Peroral administration

Most peptides and proteins are currently formulated as parenteral formulations because of their poor oral bioavailability. Nevertheless, oral delivery of peptides and proteins would be the preferred route of administration if bioavailability issues could be overcome, as it offers the advantages of convenient, pain-free administration. Although various factors such as permeability, chemical and metabolic stability and gastrointestinal transit time can affect the rate and extent of absorption of orally administered peptides and proteins, molecular size is generally considered the ultimate obstacle [36]. 

Several promising strategies have emerged from the intensive recent research efforts into the oral delivery of peptides and proteins [6, 36, 37]. Absorption enhancers may be used either to temporarily disrupt the intestinal barrier so that drug 

---

Lipid microparticles and nanopellets for oral use were first described by Speiser [11]. Nanopellets are prepared by dispersing melted lipids with high-speed mixers or via ultrasound techniques. Lipospheres developed by Domb are also prepared from dispersed lipids by stirring and sonication [12]. These preparations may contain a high degree of microparticles, which thus excludes an intravenous injection. For other routes of application (e.g., peroral administration), these microparticles might not be a serious problem. Furthermore, the dispersions may be contaminated by metal shed. With optimized conditions, however, mean particles sizes of 1(X) to 200 nm are possible [13]. 

Rumen infusion peroral administration by cannulation for 72 h of ewes given doses equivalent to 5 or 7 mg famphur/kg BW daily. After infusion for 72 h, sheep were challenged by various bloodsucking arthropods... 

Ritschel, W.A. Hardt, T.J. (1983) Pharmacokinetics of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide in the blood and brain of gerbils following intraperitoneal administration of coumaxm. Arzneim.-Forsch., 33, 1254-1258 Ritschel, W.A. Hoffmann, K.A. (1981) Pilot study on bioavailability of coumarin and 7-hydroxycoumarin upon peroral administration of coumarin in a sustained-release dosage form. J. din. Pharmacol., 21, 294-300... 

Ritschel, W.A., Denson, D.D. Gmmmich, K.W. (1988) Pharmacokinetics of coumarin and 7-hydroxycoumarin in the rhesus monkey after intravenous and peroral administration. Arzneim.-Forsch., 38, 1619-1623... 

The metabolic fate of Cisobitan is reported by Vessman et al.59. Although the compound is highly lipophilic and nearly water insoluble (solubility 3 jug/ml), it is eliminated primarily via urine and faeces after peroral administration. Analysis of... 

Investigation of the metabolic fate of compounds 64b and 71b led to the following results After peroral administration of 71b in rats, about 90% of the ingested silicon could be detected in urine within 4 days. In the ethyl ether extract of the urine, no unchanged 71b could be found. In the ethyl acetate extract the dealkylation product 85 was detected (29% of ingested sila-carbamate 71b) ... 

After peroral administration of 86b, 32—40% of radioactivity appeared in the urine within the First 24-hr period. Another 8—20% appeared during the second 24-hr period, and activity decreased to trace amounts after the second day. Three radioactive metabolites, (hydroxymethyl)dimethylphenylsilane (88), p-trimethyl-silylphenol (89), and an unknown conjugate of 90, could be isolated and characterized (cf. Scheme 9). Metabolism of 87b leads to silanol 91 (90% in the urine within 36 h). 

On local use of 1-ethoxysilatrane the area of wounds diminished considerably. The wound was completely closed within 12 days after treatment. On subcutaneous and peroral administration, healing was completed in 15 or 16 days as compared to 22 days in the control. 

Peroral administration of l-(chloromethyl)silatrane (suspension in starch) at a 20 mg/kg dose to breedless male white rats with transplantated sarcoma 45 increases the lifespan from 26 to 34 days, i.e. by 30%. Use of l-(chloromethyl)silatrane at higher doses does not produce such an effect. 

The antitumorous activity of l-(chloromethyl)-3,7,10-trimethylsilatrane does not reduce on peroral administration. The optimal doses of l-(chloromethyl)-3,7,10-trimethylsilatrane producing the strongest antitumorous effect are 50-100 mg/kg. Unlike cytolytic preparations, an increase in the dose of l-(chloromethyl)-3,7,10-trimethylsilatrane did not increase the inhibition of the tumour growth. 

In some instances, transdermal estrogens appear less likely to cause problems than other forms of administration. One group studied the treatment of polycystic ovary syndrome in 24 women, using transdermal or peroral administration of a combination of estradiol and cypro-terone acetate in doses comparable to those used in oral contraceptives (217). The peroral treatment led to a significant impairment in insulin secretion and action whereas the transdermal application of estrogens did not significantly influence insulin sensitivity. 

Bemkop-Schniirch, A. 1997. Strategies for the peroral administration of therapeutic peptides and proteins. Sci Pharm 65 61. 

Bernkop-Schniirch, A., and R. Fragner. 1996. Investigations into the diffusion behaviour of polypeptides in native intestinal mucus with regard to their peroral administration. Pharm Sci 2 361. 

Bernkop-Schniirch, A., G.H. Schwarz, and M. Kratzel. 1997. Modified mucoadhesive polymers for the peroral administration of mainly elastase degradable therapeutic (poly)peptidcs. J Control Release 47 113. 

Kratzel, M., Hiessbock, R., and Bernkop-Schniirch, A. Auxiliary agents for the peroral administration of peptide and protein drugs Synthesis and evaluation of novel pepstatin analogues. J. Med. Chem. 41 2339—2344, 1998. 

With his studies, Saffran heralded two interesting areas of research novel coating systems for colonic delivery coating and novel strategies for the peroral administration of digestible peptide drugs. 

Fig. 6.6 Blood plasma profiles of octreotide after peroral administration of 15 mg/pig A, Subject 2 B, Subject 6. Core ( ) core inside ( ) octreotide without any polymer (A) core outside with TMC (x) (Dorkoosh et al. 2002)...

In order to achieve and sustain therapeutic blood levels by peroral administration of drugs, several hurdles have to be overcome. Besides well-known barriers such as enzymatic degradation, dissolution problems, mucus barrier and others,... 

Bernkop-Schniirch, A. and Gilge, B. Anionic mucoadhesive polymers as auxiliary agents for the peroral administration of (poly)peptide drugs influence of the gastric juice. Drug Dev. Ind. Pharm. 2000 26, 2, 107-113. 

Kreuter, J. (1991). Peroral administration of nanoparticles. Adv Drug Deliv Rev 7 71-86. 

Table 1. Toxicity of Silics in the case of its peroral administration to animals.

Moxifloxacin hydrochloride was approved for the peroral treatment of AECB, CAP and ABS, and is also available as an infusion solution for the sequential treatment of CAP. In 2004, it was additionally approved by the FDA as the first intravenously and perorally administrable antibiotic for treating CAP, which is caused by multidrug-resistant S. pneumoniae (MDRSP). MDRSP is understood to include those strains of S. pneumoniae that are resistant to two or more of the following classes of antibiotics penicillins and second-generation cephalosporins such as cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole. 

Landry, F. B., Bazile, D. V., Spenlehauer, G., Veillard, M., and Kreuter, J. (1998), Peroral administration of 14C-poly(D,L-lactic acid) nanoparticles coated with human serum albumin or polyvinyl alcohol to guinea pigs,/. Drug Target., 6(4), 293-307. 

The administration of drugs by the buccal route has several main advantages over peroral administration, including the following ... 

In the past, the difficulties presented in the administration of drugs in the treatment of hypertensive emergencies were largely overcome with the use of nifedipine administered sublingually. The onset of action was rapid, and the drug was also used sublingually for the treatment of acute attacks of angina pectoris. Presently, two types of formulation of nifedipine are available, both intended primarily for peroral administration. The sustained-release formulation is... 

De Keyser, J.L. Poupaert, J.H. Dumont, P. Poly(diethyl methylidenemalonate) nanoparticles as a potential drug carrier preparation, distribution and ehmination after intravenous and peroral administration to mice. J. Pharm. Sci. 1991, 80, 67-70. 

Powdered cellulose is not absorbed systemically following peroral administration and thus has little toxic potential. 

---