Bioavailability and Efficacy

1Drugs are not invented in the manner in which it is finally available to the market. Lead compounds are invented which may ultimately result in the drug. The lead drug is a compound which has a number of attractive properties like desired biological or pharmacological activity, but may also have a host of undesirable properties like high toxicity, adsorption difficulties (bioavailability), insolubility or metabolism problems. (Richard B Silverman, The Organic Chemistry of Drug Design and Drug Action, second edn, Elsevier Academic Press, 2004, p 9.) One of the important characteristics of any drug is its bioavailability. Bioavailability determines the extent to which, and rate at which, a drug appears in the bloodstream after administration in dosage form. Where the bioavailability of one drug is the same as another drug (or the bioavailability of two different formulations of the same drug are the same) they are said to be bioequivalent.

2It is a common practice to modify the structure of the lead compound to amplify the desired properties and to suppress or eliminate the unwanted properties. The resultant drug is known as the drug candidate, which is a compound worthy of extensive biological, pharmacological and animal studies. The drug candidate is then developed into a clinical drug, which is a compound ready for clinical trials. (Richard B Silverman, The Organic Chemistry of Drug Design and Drug Action, second edn, Elsevier Academic Press, 2004, p 9.)

3The preparation of a drug will normally involve the pre-formulation stage and the testing stage. In the pre-formulation stage, the formulator will be given an appropriate specification which would, for instance, define the drug dosage to be incorporated and whether the formulations should provide for the immediate release of the drug or a more controlled release. The formulator will also have basic information about the physicochemical properties of the drug, including information about the solubility of the drug in aqueous and other media, the stability of the drug in solution; and interactions between the drug and excipients that might be required in preparation of the dosage form. In the testing stage, the formulator would perform dissolution studies in order to ascertain the dissolution rate of the drug which would give an indication of the likely bioavailability of the drug. Where the drug had a slow dissolution rate, the formulator would know that it was likely to have poor bioavailability. If the drug had a slow dissolution rate, the formulator would know techniques to improve it, such as reduction of particle size and using excipients (inert substances) to ensure that the dosage form is wetted easily, and quickly breaks up to release the drug into the surrounding fluids. (See Ivax Pharmaceuticals UK Limited v Akzo Nobel NV [2006] EWHC 1089, paras 10-13 (CH), where the court discusses the routine steps in drug formulation.)

4In determining whether there is an enhancement in efficacy or bioavailability of a drug, the court will normally have to consider the ‘common general knowledge’ with regard to bioavailability. Common general knowledge in any field refers to the ‘common knowledge in art and science to which the alleged invention relates, so as to be known to duly qualified persons engaged in that art or science’. (British Thomson-Houston Co Ltd v Stonebridge Electrical Co Ltd (1916) 33 RPC 166, p 171.) In other words, it is the knowledge which reflects the capacity of a person skilled in the art (skilled addressee). Needless to say, the common general knowledge on bioavailability will depend on various factors, which have been summarised in Ivax Pharmaceuticals UK Limited v Akzo Nobel NV: ([2006] EWHC 1089, para 7 (CH).)

The skilled addressee’s common stock of knowledge would include the following:

(i) The dissolution rate of a drug affects its bioavailability. (ii) If a drug has a low aqueous solubility it will have a low dissolution rate. (iii) The dissolution rate of a drug is directly related to its solubility. Solubility is affected by the chemical nature of the drug and also its salt form. (iv) The dissolution rate of a drug is affected by particle size, because dissolution is directly related to surface area. The greater the surface area of the particles, the faster a drug dissolves. (v) What would be a suitable particle size varies from drug to drug, but typical limits would be sizes from 5 << mu> > m to 40 << mu>>m. (vi) Different physical states of a drug can have an effect on the apparent solubility. These physical states include the formation of solvates (particularly hydrates) and whether the drug is in crystalline or amorphous form. (vii) Different crystalline forms of a drug (polymorphs) can have different energy states. As a result different polymorphs can display different physical properties. (viii) The differing properties of different polymorphs can include different apparent solubilities; and thus have different rates of dissolution, which can affect the bioavailability of the drug. (ix) However, if a drug has a high solubility in water, then the pharmokinetic properties of the drug are not affected by particle size, or by polymorphic form, because in those circumstances the rate of absorption of the drug is controlled by the permeability of the drug across the gastrointestinal tract. (x) Normally the most stable polymorph is selected for drug development. This is generally the polymorph with the lowest thermodynamic energy state. The polymorph with the lowest energy state will also be expected to be more stable chemically, because of a higher crystal density. (xi) It is important to screen for polymorphs both during processing and during storage, since changes can occur at both stages [Emphasis supplied].

5The above passage will show how bioavailability is understood by a person skilled in the art. A person skilled in the art will be imputed with knowledge that salt forms, polymorphs, particle size etc will have an effect on the bioavailability of the drug. The terms used in the above passage are reminiscent of the language used in the explanation to s 3(d) of the Patents Act.

6In a case involving a patent for steroid tibolone (a polymorphous compound which exists in more than one crystalline form) it was held that finding a particle size with bioequivalence to the marketed product was no more than a matter of routine testing. The court held that the particle sizes claimed were nothing out of the ordinary, and would have been obvious to the skilled but unimaginative formulator. The court revoked the patent on the ground of obviousness. (See Ivax Pharmaceuticals UK Limited v Akzo Nobel NV [2006] EWHC 1089, paras 71-73 (CH).)