This invention relates to pharmaceutical compositions for oral administration and in particular to pharmaceutical compositions comprising sex hormones, such as progesterone, oestradiol and testosterone.

The demand for hormonal preparations to treat menopausal symptoms has been growing rapidly as evidence has accumulated of the benefits of hormone replacement therapy for both symptomatic relief of menopausal symptoms and the prevention of osteoporosis. It is estimated that in the United Kingdom 25% of women suffer from osteoporosis . A preferred treatment for the symptoms and complications of the menopause is a cyclical treatment regimen of an oestrogen alone or a combination of an oestrogen and a progestogen. Most products available, however, contain oestrogens and progestogens from either non-human animal sources or which are synthetic analogues of human hormones.

Progesterone is a naturally occurring female progestogen. Synthetic progestogens have been used for many years as contraceptives and for preventing endometrial hyperplasia in women receiving oestrogens as hormone replacement therapy. Natural progesterone has not been widely used because of its poor oral bioavailability.

Progesterone has traditionally been administered intramuscularly or by the vaginal or rectal route in order to avoid the high rate of "first pass" hepatic metabolism for the drug. Such methods of administration are not universally popular however, and an effective oral dosage form is required. A suspension of micronised progesterone in oil encapsulated in a softgel has recently been available but, as for solid dosage forms, dissolution is still required in vivo and limits the rate of absorption, particularly as the aqueous solubility of progesterone is very low. Gradual dissolution and absorption of progesterone from a suspension provides a

steady flow of the drug to the liver where it is extensively metabolised, thereby limiting the amount of the dose reaching the systemic circulation. Increasing the rate of drug absorption beyond the rate of metabolism in the liver would be expected to result in increased oral bioavailability.

Testosterone, generally in the form of a testosterone ester, has also been administered therapeutically, e.g. in hormone replacement treatments. Testosterone has been applied by intramuscular injection, implants and orally, e.g. in the form of capsules.

PCT/US90/00721 discloses pharmaceutical compositions for oral administration comprising a therapeutically effective amount of a pharmaceutical compound, an organic solvent and an oil. A solution formulation comprising ethanol, palm oil, polyethylene glycol fatty acid ester, progesterone and N-methyl-2-pyrrolidine {organic solvent) is disclosed. The formulation exhibits improved bioavailability compared to a formulation of micronised progesterone in peanut oil. However, the high quantity of organic solvent present in the formulation is undesirable for use in softgel capsules as it is likely to cause stability problems.

US-A-4963540 discloses pharmaceutical compositions which may be filled in capsules, comprising micronised progesterone in an oil vehicle which is high in glycerides of polyunsaturated fatty acids. It is stated that micronised progesterone particles suspended in such a vehicle are more readily absorbed into the bloodstream than other types of oral progesterone formulations. W095/24893 discloses a carrier system for a hydrophobic drug which comprises a digestible oil and a pharmaceutically acceptable surfactant for dispersing the oil in vivo upon administration of the carrier system, said surfactant comprising a hydrophilic surfactant component, and being such that it does not substantially inhibit the lipolysis of the digestible oil. The

surfactant generally comprises:

(a) a hydrophilic surfactant component which substantially inhibits the in vivo lipolysis of said digestible oil, and (b) a lipophilic surfactant component capable of at least substantially reducing said inhibitory effect of said hydrophilic surfactant component.

The generally preferred range of digestible oil in the carrier system is 10 to 90% with the more preferred range being 20 to 60%, most preferably 25 to 45%. Several formulations comprising dissolved progesterone are disclosed in which ethanol is present but the maximum concentration of progesterone achieved was 4% by weight. In order to achieve a dose of 50mg of progesterone completely dissolved in the formulation in a softgel capsule it is necessary to employ a large (20 oblong) capsule size or divide the dose into two smaller capsules. Neither of these options is conducive to patient compliance. It has now been found that particular combinations of digestible oil and mixtures of lipophilic and hydrophilic surfactants provide a carrier system which is capable of solubilising significant amounts of hydrophobic drugs, such as, progesterone. According to one aspect of the present invention there is provided a pharmaceutical composition comprising: a hydrophobic drug, a digestible oil selected from triglycerides or propylene glycol esters of medium chain length (C ₈ -C ₁₂ ) and/or long chain length (C ₁₃ -C ₂₂ ) fatty acids; and propylene glycol monolaurate, a lipophilic surfactant which comprises a glyceride of a C _s to C ₁₀ fatty acid and a hydrophilic surfactant which is a polyoxyethylene hydrogenated castor oil, wherein the digestible oil is present in an amount in the

range from 3.0 to 12.0% by weight of the composition and the weight ratio of hydrophilic surfactant to lipophilic surfactant is in the range 1 : 1.5 to 1 : 2.5.

The formulations of the invention allow the drug to be completely solubilised in the liquid formulation. As a solution the drug is presented to the body in the most available form, avoiding the problems of slow disintegration and dissolution associated with other solid oral dosage formulations. This also obviates the need for micronised progesterone and subsequent control of the drug particle size. The formulations may be readily filled in hard or soft capsules.

The blend of digestible oil and surfactants used in the invention provides good solubilisation of the hydrophobic drug. The improved solvent power may be exploited by the formulators in various different ways. It is possible to employ a smaller capsule size to deliver the same drug dose compared with similar formulations in the prior art. Alternatively, or in addition, it is possible to reduce or eliminate ethanol and/or unsaturated compounds, such as maisine, which have been employed in prior art formulations to improve solubilisation of the drug.

The formulations of the invention have been designed to disperse immediately in aqueous environments such as the gastrointestinal tract, forming fine emulsions or microemulsions. In addition, the liquid excipients are chosen such that the emulsified formulation undergoes the natural rapid process of fat digestion (lipolysis) . The submicroscopic mixed micelles formed by this process incorporate the products of vehicle lipolysis and solubilised drug. Solubilised drug leaves the microemulsion droplets, the vesicles and the micelles by diffusion. The surface area is vast so the diffusion process is very rapid. Any remaining solubilised drug in the micelles is released when the micelles deaggregate at the intestinal wall. Absorption of progesterone across

the gastrointestinal wall in association with these mixed micelles is thought to contribute to the increase in drug bioavailability.

Hydrophobic drugs of interest in the present invention are sex hormones, particularly progesterone, oestradiol and testosterone. The invention allows formulations containing in excess of 5% by weight, preferably more than 6% by weight of progesterone in solution to be prepared which allows 50mg dose of progesterone to be encapsulated in softgel capsule, size 12 oblong which is considerably smaller than the size 20 oblong required to deliver 50mg of progesterone in the formulations disclosed in 095/2493.

Furthermore, the invention allows ethanol to be completely eliminated from the formulations containing hydrophobic drugs. For example, an ethanol free formulation containing progesterone in solution and providing a 25mg dose in a softgel capsule may be formulated and filled into a size 9.5 oblong.

The reference to capsule sizes and shapes herein refer to softgel capsules. The capsule size provides an indication of the nominal fill volume (NFV) . Examples of capsule sizes include:

Capsule NFV (minims) NFV (crtr )

Size

4 3.0 - 4.0 0.185 - 0.246

9.5 7.5 - 9.5 0.462 - 0.585

20 16 - 20 0.986 - 1.232

10 7.5 - 10.0 0.462 - 0.616

18 15.0 - 18.0 0.924 - 1.109

The compositions of the invention employ smaller amounts of digestible oil than used in 092/24893. Generally 3 to 12%, preferably 4 to 7. The preferred digestible oil is fractionated coconut oil although other digestible oils, such as, peanut oil, soyabean oil,

propylene glycol monolaurate and propylene glycol ester of fractionated coconut oil which is commercially available under the trade name Miglyol 840 may be used.

A blend of hydrophilic and lipophilic surfactants is present in the composition of the invention. The hydrophilic surfactant comprises a polyoxyethylene hydrogenated castor oil, preferably polyoxyethylene (40) hydrogenated castor oil, such as the product commercially available under the trade name Cremophor RH40. The lipophilic surfactant is preferably a mixture of glyceryl mono-and di-caprylate, such as the product commercially available under the trade name Imwitor 988. Other suitable lipophilic surfactants include a mixture of glyceryl mono- and dicaprates in combination with glyceryl mono- and di-caprylates . Such products are commercially available under the trade names Imwitor 742 and Capmul MCM.

The weight ratio of hydrophilic to lipophilic surfactant is important to achieve optimum solubilisation of the drugs. The weight ratio of hydrophilic to lipophilic surfactant is generally in the range from 1 : 1.5 to 1 : 2.5, usually 1 : 1.7 to 1 : 2.1. For progesterone and oestradiol formulations the ratio is preferably 1 : 1.80 to 1 : 1.90, most preferably about 1.85. Testosterone may be used in larger concentrations e.g. 8 to 16% by weight and the preferred weight ratio of hydrophilic to lipophilic surfactant is in the range 1 : 1.7 to 1 : 2.1.

The compositions may additionally comprise a co-solvent, such as ethanol. The presence of ethanol assists in increasing the concentration of drug which may be dissolved thereby allowing smaller volumes of formulation to achieve a desired unit dose. However, the presence of ethanol may result in an increased level of shell-fill interactions in capsules compared to formulations in which ethanol is absent. In addition ethanol can complicate the manufacturing process and

packaging costs can increase where the final package must be impervious to ethanol. Formulations of the invention may be ethanol-free and still provide acceptable dosage levels of drug. The effective ratio of hydrophilic to lipophilic surfactant is not affected by the presence of ethanol .

The formulations of the invention do not require the presence of unsaturated components to solubilise the drug. Thus, compounds, such as Maisine 35-1, which could potentially react with other excipients or the drug itself, may be avoided. Additionally, unsaturated compounds could lead to cross-linking of the gelatin of capsules and ultimately a significantly increased disintegration time, possibly leading to poor adsorption. Preferably, the formulations are free from additives which are unsaturated compounds.

Suitable progesterone formulations containing ethanol in accordance with the invention comprise: at least 5% by weight of progesterone 40 to 50% by weight of lipophilic surfactants

20 to 30% by weight of hydrophilic surfactants

3 to 10% by weight of digestible oil 15 to 25% by weight of ethanol.

Preferred formulations comprise: 5.5 to 6.5% by weight or progesterone

43 to 45% by weight of lipophilic surfactants

23 to 25% by weight of hydrophilic surfactants

4 to 9 by weight of digestible oil 18 to 20% by weight of ethanol. A particularly preferred formulation comprises about :

6 parts by weight of progesterone 45 parts by weight of lipophilic surfactants

24 parts by weight of hydrophilic surfactants 4.5 parts by weight of digestible oil

20 parts by weight of ethanol. Suitable ethanol-free formulations in accordance

with the invention comprise a pharmaceutical composition comprising: from 4 to 5% by weight of progesterone 55 to 60% by weight of lipophilic surfactants 30 to 35% by weight of hydrophilic surfactants

3 to 10% by weight of digestible oil. A preferred formulation comprises about: 4.5 parts by weight of progesterone 58 parts by weight of lipophilic surfactants 31.5 parts by weight of hydrophilic surfactants

6 parts by weight of digestible oil. The ethanol-containing and ethanol-free progesterone formulations may additionally comprise from 0.02 to 0.4% oestradiol without substantially altering the ratio of the other components.

The invention also provides ethanol-containing oestradiol formulations comprising:

0.05 to 2% by weight of oestradiol 45 to 50% by weight of lipophilic surfactants 22 to 27% by weight of hydrophilic surfactants

3 to 10% by weight of digestible oil 15 to 25% by weight of ethanol. A preferred oestradiol formulation comprises about : 1 part by weight of oestradiol 48 parts by weight of lipophilic surfactants

26 parts by weight of hydrophilic surfactants

5 parts by weight of digestible oil 21 parts by weight of ethanol . Ethanol-free oestradiol formulation in accordance with the invention comprise:

0.05 to 2% by weight of oestradiol 58 to 62% by weight of lipophilic surfactants 30 to 35% by weight of hydrophilic surfactants 5 to 7% by weight of digestible oil. A preferred oestradiol formulation comprises about:

1 part by weight oestradiol 60 parts by weight of lipophilic surfactants

33 parts by weight of hydrophilic surfactants

6 parts by weight of digestible oil. Suitable testosterone formulations in accordance with the invention comprise: 4 to 18% by weight of testosterone

40 to 48% by weight of lipophilic surfactants 20 to 25% by weight of hydrophilic surfactants

7 to 10% by weight of digestible oil about 15% by weight of ethanol. The formulations of the invention may comprise minor amounts of other components e.g. antioxidants.

In all of the above formulations the preferred components are fractionated coconut oil, Imwitor 988 and Cremophor RH40. The formulation of the invention spontaneously form microemulsions when contacted with aqueous media and maintain the benefits of the composition disclosed in W095/24893 maintaining lipolysis and bioavailability of the drug. The composition of the invention may readily be prepared by known methods, such as described in W095/24893. The compositions may be encapsulated in softgel or hardshell capsules. Methods of softgel encapsulation are disclosed in Theory and Practice of Industrial Pharmacy - Lachman & Leibermann, 2nd Edition, published by Henry Kimpton Publishers, London. Methods of liquid-fill hardshell encapsulation are disclosed in Hardcapsules - Development and Technology - Edited by K. Ridgeway, published by Pharmaceutical Press 1987. The invention will now be illustrated by the following Examples.

The formulations reported in the following Tables in which all figures are in parts by weight were prepared.

Comparative

Example Example 5 1 2 3 095/24893

Progesterone 4.52 5.56 5.56 6.15

USP

Imwitor 25.79 43.44 45.27 988

Imwitor 43.44 742

Cremophor 25.79 23.42 23.42 24.40 RH40

Maisine 8.60 35-1

Ethanol 18.10 18.89 18.89 19.68 USP/BP

Frac . Coconut 17.19 8.69 8.69 4.50

Oil BP

Example 4 5 6 7 8

Progesterone 4.50

USP

Oestradiol 1.01 1.01 1.01 1.01 USP

Imwitor 58.29 47.74 47.73 60.41 60.39 988

Cremophor 31.42 25.74 25.73 32.57 32.56 RH40

Ethanol 20.76 20.75 USP/BP

Frac . Coconut 5.79 4.75 4.75 6.01 6.01 Oil BP

Tocopherols 0.03 0.03

Example 9 10 11 12 13 14

Oestradiol 0.09 0.18 0.06 0.12 0.25 0.045 USP

Progesterone 4.50 4.50 6.14 6.14 6.14 4.500 USP

Imwitor 58.20 58.11 45.27 45.21 45.15 58.245 988

Cremophor 31.42 31.42 24.37 24.37 24.34 31.420 RH40

Ethanol 19.66 19.66 19.63

F r a c . 5.79 5.79 4.50 4.50 4.49 5.790 Coconut Oil BP

The formulation of each Example comprised stable, solutions of the drug.

The formulations may be filled into softgel capsules to provide a dosage form as follows:

Example Dose/Capsule Softgel Capsule Size

Comparative 50mg progesterone 20 oblong

1 50mg progesterone 12 oblong

2 50mg progesterone 12 oblong

3 50mg progesterone 12 oblong

4 25mg progesterone 9.5 oblong or 10 oval 50mg progesterone 18 oblong

5 2mg oestradiol 4 oblong

6 2mg oestradiol 4 oblong

7 2mg oestradiol 4 oblong

8 2mg oestradiol 4 oblong

9 0.5mg oestradiol 9.5 oblong or 10 oval 25mg progesterone lmg oestradiol 18 oblong 50mg progesterone

10 lmg oestradiol 9.5 oblong or 10 oval 25mg progesterone

11 0.5mg oestradiol 12 oblong 50mg progesterone

12 lmg oestradiol 12 oblong 50mg progesterone

13 2mg oestradiol 12 oblong 50mg progesterone

14 0.5mg oestradiol 18 oblong 50mg progesterone

0.25mg oestradiol 9.5 oblong or 10 oval 25mg progesterone

Relative Rates of Lipolysis

The relative rates of lipolysis for formulations of the Comparative Example and Examples 3 and 4 were measured in accordance with the in vitro test procedure described in 095/24893. The results are reported in Figure 1 of the accompanying drawings which represents a plot of NaOH dispensed against time for the formulations. The composition of the invention, both with and without ethanol indicate effective lipolysis is maintained. Bioavailability Study

The bioavailability of progesterone from the formulations of the Comparative Example delivered in a 20 oblong softgel capsule and Example 3 delivered in a 12 oblong softgel capsule was measured. The results of the study are reported in Figure 2 of the accompanying drawings which represent a plot of mean serum concentration of progesterone against time for following the administration to 12 subjects of a single oral dose of each softgel capsule containing the progesterone. It will be seen the bioavailability of the formulation of the invention is substantially identical to the Comparative Example.

Examples 15 to 20 The oestradiol formulation reported in the following

Table were prepared in which all figures are in parts by weight. All formulations were in the form of solutions of oestradiol .

Example 15 16 17 18 19 20

Oestradiol USP 0.047 0.094 0.188 0.033 0.066 0.132

Imwitor 988 60.993 60.946 60.852 48.197 48.164 48.098

Cremophor RH40 32.900 32.900 32.900 26.000 26.000 26.000

Ethanol USP/BP 20.970 20.970 20.970

Frac. Coconut 6.060 6.060 6.060 4.800 4.800 4.800 Oil BP

The formulations were filled into softgel capsules as follows:

Example 15 0.25mg oestradiol (fill weight of 531mg) in 9.5 oblong or 10 oval capsule. Example 16 0.5mg oestradiol (fill weight of 53lmg) in 9.5 oblong or 10 oval capsule.

Example 17 1. Omg oestradiol (fill weight of 531mg) in 9.5 oblong or 10 oval capsule.

Example 18 0.25mg oestradiol (fill weight of 763mg) in 12 oblong capsule.

Example 19 0.5mg oestradiol (fill weight of 763mg) in 12 oblong capsule.

Example 20 1. Omg oestradiol (fill weight of 763mg) in 12 oblong capsule. Examples 21 to 38

The following Table, in which all figures are in parts by weight, illustrate testosterone formulations in accordance with the invention. Examples 21 to 26 may be encapsulated to provide a dose of 20mg, Examples 27 to 32 may be encapsulated to provide a dose of 4Omg and

Examples 33 to 38 may be encapsulated to provide a dose of 8Omg.

Example 21 22 23 24 25 26

Testosterone 4 4 4 4 4 4 undecanoate

Imwitor 988 46 - - 46 - -

Imwitor 742 - 46 - - 46 -

Capmul MCM - - 46 - - 46

Cremophor 25 25 25 - - - RH40

Tween 80 - - - 25 25 25

Miglyol 10 10 10 10 10 10

Ethanol 15 15 15 15 15 15

Example 27 28 29 30 31 32

Testosterone 8 8 8 8 8 8 undecanoate

Imwitor 988 44 - - 44 - -

Imwitor 742 - 44 - - 44 -

Capmul MCM - - 44 - - 44

Cremophor 24 24 24 - - - RH40

Tween 80 - - - 24 24 24

Miglyol 9 9 9 9 9 9

Ethanol 15 15 15 15 15 15

Example 33 34 35 36 37 38

Testosterone 16 16 16 16 16 16 undecanoate

Imwitor 988 41 - - 41 - -

Imwitor 742 - 41 - - 41 -

Capmul MCM - - 41 - - 41

Cremophor 20 20 20 - - - RH40

Tween 80 - - - 20 20 20

Miglyol 8 8 8 8 8 8

Ethanol 15 15 15 15 15 15