Abstract:
This invention relates to a method for administering drugs. In particular a lipophilic drug is solubilized by a food, such as chocolate, and admixed with an oil-based carrier. The lipid soluble drug is thus conveyed to the gastrointestinal tract. Because this type of food is digested readily, the drug is absorbed as intended, and the dose is not subject to day-to-day variations.

Description:
FIELD OF THE INVENTION 
     This invention relates to a method for administering drugs, involving solubilizing a drug in acceptable foods admixed with an oil. Because the food is digested readily, the drug is absorbed as intended, and the dose is not subject to day-to-day variations. 
     BACKGROUND OF THE INVENTION 
     Presently almost all forms of oral medication are manufactured in a form to be swallowed, thereafter to be dissolved within the lumen of the gasterointestinal tract and absorbed into the circulation whence it is distributed throughout the body. Occasionally, a suitable oral form is a liquid when it is swallowed, but to be sure a patient is receiving the entire dose of liquid medicine, often it must be coalesced with a diluent. In the instances the liquid medicine does not make a solution with a diluent that is agreeable to most people, there is considerable risk of day to day variation in dose received by the patient. When such a drug has a therapeutic dose and a toxic dose which are nearly equal, the disadvantage of the variation is enhanced, and the danger to the patient increased. 
     Some drugs, such as cyclosporine, are particularly difficult to administer. B. Ota, in an article entitled Administration of Cyclosporine, Transplantation Proceedings, Vol. XV, No. 4 Suppl. I. (December) 1983, points out that cyclosporine is soluble in alcohol and fat solvents, but not in acqueous solutions, thus making the administration of cyclosporine difficult. The article notes that because cyclosporine is fat soluble and dispensable in an oil base, it is considered quite distasteful by most patients. 
     In spite of mixing with chocolate milk, some patients vomited the liquid initially although later adapting to it and tolerating the drug for long term therapy. It is noted, however, that in one instance, the early nausea produced low blood levels and an early rejection episode. A convenient means of orally administering a lipophilic drug is therefore desirable. 
     SUMMARY OF THE INVENTION 
     This invention involves the use of a food, such as chocolate, which is palatable and into which drugs can be solubilized. The pharmaceutical agent is dissolved readily in the food which accepts drugs such as lipid soluble agents, permitting the patient to ingest fixed quantities of drug by eating standard amounts of the food. Because the food is digested readily, the drug is absorbed as intended, and the dose is not subject to day to day variation. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention, in one exemplification, uses one of many forms of chocolate made into candy-bar-type sections to dissolve and then convey a lipophilic drug such as cyclosporine into the gastrointestinal tract. Chocolate typically contains a portion of oil along with other ingredients. In this embodiment, cyclosporine in olive oil is substituted for some of the regular portion of coconut oil. Chocolate does not require substantial heat for subsequent handling, so relatively heat-labile drugs can be submitted to this process. 
     After blending, which produces a homogenous mixture in which the drug is distributed evenly, the chocolate, or other food substance, is carried to completion and made in a form suitable for administration by molding. Packaging is employed which distinguishes the product from a regular food or candy. Different doses can be prescribed by making scoring marks in the chocolate. 
     Depending on the solubility characteristics of a chosen drug, a food can be selected which will form a solution which predictably will contain precise amounts of drug based on weight or volume. It is helpful if the food can be made into subsegments of various sizes in order to be able to alter the dose of drug with some ease. 
     To demonstrate even distribution throughout a batch of chocolate of beta hydroxy triptamine (BHT), a cyclosporine simulator, the BHT was mixed with chocolate, the mixture was made into wafers, and different portions of the wafers were analyzed to determine the concentration of BHT. As can be seen from the following tables, the BHT was evenly distributed throughout the wafers and the various portions of the wafers. 
     The invention can be utilized with any drug which can be incorporated into an oil base carrier. The vehicle for the oral drug can comprise sugar, cocoa butter, whole milk powder, chocolate liquor, lecithin, and vanillin, each in a range of from about 10% to 20%. Each constituent can be varied to some extent to achieve different tastes, consistencies or packaging, handling or storage characteristics. For cyclosporine, an olive oil solution in a concentration of 100 milligrams per milliliter is made for mixing with the vehicle. Doses of from about 25 mg to 500 mg are desirable for pediatric and adult use, the conventional adult dose being about 250 mg to 300 mg. 
     A suitable dosage would comprise 24 ml of a chocolate mixture vehicle of sugar, cocoa butter, whole milk powder, chocolate liquor, lecithin and vanillin, each in a range of from about 10% to 20%, and 6 ml of cyclosporine/olive oil for a total of 30 ml, to produce an equivalent one ounce chocolate bar. 
    
    
     EXAMPLE 1 
     CHOCOLATE AS A VEHICLE FOR THE DELIVERY OF LIPID SOLUBLE MEDICATIONS 
     Chocolate can serve as a vehicle for delivery of some potent lipid soluble medications that are presently only available in liquid forms because it has the advantage of easy divisibility to accomodate a wide range of dosages and pleasant taste to enhance compliance. 
     This example demonstrates that a lipid soluble drug will form homogeneous mixture when mixed in chocolate. Butylated hydroxytoluene (BHT) was the &#34;drug&#34; used due to its simple chemical nature, complete solubility in olive oil, nontoxic nature, and ease of analysis using HPLC. 
     MATERIALS AND METHODS 
     A known amount of BHT was mixed into a 5 pound lot of milk chocolate. Thirty-two (32) grams of BHT were dissolved in 253  grams of olive oil. The chocolate/BHT/olive oil mixture was then formed into approximately 20 gram bars which were assayed for BHT content by dividing a bar into sixteen pieces and assaying each piece. Pieces of nine randomly chosen bars also were measured to determine BHT. The two methods of measurement demonstrated a homogeneous mixture within a single bar and also from bar to bar. 
     Assays were done by the HPLC method. Each sample of chocolate to be assayed was first dissolved in 5 ml of ethyl ether. Acetonitrile was added to bring the volume to 20 ml. A 100 microliter aliquot was taken and brought to a volume of 20 ml with acetonitrile. This dilution was assayed by the HPLC method. BHT standards were run before each batch. 
     RESULTS 
     The range of BHT concentration in the single bar divided into sixteen pieces was 12.7 to 13.7 mg/gram. The mean was 13.2, standard deviation 0.300832 and standard error 0.075208. The BHT range between the nine randomly chosen bars was 13.5 to 13.7 mg BHT per gram chocolate. The mean was 13.6, standard deviation 0.09718 and standard error 0.0322942. 
     
                       TABLE NUMBER ONE______________________________________CONCENTRATION OF BHT IN ASINGLE BAR OF CHOCOLATEUNITS - MG BHT PER GRAM OF CHOCOLATE______________________________________1         2              3     45         6              7     89        10             11    1213       14             15    16______________________________________POSITION #    1      2      3    4    5    6    7    8WEIGHT   .93    1.30   1.17 1.12 1.08 1.09 1.10 1.07(GM)BHT CONC 13.7   13.2   12.8 12.6 13.3 13.4 13.4 13.2(MG BHT/GM CHOC)______________________________________POSITION #    9      10     11   12   13   14   15   16WEIGHT   .90    1.05   .92  1.04 .94  1.19 1.01 1.01(GM)BHT CONC 13.4   13.2   12.6 13.3 13.4 13.3 13.2 13.4MG BHT/GM CHOC______________________________________ N = 16 SUM 211.4 MEAN 13.2 T VALUE 2.13 +/-.160 STD DEV .301 COEFFICIENT OF VARIATION = 2.28% 
    
     
                                           TABLE NUMBER TWO__________________________________________________________________________CONCENTRATION OF BHT IN RANDOMLY CHOSEN BARS (N = 9)SAMPLING SITE WAS ROTATED IN EACH BAR__________________________________________________________________________1                  2 34                  5 67                  8 9__________________________________________________________________________BAR #       1  2  3  4  5  6  7  8  9SITE #      1  2  3  4  5  6  7  8  9WEIGHT(GM)  .73          .83             1.02                .79                   .79                      .76                         .86                            .77                               .76CONC BHT    13.8          13.6             13.7                13.5                   13.6                      13.6                         13.6                            13.5                               13.7MG BHT/GM CHOC__________________________________________________________________________ N = 9 SUM 122.6 T VALUE 2.31 +/-.075 STD DEV .097 COEFFICIENT OF VARIATION = 0.71%