United States Patent:  6,096,338

Assignee:  R. P. Scherer Corporation (Basking Ridge, NJ)

Filed:  June 27, 1997

There is provided a carrier for hydrophobic drugs, and pharmaceutical compositions based thereon, which carrier comprises a digestible oil and a pharmaceutically acceptable surfactant component for dispersing the oil in vivo upon administration of the carrier, which comprises a hydrophilic surfactant, said surfactant component being such as not to substantially inhibit the in vivo lipolysis of the digestible oil.

Description of the Invention

This invention relates to oral drug delivery systems for hydrophobic drugs, and in particular is concerned with improving the bioavailability of hydrophobic drugs from such systems.

As is well known, many pharmaceutically active compounds intended for oral administration are poorly soluble in water. This hydrophobic property often makes it difficult to formulate a drug so that it exhibits a satisfactory bioavailability profile in vivo. Poor bioavailability may lead to ineffective therapy, the need for higher dosing and/or undesirable side effects.

Over the years the drug formulation art has developed numerous oral delivery systems for hydrophobic drugs. Many such systems are oil-based, the hydrophobic drug being dispersed or dissolved in an oil which may sometimes contain a co-solvent. For such formulations the oil appears to be an important component for promoting drug absorption. However, the administration of a drug in oil alone is not advantageous because of the poor miscibility of the oil with the aqueous environment of the gastrointestinal tract. This poor miscibility can lead to highly variable gastric emptying which, in turn, produces variable absorption of drug from the small intestine.

Accordingly, in order to increase the dispersibility of the oil in aqueous fluids it is the normal practice in oil-based pharmaceutical formulations to include a surfactant component. Lipophilic surfactants (i.e. HLB<10) are capable of promoting some emulsification of the oil but the resulting emulsions are normally too crude, in terms of size, to be useful. Hydrophilic surfactants (i.e. HLB>10) are much superior with respect to forming oil-in-water (o/w) emulsions and can be used to produce fine, uniform emulsions which are more likely to empty rapidly and uniformly from the stomach and coupled with a very large surface area will promote faster and more complete absorption. However, hydrophilic surfactants, by themselves, are often not sufficiently miscible with the oil component to ensure good homogeneity, and consequently the surfactant component of an oil-based drug formulation usually consists of a mixture of lipophilic and hydrophilic surfactants.

For convenience of storage and use by the patient, oil-based drug formulations are generally filled into hard or soft capsules.

A few examples of oil-based formulations of hydrophobic drugs which have appeared in the recent patent literature will now be briefly described, by way of illustration.

GB-A-2015339 discloses pharmaceutical compositions in which the drug is cyclosporin, a valuable immuno-suppressive agent, and the carrier for the cyclosporin comprises the following components:

(a) a transesterification product of a natural or hydrogenated vegetable oil triglyceride and a polyalkylene polyol,

(b) ethanol, and

(c) a vegetable oil.

GB-A-2228198 in contrast seeks to provide an ethanol-free formulation of cyclosporin. The carrier formulation which this specification discloses comprises:

(a) a fatty acid triglyceride,

(b) a glycerol fatty acid partial ester or propylene glycol or sorbitol complete or partial ester, and

(c) a tenside having a hydrophilic-lipophilic (HLB) balance of at least 10.

It is suggested that these compositions enable absorption of cyclosporins in a manner that is at least substantially independent of the relative availability of bile acids or salts in the patient's gastrointestinal tract.

Another carrier system for cyclosporin is proposed in GB-A-222770. This takes the form of a microemulsion or microemulsion pre-concentrate which may typically comprise:

(a) a hydrophilic phase,

(b) a lipophilic phase such as a medium chain fatty acid triglyceride, and

(c) a surfactant.

Yet another cyclosporin carrier system is disclosed in GB-A-2257359. This consists essentially of:

(a) 1,2-propylene glycol,

(b) a mixed mono-, di- and triglyceride; and

(c) a hydrophilic surfactant.

WO92/10996 is concerned with improving the bioavailability of probucol, a serum cholesterol lowering agent. It proposes that the probucol be dissolved in a propylene glycol ester of fatty acids of the formula C_x H_2x O₂ wherein x is 4, 6, 8, 10, 12, 14, 16.

Finally, WO92/21348 discloses a pharmaceutical formulation for a specific benzodiazapine, viz 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N' -(3-methylphenyl)-urea, in which the carrier comprises a pharmaceutically acceptable oil selected from the esterification or polyether products of glycerides with vegetable oil fatty acids of chain length C₈ -C₁₀ and a pharmaceutically acceptable surfactant selected from oleate and laurate esters of a polyalcohol copolymerized with ethylene oxide.

The above-discussed patent specifications are not intended to constitute a comprehensive review of the patent literature concerned with orally administratable formulations of hydrophobic drugs. However, they do serve to illustrate an important feature of current formulation technology, namely that it is generally found to be necessary to develop, more or less empirically, a separate carrier system for each hydrophobic drug. Thus, there currently exists no single drug carrier system which is suitable for a wide range of different hydrophobic drugs. The necessity to devise a separate carrier system for each drug is, of course, time-consuming and expensive.

Moreover, the existing drug carrier systems which have been developed for hydrophobic drugs often do not provide a desired level of bioavailability, and accordingly for many hydrophobic drugs there remains the need to find a carrier system which will enhance the bioavailability of the drug in the gastrointestinal tract.

It has long been observed that the bioavailability of many hydrophobic drugs can be improved if the drugs are administered with food. The patient is therefore often instructed to take the drug at meal times. A number of theories have been developed to explain this observation and these include:

(a) delayed gastric emptying, allowing more drug to dissolve before reaching the small intestine or producing a longer residence time at specific absorption sites in the small intestine,

(b) direct interaction and solubilization of drug by food (e.g. high-fat meals),

(c) food-related increases in hepatic blood flow causing a decrease in first-pass metabolism, and

(d) increased gastrointestinal secretions (e.g. of bile) improving drug solubility.

However, it is usually not possible to identify the precise mechanism for any particular drug, and certainly no generally applicable theory which can be used to devise improved formulation systems has been developed.

We have now conducted an extensive investigation into factors which affect the solubilization of hydrophobic drugs in the gastrointestinal tract, and as a result we have been able to develop a carrier system for such drugs which in many cases can give enhanced bioavailability as compared with existing formulations of such drugs.

Moreover, the carrier system which we have developed is found to be generally suitable for a wide range of different hydrophobic drugs, whereby there is opened up the prospect of being able to provide satisfactory formulations of individual hydrophobic drugs with considerably less research effort and expense than has been usual hitherto .

Claim 1 of 25 Claims

1. A carrier system for a hydrophobic drug which comprises:

(a) a digestible oil;

(b) 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, said surfactant comprising:

(i) a hydrophilic surfactant component which substantially inhibits the in vivo livolysis of said digestible oil, and

(ii) a lipophilic surfactant component capable of at least substantially reducing said inhibitory effect of said hydrophilic surfactant component, said lipophilic surfactant component being present in an amount sufficient to achieve the required counteracting of the lipolysis-inhibiting properties of said hydrophilic surfactant,

said lipophilic surfactant component comprising one or more of oleic acid, a glyceryl mono-/di-caprylate surfactant and a glyceryl mono-/di-caprylate/caprate surfactant.

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