Pharmaceutics I - Case Study 1
(September / October, 1998)
Your group has been asked to provide advice to a research team that is interested in developing novel anti-tumor therapies based on a combination formulation of drugs that are known to have anti-tumor properties. All the drugs are also known to be substrates for the protein efflux pump p-glycoprotein, which leads to a phenomenon called multi-drug resistance. It is hoped, but not known, that when a combination of drugs is used, this problem may be reduced, and the combination formulation will have improved therapeutic properties.
The task you are presented with is to develop an aqueous solution dosage form containing two drugs that could be administered i.v. The drugs your group should consider are given in the table on page 3.
The research formulation must contain the following compoents:
A 0.005M concentration (if possible) of drug 1 and a 0.004M concentration (if possible) of drug 2.
An isotonic solution at an appropriate pH, buffered with a citric acid or a phosphoric acid buffer solution.
A total volume of 50ml.
Any other components you feel to be necessary.
In addition, the other members of the research team (who do not have training in pharmacy, but are scientifically and chemically literate) have asked you to supply the following information:
A description of the importance of p-glycoprotein in the development of multi-drug resistance, and a discussion of this phenomenon in the context of your particular drugs.
A report on the clinical usage of each drug, on the types of tumors that the drugs can be used against, on the normal way in which the drug is formulated, and on the normal route of administration of the drug.
A description of the physicochemical properties of each drug. This should include identification of all the functional groups in each molecule, an IUPAC name for each drug, the pKa values of any ionizable functional groups, an estimation of the dimensions (in Angstroms) of each molecule, and a consideration of any likely interactions between the two drugs.
The shelf-life of the formulation at (a) 25°C and (b) 10°C, and the most appropriate storage conditions.
A complete and accurate description of the experimental aqueous formulation, including all the weights of the components to be included.
An assessment of the potential improvement in therapeutic properties against specific tumor types which might be achieved by the combination therapy.
In order to perform this task, you first need to fully understand the physicochemical properties of the drug molecules. After finding this information, you will then be in a position to assess the viability of creating such a formulation, to describe the difficulties associated with doing so, and to determine possible approaches to dealing with these difficulties. You will also be in a position to determine the most appropriate pH for your formulation, which in turn will allow you to identify the most appropriate buffer solution, and to determine the requirements to make the solution isotonic. With all this information, you will be able to calculate or estimate a shelf-life, and then determine appropriate storage conditions.
To approach the problem, you need the following information :
(i) A molecular structure of each drug. Identify all the functional groups and try to estimate the dimensions of the molecule.
(ii) An IUPAC name for each drug, or, at least, a name that conveys the structure of the drug to a chemist who may not be familiar with the common name of the drug.
(iii) A list of all pKa values in each drug. These may be obtained from literature, either by a direct reference to your drug, or by analogy with a similar drug (show all references, and provide evidence that your analogy is accurate). Alternatively, in some cases you could use empirical calculations, or just estimates (again, these must be fully justified) to arrive at these pKa values.
(iv) An estimate of the water solubility of each drug. Again, you may need to use analogy to other molecules.
(v) A description of the possible degradation reactions the drugs might undergo in aqueous solution, if any, as a function of pH, and an assessment of which of these reactions is likely to be of most significance. You will also need to assess which drug might cause most problems in terms of stability in aqueous solution. A rate constant for the degradation reaction will be necessary to calculate the shelf-life.
(vi) The pKa values of the weak acids of each buffer solution. This will help in your final choice of pH for the formulation, and in your choice of which buffer solution to use.
To complete the case study, you then need to discuss all this information in the context of the formulation you are required to prepare. It is essential that you do not simply provide a list of the above data. You must apply the information in an appropriate manner to the problem at hand.
Suggested Page Limits
Note that these are only suggested page limits, and they do not have to be followed exactly. Also, the order of the report need not necessarily follow the order given below. You can use appendices to show detailed calculations. The appendices are not included in the 10 page limit.
|
number of pages |
|
p-glycoprotein and multi-drug resistance |
1 |
|
clinical usage and tumor specificity of each drug |
1 |
|
physicochemical properties |
2 |
|
solubility |
1 |
|
degradation, shelf-life |
2 |
|
choice of pH, choice of buffer, isotonicity, complete formulation table |
2 |
|
assessment of the therapeutic potential of the combination therapy |
1 |
|
total length of report |
10 pages |
Due Date
The case study report should be completed by Thursday, October 15th, by 5p.m. In addition, a complete electronic version of the report (including all figures) should be submitted (the location of the directory for this submission will be announced). Included with the report should be a peer evaluation form from each student in the group. The case study organization form should be completed by each group and given to Dr. Haworth by the group leader no later than Thursday, September 24th.
Table of Drug Combinations