United States Patent:   5,993,858

Assignee:  Port Systems L.L.C. (Ann Arbor, MI)

Filed:  June 13, 1997

A self-microemulsifying excipient formulation for increasing the bioavailability of a drug which includes an emulsion including an oil or other lipid material, a surfactant, and a hydrophilic co-surfactant. A method for making a drug delivery system for increasing the bioavailability of a drug by emulsifying at least one drug with a self-microemulsifying excipient comprising an oil or other lipid material, a surfactant, and a hydrophilic co-surfactant and drugs formulated thereby.

DETAILED DESCRIPTION OF THE INVENTION

A self-microemulsifying excipient formulation for increasing the bioavailability of poorly water-soluble drugs or pharmaceutical compositions is disclosed. The formulation generally includes an emulsion including an oil or lipid material, a surfactant, and a hydrophilic co-surfactant. A poorly water-soluble drug or pharmaceutical is emulsified in the self-microemulsifying excipient formulation thereby increasing the in vivo bioavailability of the drug or pharmaceutical formulation.

More than one drug or pharmaceutical ingredient and/or formulation at a time can be treated according to the present invention to yield a desired pharmaceutical composition. Additionally poorly water-soluble drugs and/or pharmaceutical ingredients can be treated according to the present invention and can then be used in combination with other drugs and/or pharmaceutical ingredients which may or may not be poorly water-soluble.

The terms "drug" and/or "pharmaceutical ingredient" or "formulation" include any pharmaceutical compound, drug, or composition, including peptides, in a solid form such as powder or granules.

The term "self-microemulsifying" describes a system in which emulsifies when mixed with an aqueous solvent and which, upon exposure to gastrointestinal fluids, forms stable-microemulsions with diameters in the range of 1 .mu.m.

The oil phase of the self-microemulsifying formulation includes lipid or glycerides containing compounds such as GELUCIRE, Gattefosse Corporation, Westwood, N.J.) but can also include other suitable oil phase compounds for example, digestable or non-digestable oils and fats such as olive oil, corn oil, soybean oil, cottonseed oil, palm oil, and animal fats.

Suitable surfactants or emulsifying agents used in the self-microemulsifying formulation of the present invention include LABRAFAC CM 10, a mixture of saturated C.sub.8 -C.sub.10 polyglycolysed glycerides (HLB=10, Gattefosse Corporation, Westwood, N.J.) and other suitable surfactants, for example, long alkyl chain sulfonates/sulfates such as sodium dodecylbenzene sulfonate, sodium lauryl sulfate, and dialkyl sodium sulfosuccinate, quaternary ammonium salts, fatty alcohols such as lauryl, cetyl, and steryl, glycerylesters, fatty acid esters, and polyoxyethylene derivatives thereof. However, the choice of surfactant appears to be less critical than the choice of co-surfactant as discussed below in greater detail.

The co-surfactants suitable for use with the self-emulsifying excipient formulation of the present invention are preferably hydrophilic in nature. In particular, co-surfactants utilized in the present invention should possess an HLB number of greater than 8 based on the HLB system on which is well known to those skilled in the art. The HLB number provides a means for ranking surfactants based on the balance between the hydrophilic and lipophilic portions of the surfactant or emulsifying agent. That is, the higher the HLB number, the more hydrophilic the surfactant or emulsifying agent. In the present invention, the hydrophilic co-surfactant has a hydrophilic-lipophilic balance (HLB) of greater than 8. Typically, surfactants or emulsifiers within HLB in the range of 8-18 form oil/water emulsions. In the present invention, the preferred HLB range for the hydrophilic co-surfactant is between approximately 10 and 14. Additionally, hydrophilic co-surfactants utilized in the present invention are preferably alcohols of intermediate chain length such as hexanol, pentanol, and octanol which are known to reduce the oil/water interface and allow the spontaneous formulation of the emulsion. Preferred hydrophilic co-surfactants utilized in accordance with the present invention include LABRASOL, (Gattefosse Corporation, Westwood, N.J.), which is comprised of medium chain triglycerides derived from coconut oil having an HLB of 14 as well, as other co-surfactants having an HLB of greater than 8 such as lauryl alcohol.

The self-microemulsifying formulation can also include the addition of an aqueous solvent such as triacetin, an acetylated derivative of glycerol, i.e., glyceryl triacetate or other suitable solvents. Triacetin is suitable since it is miscible in the oil/lipid phase and can be used to solubilize a hydrophobic drug.

Additional materials and/or compounds can be added to alter the consistency of the emulsion. This may be done to increase the stability or emolliency of the emulsion. Such materials can include tragacanth, cetyl alcohol, stearic acid, and/or beeswax [Remington's Pharmaceutical Sciences, 1975].

The method of making a drug delivery system for increasing the bioavailability of a drug and/or pharmaceutical ingredient or formulation by emulsifying the drug with the self-microemulsifying excipient formulation of the present invention includes the steps of solubilizing a poorly water-soluble drug, pharmaceutical ingredient, or formulation thereof, in a mixture of surfactant, co-surfactant and solvent. The oil phase can then be suitably prepared, if necessary, by heating or other preparatory means and can then be added to the solubilized drug formulation and thoroughly mixed. The emulsion can then be added to a suitable dosage form such as soft or hard-filled gelatin capsules and allowed to cool.

The relative proportions of surfactant and co-surfactant in the self-microemulsifying formulation of the present invention can influence the solubilizing and dissolution properties of the formulation. In general, the range of concentration of the surfactant/co-surfactant broadly ranges from 15 to 90% (v/v) and more preferably ranges from approximately from 45 to 55% (v/v). The concentration of the co-surfactant broadly ranges from 16 to 89% (v/v) and more preferably ranges from 30 to 40% (v/v). The relative amounts of surfactant to co-surfactant in the formulation of the present invention range from approximately 45 to 50% (v/v) with the preferred range being approximately 25 to 35% (v/v). Generally, the ratio of surfactant to co-surfactant ranges from approximately 1:2 to 1:3 depending on the properties of the surfactant and/or the co-surfactant.

The lipophilic, poorly water-soluble active drug or pharmaceutical ingredient utilized in accordance with the present invention can include nifedipine, griseofulvin, cyclosporin, digoxin, itraconozole, carbamazepine, piroxicam, fluconazole, indomethacin, steroids, ibuprofen, diazepam, finasteride, and diflunisal, for example. Other pharmaceutical ingredients or other drugs which are lipophilic or poorly water-soluble can also be used in accordance with the present invention. This list is not meant to be exhaustive, but rather provide examples of suitable compounds may be used in accordance with the present invention.

Applicant has conducted dissolution/bioavailability studies demonstrating the increased dissolution rate of water-insoluble pharmaceutical ingredients and drugs according to the present invention. Specifically, as described in greater detail below, applicant has demonstrated an improvement in the bioavailability of the poorly water-soluble drug, nifedipine, using a co-surfactant with a high HLB (HLB=14) value or that of a co-surfactant with a low HLB (HLB=4) value even though both formulations appeared to solubilize the drug equally. The area under the plasma-time curve (AUC) for the formulation with the high HLB co-surfactant was five times greater than that of the drug alone (powder) and two times greater than that of the formulation with the low HLB value. This result suggested that the HLB value of the co-surfactant plays an important role in increasing the bioavailability of lipophilic or poorly water-soluble drugs by possibly facilitating the solubilization of the poorly water-soluble drugs, by increasing the permeation of the drug across the intestinal wall, or both.

Theoretical considerations of drug dissolution and absorption in the human gastrointestinal tract indicate that for water insoluble drugs two independent variables will control drug absorption: the dissolution rate extent of dissolution and dose of drug given. The significance of this analysis is that for water insoluble drugs, the fraction dose absorbed is inversely proportional to dose and is directly proportion to the dissolution rate. Therefore, in vivo solubilization and dissolution are important determinants of drug absorption.

Intestinal Drug Absorption-Theoretical Considerations

Membrane Permeability and Luminal/Wall Concentration

The fundamental equation describing drug absorption is;

Jw=Pw.Cw equation 1

where, Jw(x,y,z,t) is the drug flux (mass/time/area) through the intestinal wall at any position and time, Pw(x,y,x,t) is the permeability of this (complex) membrane, and Cw(x,y,z,t) the drug concentration at the membrane (wall) surface (know as Ficks' First Law) [Bird et al., 1960]. This is Ficks' First Law applied to a membrane and applies at each point along the membrane, i.e., equation 1 is a local law pertaining to each point along the intestinal membrane. Equation (1) states that the critical parameters governing drug absorption are the intestinal permeability and the concentration of drug in solution at the intestinal surface. Pw here is assumed to be high since the drugs are lipophilic. Therefore the focus will be the term Cw.

However, the fraction dose absorbed may be independent of the dissolution of the drug if the solubility is very low or the dose very high. This region, termed the solubility limited region of drug absorption, clearly indicates that the extent of drug absorption will be very dependent on the solubility of the drug in the gastro-intestinal luminal contents [Hernell et al., 1990; Staggers et al., 1990; and Davenport, 1982].

Based on the discussion above and the accompanying experimental data, applicant has shown that a more hydrophilic co-surfactant, that is, a co-surfactant with a high HLB number, not only increases the dissolution of poorly water-soluble drugs and pharmaceuticals but, that it also greatly increases the in vivo bioavailability of the poorly water-soluble drug or pharmaceutical. That is, not only is more of the poorly water-soluble drug or pharmaceutical solubilized but, the self-microemulsifying formulation of the present invention also presents the drug or pharmaceutical ingredient to an organism in a form which is more readily utilized and thus, enhances the bioavailability of the drug or pharmaceutical ingredient.

Claim 1 of 12 Claims

1. A self-microemulsifying excipient formulation for increasing the bioavailability of a drug which comprises:

an emulsion including an oil or other lipid material, a surfactant, and a hydrophilic co-surfactant, said hydrophilic co-surfactant having a hydrophilic-lipophilic balance (HLB) greater than 8.

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