suitable means, such as with a nebuliser. Nebulisers are commercially available devices which transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air/oxygen, through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in nebulisers consist of the active ingredient in a liquid carrier, the active ingredient comprising up to 40% w/w of the formulation but preferably less than 20%. The carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if a formulation is not prepared sterile, for example methyl hydroxybenzoate. antioxidants, flavouring agents, volatile oils, and other surfactants.

An example of an aerosol generator comprises a metered dose inhaler. Metered dose inhalers are pressurised aerosol dispensers, typically containing a suspension or solution of the formulation of the active ingredient in a liquified propellant. During use these devices discharge the formulation through a valve adapted to deliver a metered volume, typically firom 10-150 micro litres, to provide a fine particle spray containing the active ingredient. Suitable propellants include chlorofluorocarbon compounds for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents for example ethanol, surfactants such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavouring agents.

The aerosol may be produced by the aerosol generator at a rate of from about 10-150 litres per minute, more preferably from about 30-150 litres per minute and most preferably about 60 litres per minute. Aerosols containing greater amounts of medicament may be administered more rapidly.

Pharmaceutical formulations for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of the active ingredients. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compression tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, or dispersing agent. Moulded tablets may be made by moulding an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules may be prepared by filling the active ingredients, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein the active ingredients are sealed in a paper envelope. The active ingredients may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged e.g. in a sachet. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous liquid or a non- aqueous liquid or as an oil-in-water liquid emulsion. Formulations for oral administration include controlled release dosage forms e.g. tablets wherein the active ingredients are formulated in an appropriate release-controlling matrix, or are coated with a suitable release-controlling film. Such formulations may be particularly convenient for prophylactic use.

Tests to measure the bioavailability of atovaquone in vivo indicate that formulations of atovaquone and non-protein pulmonary surfactants, for example Exosurf have improved bioavailability compared to prior art formulations of atovaquone. The invention therefore provides in a further aspect, formulations comprising atovaquone and a non-protein pulmonary surfactant eg Exosurf, for use in therapy, in particular in the treatment and prophylaxis of protozoal parasitic infections, e.g. malaria and toxoplasmosis, and infections caused by P. carinii.

The invention will now be further illustrated by the following non-limiting examples:

Example 1

Biological Examples

A. Formulations of atovaquone with a variety of non-protein pulmonary surfactants were prepared and administered orally to fasted dogs (n = 3). The bioavailability of atovaquone administered in such formulations was compared with the bioavailability of atovaquone administered alone.

The results are set out in Table 1.

Table 1

Formulation Molar Ratio Bioavailability (Atovaquone:DPPC) (%)

Atovaquone (spray-dried) n/a * 3±2

Homogeneously Spray-dried:

Atovaquone + EXOSURF** 1:1 11±3

Atovquone + EXOSURF 1:2 83±9

Atovaquone + EXOSURF 1:4 23±6

Atovaquone + EXOSURF 1:6 23±7

Atovaquone + EXOSURF 1:8 41±5

Atovaquone + EXOSURF 1:8 30±4

Atovaquone + EXOSURF 1:12 32±4

Atovaquone + DPPC 1:4 27±18

Atovaquone + DPPC + Tyloxapol 1:4 31±5

Atovaquone + DPPC (dry-blended) 1:4 15±6

* Not applicable

** Exosurf contained DPPC, cetyl alcohol, and tyloxapol only. Sodium chloride was excluded.

B. Formulations (a) to (f) of atovaquone with Exosurf were prepared by standard methods.

Formulation ( ) (b) (c) (d) (e) (f)

Atovaquone (mg) 20.0 20.0 20.0 20.0 20.0 20.0

DPPC (mg) 40.0 160.1 240.2 162.0 243.0 162.0

Cetyl Alcohol (mg) 4.45 17.97 26.69 18.0 27.0 18.0

Tyloxapol (mg) 2.96 11.86 17.78 12.0 18.0 12.0

Each formulation was administered orally to fasted dogs (n = 3) . A control group (n=3) received a tablet (formulation (g)) containing atovaquone as the sole active ingredient. _*

Formulation (g)

Atovaquone 250.0 mg

Hydroxypropyl Cellulose 33.0 mg

Magnesium Stearate 1.7 mg

Microcrystalline Cellulose 28.3 mg

Povidone 12.0 mg

Sodium Starch Glycollate 10.0 mg

The pharmacokinetic parameter values for atovaquone were measured and the results for formulations (a) to (g) are shown in Table 2.

Table 2

C. Formulation (h) was prepared by standard methods.

Formulation (h)

Atovaquone 1.74 mg DPPC 6.97 mg

Cetyl Alcohol 0.77 mg Tyloxapol 0.52 mg Hydrochloric Acid adjust pH to 5.8-6.4 Sodium Hvdroxide adjust pH to 5.8-6.4

0.45% Sodium Choride Solution q.s.

1.0 mL Formulation (h) was administered intratracheally to dogs and the pharmacokinetic parameters for atovaquone were measured. The results are shown in Table 3.

IaMeΛ

Dose (mg kg atovaquone) 3.2

C_max (μ/mL) 1.4±0.16 ^τmax (^h) 44.00=30.20

AUC (h.μg/mL) 186.03±42.28

Bioavailability (%) 82.52±8.68

D. Formulation (i) was prepared by the preferred method described below.

Formulation (i)

Atovaquone (micronized) 10.12 mg

DPPC 40.50 mg

Cetyl Alcohol 4.50 mg

Tyloxapol 3.00 mg

Sodium Chloride 5.85 mg

Hydrochloric Acid, q.s. *

Sodium Hydroxide, q.s. *

Water for Injection, q.s.

Tetrahydrofuran q.s. +

* Hydrochloric acid and/or sodium hydroxide were added as needed to adjust the pH of the suspension to the desired range (6.7-6.9) + Tetrahydrofuran was removed during the spray drying process

The DPPC, cetyl alcohol and tyloxapol were dissolved in an appropriate amount of tetrahydrofuran. The atovaquone was then added to the DPPC/cetyl alcohol/tyloxapol tetrahydrofuran and mixed until dissolved. This solution was then spra dryed using the following parameters : Feed rate : 3.5 litres/hour (approximately) Air Inlet Temperature : 115°C Air Outlet Temperature : 80°C (approximately) Drying Gas Flow (IV_:) : 40 mm H₂O (approximately) Atomizing Gas (N₂) • 4.0 bar (±0.4 bar)

The spray dried DPPC/cetyl alcohol/tyloxapol/atovaquone material was added to a saline solution at 65-70°C comprising the appropriate amount of sodium chloride in water for injection, followed by mixing. The pH was adjusted using hydrochloric acid and/or sodium hydroxide. The resulting suspension was microfluidized at 10000 psig until 90% of the particles were less than three microns in size. The microfluidized atovaquone/Exosurf suspension was filled into 50mL amber glass vials and terminally sterilized for fifteen minutes at 121 °C.

Claims

1. A composition which comprises 2 to 50% atovaquone and 50 to 98% of a non- protein pulmonary surfactant by weight.

2. A composition according to claim 1 which comprises 10 to 30% atovaquone by weight and 70% to 90% at a non-protein pulmonary surfactant by weight.

3. A composition according to Claim 1, or Claim 2 wherein the non-protein pulmonary surfactant comprises a phospholipid.

4. A composition according to Claim 3 wherein the non-protein pulmonary surfactant contains 50-60% of a phospholipid, 20-40% of an alkaline metal salt and 4-10% of an agent that provides mobility for the phospholipid film.

5. A composition according to Claim 4 wherein the non-protein pulmonary surfactant contains 50-60% DPPC. 20-40% sodium chloride, 4-10% cetyl alcohol and optionally 4-10% tyloxapol.

6. A pharmaceutical formulation comprising a composition according to any of Claims 1 to 5 and optionally one or more pharmaceutically acceptable carriers therefor.

7. A pharmaceutical formulation according to Claim 6 adapted for pulmonary administration.

8. A composition according to any of Claims 1 to 7 for use in therapy.

9. A composition according to any of Claims 1 to 6 for use in treatment and/or prophylaxis of a protozoal infection or an infection caused by P. Carinii.

10. The use of a composition according to any of Claims 1 to 6 in the manufacture of a medicament for the treatment and/or prophylaxis of a protozoal infection or an infection caused by P. Carinii.

11. A method for treating a protozoal infection or an infection caused by P. Carinii in a mammal which method comprises administering an effective treatment amount of a composition according to any of Claims 1 to 6.

12. A method according to Claim 10 wherein the composition is administered directly to the mammal's lungs.

13. A method for preparing a composition according to any of claims 1 to 5, which method comprises the steps of

a) spray drying a solution of atovaquone and non-protein pulmonary surfactant; and

b) microfluidizing a suspension of the spray dried material prepared in step a).