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Chapter 3 3 .
PHARMACEUTICS AND BIOPHARMACEUTICS Takeru Higuchi and Kenneth F. Finger School of Pharmacy, University of Wisconsin, Madison, Wisconsin William I. Higuchi School of Pharmacy, University of Michigan, Ann Arbor, Michigan
Basic investigations and developments in both pharmaceutics and biopharmaceutics area continue with increasing vigor. Although the bulk of published works still originates from academic institutions, an increasing proportion appears to be contributed by industrial organizations. General developments during the past year in these fields are summarized below. THERMODYNAMIC AND EQUILIBRIUM RELATIONSHIPS The tendency of polyethylene glycol (PEG) to form addition complexes with iodine was reported again by Hiskey and Catwell.' Unfortunately, the authors were apparently not aware of a more extensive study of similar systems carried out ten years earlier' which suggested formation of at least two types of adduct involving PEG, K+, I- and Iz. The more recent report differs in part from the earlier work in that PEGI, complex containing Iz/monomeric unit ratio of one is suggested among others. Bates, Gibaldi and Kanig3 have studied the relative solubilizing tendencies of four bile salts with respect to hexesterol, griseofulvin and glutethimide. The effect, which is ascribed entirely to micellar solubilization, was determined at several temperatures and at salt concentrations up to 0.6M. The most marked effect was noted with hexestrol and least for glutethimide. Connors and Mollica4 have compared the theoretical relationships of stability constants obtainable by solubility and other methods. Chelation equilibria involving five different tetracyclines with cupric copper have been examined by Benet and Goyan.5 These interactions appear to form essentially 2 : l (1igand:metal) complexes, the reaction showing large positive entropy changes.
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DRUG STABILITY The past year was marked by relatively little activity in this area. -Wadke and Guttman' reported on the base induced degradation of 9-methylisoalloxazine under both aerobic and anaerobic conditions. The initial product formed appears to be a carbinol amine. Finholt et a17 have continued their investigation of anaerobic hydrolytic degradations of ascorbic acid with a study on the effect of metallic ions on the over-all rate. Although the reaction appears to be accelerated by doubly and triply charged species, the effect was surprisingly small. HETEROGENEOUS SYSTEMS Powders, Suspensions, and Emulsions - One of the most significant articles in recent years is that by Hiestands on particle-particle interaction in powders. The author has brought together much information from pharmaceutical research and from other disciplines and has perspectively assembled a rational treatise. The importance of plasticity and the true area of contact is clearly described. In addition, several novel methods for evaluating cohesion and adhesion of powder particles are described in this paper. Nash and Haeger9 have described the applications of the Zeta-Meter, a device which conveniently measures the electrophoretic mobility of suspension particles. The instrument appears to be useful in suspension and emulsion formulation work and in basic studies related to dispersed systems. Mima and Kitamori'' and Groves" have employed the Coulter Counter in studying the aggregation behavior of emulsions. This instrument continues to be useful for work of this type. Ho12 has described a modification of this instrument which involves the simultaneous sorting of the particles into 400 size ranges. This improvement significantly extends the applicability of this technique. Drug Release Rate Behavior - Desai et all3 have reported results of extensive studies on the release of druq from matrices. Taking the basic physical model approach and beginning with the Higuchi relati~nship'~ these authors have quantitatively investigated the influence of many factors upon the rate of release. The equation was also found by Lapidus and Lordi15 to apply to a system having hydrophillic gum as the matrix. Goldberg et al" have continued their extension of the Japanese workI7 on utilizing melts to increase dissolution
Sect. V I
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rates of drugs. Succinic acid as well as urea was used as the vehicle in these studies. Since at elevated temperatures the dicarboxylic acid readily cyclizes to form succinic acid, some of the results should, perhaps, be re-examined. BIOPHARMACEUTICS The pharmacological activity, efficacy, and toxicity of an administered medicament may be profoundly affected by the physic-chemical properties of the drug and the drug dosage form. Thus, such parameters as solubility, particle size, diffusional characteristics, availability and rate of dissolution of the drug have been the areas emphasized in most biopharmaceutical studies. The effect of these parameters on drug absorption is the subject of this review. Diffusional Characteristics - The everted intestinal sac technique was employed by Aguiar and Fifelski” to quantitate the absorption of flufenamic acid. These workers determined the rate of permeability of flufenamic acid through the intestinal wall of the golden hamster, in vitro, and interpreted their results in terms of Fick’s first law of diffusion. They observed a -linear relationship between the concentration of the drug employed and the rate of intestinal permeation, thus establishing that the transport of flufenamic acid through the gut was by passive diffusion. By varying the pH of the external (mucosal) media, they found that the rate of permeation was inversely proportional to the degree of ionization, thus supporting the hypothesis that only the unionized moiety permeates the biological membrane. While most drug systems evaluated have shown passive diffusional characteristics, Levy and Jusko19 have reported that the oral absorption of riboflavin in man possesses characteristics indicative of specialized transport mechanisms. The evidence in support of such a conclusion was based on the finding that as the dose of riboflavin was increased, the per cent absorbed (based on urinary recovery) decreased. This effect was observed only in fasted patients and was not observed when riboflavin was administered with a meal. The authors suggest that the presence of food in the alimentary tract delays the transit time of riboflavin, thus keeping it in the presence of absorptive sites for longer periods of time. In an interesting study utilizing tritiated mineral oil, Ebert, Schleifer, and HessZo have shown that contrary to previous opinions, a small but significant amount of mineral oil is absorbed from the alimentary tract following oral
Higuchi, F i n g e r and Higuchi
administration. Their findings, employing doses consistent with those usually utilized for laxative purposes in humans, indicated that approximately 1.5% of the administered dose was absorbed unchanged with an additional 1.5% appearing in the carcass of the animals but arising from non-mineral oil sources. The origin of the non-mineral oil sources was not proved but may have arisen from exchange reactions prior to or after absorption or from non-polar metabolic products of mineral oil metabolism. The authors noted that once absorbed, the mineral oil was slow in leaving the body. The elimination curves illustrated a dephasic characteristic, the more rapid component resulting in a reduction of the mineral oil content of the body from 1.5% of the administered dose down to 0.3% in approximately two days. The slower component of elimination reduced the content further down to 0.1% in 21 days. In agreement with studies previously reported,21 Ebert et a1 found that emulsification of the mineral oil greatly facilitated the oral absorption of mineral oil. Although a mechanism to rationally explain their findings is not presented, Green et a122 have reported data substantiating their previous observations on the influence of cholinesterase inhibitors on the oral absorption of sulfonamides.23 These workers found that the four-hour plasma levels of sulfacetamide, sulfonilamide and sulfaguanidine were enhanced when the rats were pre-treated with neostigmine as compared to those plasma levels found in the controls. The earlier studies had indicated that this enhancement was not blocked by atropine, thus minimizing the possibility of an increased blood flow at the absorption site as being the mechanism for enhanced absorption. While perhaps not representing a major factor in the absorption of drugs through the intestinal membranes, the role played by cholinergic systems is worthy of further elucidation. It would be desirable, in this regard, to ascertain whether or not other drug systems are similarly affected by inhibitors of cholinesterase. Particle Size - The influence of particle size on the overall absorption of medroxyprogesterone in man has been studied by Smith, Pulliam and Forist.24 Utilizing an eight-hour urinary excretion of metabolite as an index of the absorption of drug, they found that 2 . 2 3 times as much medroxyprogesterone was absorbed from the micronized formulation as was obtained from the non-micronized drug formulation. While these data could also be interpreted to indicate only an increased rate of absorption with no change in the total amount of drug absorbed, the authors feel that because of the finite transit' time of the drug through the gastrointestinal tract, and the 1 previously reported excretion studies of Helmreich and Huseby,25 these data are best interpreted to indicate an
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enhanced total absorption of the drug. Drug Interactions and Availability - The role of surfactants in modifying the availability and/or the absorbability of various barbiturates via the rectal route was the subject of a report by Fincher, Entrekin, and Hartman.26 These workers, employing a petrolatum-paraffin base suppository, added various surfactants of known HLB values, and determined the effect of the incorporated barbiturate on the rate of respiration of the rabbit. The authors concluded that while the inclusion of a surfactant enhanced the rate of absorption of the barbiturates in some cases, it could also bind the drug, thus making it less available for the absorption process. The chemical type of drug and surfactant were deemed more important than either the apparent HLB of the system or the relative distribution coefficient. Similarly, Levy, Miller, and Reuningz7 found that by adding various concentrations of polysorbate 80, a nonionic surfactant, to aqueous drug solutions, the absorbability of a barbiturate could be both increased or decreased. These authors employed goldfish as the test species and investigated the lethality times of low molecular weight alcohols and two barbiturates. The inclusion of the polysorbate 80 had no effect on the lethality times of the alcohols while it was concluded that low concentrations of the surfactant (below the critical micelle concentration) enhanced the absorption of sodium secobarbital,and higher concentrations decreased the rate of absorption of the barbiturate. In both this study and the work of Fincher et a1,26 the possibility of drug-surfactant interactions detrimental to the availability of the drug for absorption is a probability worthy of further study. Singh et allz8 studied the interaction of various barbiturates with polyethylene glycol 4000 and found that phenobarbital formed a complex with the glycol. The solubility of the complexed phenobarbital was much lower than the intrinsic solubility of phenobarbital in the absence of polyethylene glycol 4000. Utilizing the everted sac technique to measure the rate of intestinal permeability, they found that the decreased solubility greatly decreased the rate of permeation. The other three barbiturates'studied, pentobarbital, barbital, and barbituric acid, did not interact with the polyethylene glycol 4000 and the inclusion of this material did not decrease their rates of intestinal permeation. Sorby and LiuZ9 investigated the effect of adsorbents on the intestinal absorption of promazine in humans. The
B i o p h a rm a ce u t i c s
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results of this study point out the importance of knowing the reactivity of the drug with materials either contained in the dosage form or administered as concurrent therapy. They found that an antidiarrhea mixture containing attapulgite and pectin had a very strong affinity for promazine by in vitro adsorption techniques. When promazine was administered to humans along with the attapulgite-pectin mixture, the rate and extent of gastrointestinal absorption of promazine was decreased. Influence of Dosaqe Form - The oral absorption of indoxole, an experimental non-steroidal anti-inflammatory compound, was studied by Wagner, Gerard, and Kaiser.30 These workers employed four different dosage forms of indoxole in their studies, an emulsion, soft elastic capsules, an aqueous suspension, and a hard capsule. They found that solutions of the drug (the emulsion and the soft elastic capsule) gave superior absorption characteristics as measured by drug plasma levels than did the solid drug forms (the suspension and the hard capsule). It would appear that indoxole represents another case where dissolution rate and/or drug availability is the rate determining process in the over-all absorptive process. References 1. 2.
3. 4. 5. 6. 7.
10. 11. 12. 13. 14. 15.
C. F. Hiskey and F. F. Cantwell, J. Pharm. Sci., 55, 166 (1966). D. E.' Guttman and T. Higuchi, J. Am. Pharm. Assn. Sci. Ed. 44, 668 (1955). T. B z e s , M. Gibaldi, and J. L. Kanig, J. Pharm. Sci., 55, 191, 901 (1966). K. A. Connors and J. A. Mollica, ibid, 55, 772 (1966). L. Z . Benet and J. E. Goyan, ibid, 55, -84 (1966). D. A. Wadke and D. E. Guttman, i b i d T z , 1088, 1363(1966). P. Finholt, H. Kristiansen, L. Krowczynski, and T. Higuchi, ibid, 55, 1435 (1966). E. N. Hiestand, J. Pharm. Sci., 55, 1325 (1966). R. A. Nash and B. E. Haeger, J. %%arm. sci., 55, 829 (1966). H, Mima and N. Kitamori, J. Pharm. Sci., 55, 44 (1966). M. J. Groves, J. Pharm. Pharmacol., 305 (1966). N. F. H. Ho and W. I. Higuchi, Abstracts of the 1966 Meetings, Acad. Pharm. Sci., Dallas. S. J. Desai, P. Singh, A. P. Simonelli, and W. I. Higuchi, J. Pharm. Sci., 55, 1224, 1230, 1235 (1966). T. Higuchi J. Pharm. Sci., 52, 1145 (1963). H. Lapidus and N. G. Lordi, ibid,55, 840 (1966).
346 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
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H . G o l d b e r g , M. G i b a l d i , and J . L. K o n i g , i b i d , 55, 4 8 2 , 487 ( 1 9 6 6 ) . K. S e k i g u c h i , N. O b i , and Y. U e d a , C h e m . Pharm. B u l l . , 12, 1 3 4 (1964). A. J . A g u i a r , a n d R . J . F i f e l s k i , J . P h a r m . S c i . , 55, 1387 (1966). G. Levy and W. J . J u s k o , J . Pharm. S c i . , 55, 285 ( 1 9 6 6 ) . A. G. E b e r t , C . R . S c h l e i f e r , a n d S . M. H e s s , J . P h a r m . S c i . , 55, 923 ( 1 9 6 6 ) . J . G. Wagner, E . S . G e r a r d , and D . G. K a i s e r , C l i n . Pharmacol. Therap., 2, 929 ( 1 9 6 6 ) . V. A . G r e e n , T . M. G l e n n , S . J . S t r a d a , and G. M e d i n a , J . Pharm. S c i . , 55, 516 ( 1 9 6 6 ) . D . L . S m i t h , A. L. P u l l i a m , and A. A. F o r i s t , J . P h a r m . S c i . , 55, 519 ( 1 9 6 6 ) . I b i d . , 398. I b i d . , 403. J. H. F i n c h e r , D. N . E n t r e k i n , and C . W. H a r t m a n , J . Pharm. S c i . , 55, 23 ( 1 9 6 6 ) . G. Levy, K. E . M i l l e r , and R . H. R e u n i n g , J . Pharm. S c i . , 55, 394 (1966). P . S i n g h , J . K . G u i l l o r y , T . D . Sokoloski, L . Z . B e n e t , and V . N . B h a t i a , J . Pharm. S c i . , 55, 63 ( 1 9 6 6 ) . D . L . Sorby and G. L i u , J . Pharm. S c i . , 55, 5 0 4 ( 1 9 6 6 ) . J . G. Wagner, E . S . G e r a r d , and D . G. K a i s e r , C l i n . Pharmacol. Therap., 2, 610 ( 1 9 6 6 ) . A.