DRUG ABSORPTION FROM CONVENTIONAL FORMULATIONS

2. DRUG ABSORPTION FROM CONVENTIONAL FORMULATIONS

2.1. Drug Absorption from Aqueous Vehicles

2.1.1. Variation in Absorption It is often thought that drugs are rapidly and completely

absorbed from the s.c. and i.m. injection site particularly when formulated in aqueous systems. However, it appears that the rate as well as the extent of drug absorption is often erratic and variable (1). Several factors may account for the variability in absorption rate and extent. Differences in physiological parameters such as drainage and blood flow due to muscle activity, inflammation, and physiological reac- tions to the injection trauma are possible explanations (2,3). For example, after i.m. injection, the absorption of artelinic acid, a water-soluble derivative of the anti-malaria drug arte- misinin, is found to be very variable (Fig. 1) (4). Hydrophilic

Figure 1 Fraction of the injected dose remaining to be absorbed after i.m. injection of sodium artelinate (20 mg/kg) aqueous solution in rabbits. Each line represents the data of an individual animal (n = 10). (From Ref. 4.)

Injectable Dispersed Systems 43

compounds with rather low molecular weights (such as arte- linic acid) are preferentially absorbed by the paracellular route. This transport capacity is influenced by several factors including muscle activity, inflammation, and flow of the tissue fluid and, therefore, absorption by this route is generally very variable (2). Another cause of variable drug absorption is injection technique. Intra- and intermuscular injections, within and between the muscle fibrils, respectively (5), may result in different absorption profiles. This would result in

a bimodal distribution in the absorption rate; however, experimental evidence for bimodality is lacking in the litera- ture. Another likely explanation, which is not definitely pro- ven, is a variation in the shape of the depot. The shape may vary from spherical to almost needle-shaped in different sub- jects. These differences depend on local cohesion between the muscle components and the tendency for these to be torn open by the injection procedure. Differences in the shape of the depot cause differences in the contact area between the depot and the surrounding tissue, the effective permeation area, and thus in the absorption rate.

2.1.2. Extent of Absorption Hydrophilic drugs in solution injected i.m. and s.c. are gener-

ally rapidly absorbed from a local depot. However, complete absorption in a time relevant for therapy does not always occur (6–9). Absorption only takes place as long as enough vehicle or essential elements of the vehicle are present to keep the drug in solution or to drive the absorption process. After the vehicle has been absorbed, the absorption, rate of the drug decreases rapidly due to precipitation at the injection site. Particularly, salts with an alkaline or acidic reaction have the potential to precipitate after injection due to the neutra- lizing or buffer capacity of the tissue fluids. This has been briefly mentioned in the literature for quinidine hydrochlor- ide (9) and is clearly illustrated in a study using human volunteers by Kostenbauder et al. with i.m. injected pheny- toin (10). Relatively high concentrations of phenytoin in solu- tion require a relatively high pH (pH 11 or higher) as well as

44 Oussoren et al.

co-solvents and =or complexing agents. After i.m. injection, phenytoin is slowly absorbed over a period of approximately

5 days. After 40 hr, 20% of the drug remained unabsorbed. Precipitation and slow redissolution of the drug by tissue fluids at the injection site may explain the slow absorption. The authors developed a mathematical model based on this concept. The observed drug concentration curves in plasma fitted well with this model. Precipitation is probably a result of the pH neutrali-zing effect of the tissue components and possible relatively rapid absorption of one or more of the essential solvent components (10).

Slow absorption due to precipitation is a potential risk for reduced bioavailability as shown for i.m. injection of pheno- barbital. After i.m. injection in the deltoid muscle of children, phenobarbital appeared to be completely absorbed, however bioavailability was only 80% compared to oral administration in adults (11). A lack of stability of phenobarbital at the injec- tion site (amide bond hydrolysis) was proposed as an explana- tion for the incomplete bioavailability. Another possible explanation is precipitation of phenobarbital at the site of injection, since this formulation is very similar to the pheny- toin formulation, described above. The detection limit of the analytical method is also very important since slow adsorption of precipitated drug may result in very low and clinically irre- levant concentrations which may not be detected.

Prevention of precipitation of salts and thus enhance- ment of absorption may be achieved by the use of cosolvents as demonstrated in a study on the effect of propylene glycol on the absorption of benzimidazole hydrochloride (12). It appeared that propylene glycol, which apparently is absorbed slower than water, may prevent, at least partly, precipitation of the free base (or free acid) in certain circumstances. This may enhance the absorption rate of the drugs in question.

2.1.3. Physicochemical Characteristics of Drugs Physicochemical factors such as the lipophilicity of the drug

are important factors that determine bioavailability. Hydro- philic drugs are usually absorbed completely. In contrast,

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aqueous solutions and suspensions of relatively lipophilic drugs are often absorbed incompletely within a therapeutically relevant time. The influence of drug lipophilicity on absorption rate is illustrated by the difference in absorption rate between midazolam and diazepam. Midazolam is absorbed signific- antly faster following i.m. injection than the more lipophilic diazepam (13).

b-Blocking agents are an ideal group of compounds for investigation of the effect of drug lipophilicity and release from i.m. and s.c. injection sites since they have similar molecular

weights and pK a values, but differ markedly in lipophilicity. Studies in pigs using crossover experiments have been published with b-blocking agents with varying lipophilicity: ate- nolol, metoprolol, alprenolol, propranolol, and carazolol (14,15). Figures representing the fraction remaining at the site of injec- tion after s.c. and i.m. injection using i.v. data as references showed biphasic declines; a rapid first phase and a very slow sec- ond phase ( Fig. 2 ) (15). Initial release rates appeared to be nega- tively correlated with drug lipophilicity expressed as fat-buffer partition coefficients, especially after injection into the s.c. fat layers, also called the intra-adipose layers ( Fig. 3 ) (14). The more lipophilic the compound the lower the release rate and the bioavailability. The most hydrophilic compound, atenolol, was the only one which was completely absorbed or bioavailable within 8 hr after i.m. injection and within 24 hr after s.c. injec- tion. The relatively high absorption of relatively hydrophilic drugs is a result of fast transition of the drug into the hydrophi- lic tissue fluid. More lipophilic drugs, which transit slower into the aqueous phase, are absorbed slower. As a result of the slower absorption process, the aqueous vehicle may be absorbed before drug absorption is complete, which consequently results in reduced bioavailability as discussed above (14,15).

In contrast to what one would expect based on lipophili- city, propanolol was better and faster absorbed from the i.m. injection site (15). This may be related to local tissue irritation by the drug. Propranolol is known to have local irritating properties which may improve blood perfusion in the muscles and account for the deviant behavior after i.m. injection. Absorption of propranolol after s.c. administration was as

46 Oussoren et al.

Figure 2 Typical example of the fraction of the injected dose remaining at the injection site after intra-adipose (s.c.) and intra- muscular administration of a series b-blocking agents. In order of increasing lipophilicity: atenolol (black squares); metoprolol (black dots); alprenolol (open circles); propranolol (open squares). (From Ref. 15.)

anticipated based on its lipophilicity since the s.c. fat layer or adipose layer is less sensitive to irritating compounds and is less well perfused compared to the i.m. site (15).

Molecular weight appears inversely related to the absorption rate. It has been shown that relatively small mole- cules are absorbed primarily via the blood capillaries, while

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Figure 3 Correlation between the fat-buffer distribution constants and release rates on intra-adipose administration of atenolol (At), metoprolol (Me), alprenolol (Al), and propranolol (Pr). (From Ref. 14.)

compounds with molecular weights larger than approxi- mately 16 kDa and particulate matter such as drug carriers appear to be absorbed mainly by the lymphatics, which results in a lower rate of absorption (6,16). (The reader is

referred to chapter 6 in this book for a discussion of the biopharmaceutical principles with respect to injectable suspensions.)

2.2. Drug Absorption from Oily Vehicles Drug solutions in oil and even suspensions in oil are often

thought to be sustained release preparations. However, rapid absorption is often observed. Most likely, slow release is not a property of the oily vehicle but it is the result of relatively high lipophilicity of the drug or interactions between the drug and the vehicle.

Oily vehicles are absorbed slowly and remain present at the injection site for several months. As long as the oily vehicle is present at the site of injection and contains drug in solution, the drug will be released and absorbed from the

48 Oussoren et al.

injection site. The same applies to drug suspensions in oil. For example, the relatively hydrophilic anti-malaria drug artemi- sinine is relatively rapidly absorbed when injected as a suspension in oil (17). Due to drug absorption, drug concentra- tion in the oily vehicle decreases and consequently suspended drug will dissolve and be absorbed from the site of injection into the blood circulation. Additionally, drugs in suspension may migrate in particulate form to the interface of the oily vehicle and the aqueous tissue fluid. At the interface, hydro- philic drugs may rapidly dissolve and become absorbed ( Fig. 4A ). In contrast, absorption of artemisinine from a sus- pension in an aqueous vehicle is much slower, which is most likely the result of rapid absorption of the aqueous vehicle and consequently low dissolution of the drug at the site of injec- tion. As discussed in the previous section, precipitated drug is absorbed slowly and erratically (Fig. 4B).

Drug release and absorption from an oily vehicle into the blood circulation depends mainly on the lipophilicity of the drug. At the oily vehicle =tissue fluid interface, the transition of drugs from oily vehicles into the aqueous phase is con- trolled by the oil =water partition coefficient. More lipophilic drugs will transit slowly into the aqueous tissue fluid and consequently will be released and absorbed slowly. Hence, lipophilic derivatization can be used as a tool to optimize the sustained release characteristics of the formulation.

The importance of the partition coefficient is illustrated by experiments in which the influence of the lipophilicity of the vehicle on the in vivo release of testosterone-decanoate was studied (18). Disappearance of the drug from the injection site was determined to be proportionally related to the in vitro partition coefficient ( Table 2 ). The slowest absorption rate occurred when ethyloleate, to which the drug has the highest affinity, was used as the vehicle. The mean absorption half-life value increased from 3.2 hr in light paraffin to 10.3 hr in ethy- loleate. Thus through formulation in a vehicle with a high lipo- philicity sustained release of this drug was achieved (18). These observations illustrate and endorse the importance of the choice of vehicle and the affinity of the drug for the vehicle on drug absorption following i.m. injection.

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Figure 4 Plots of artemisinin concentrations in serum vs. time after an i.m. administered dose of 400 mg artemisinin to human volun- teers. A) Suspension in oil; B) Suspension in an aqueous vehicle. Each line represents the data of an individual volunteer (n = 10). (From Ref. 17.)