Gordon L. Flynn

Absorption of Polyethylene Glycols 600 Through 2000: The Molecular Weight Dependence of Gastrointestinal and Nasal Absorption

Polyethylene glycols (PEGs) 600,1000, and 2000 were used to study the molecular weight permeability dependence in the rat nasal and gastrointestinal mucosa. Absorption of the PEGs was measured by following their urinary excretion over a 6-hr collection period. HPLC methods were used to separate and quantitate the individual oligomeric species present in the PEG samples. The permeabilities of both the gastrointestinal and the nasal mucosae exhibited similar molecular weight dependencies. The steepest absorption dependence for both mucosae occurs with the oligomers of PEG 600, where the extent of absorption decreases from approximately 60% to near 30% over a molecular weight range of less than 300 daltons. Differences in the absorption characteristics between the two sites appear in the molecular weight range spanned by PEG 1000. For these oligomers, the mean absorption from the nasal cavity is approximately 14%, while that from the gastrointestinal tract is only 9%. For PEG 2000, mean absorption decreases to 4% following intranasal application and below 2% following gastrointestinal administration. Within the PEG 1000 and 2000 samples, however, very little molecular weight dependency is seen among the oligomers. In the range studied, a distinct molecular weight cutoff was not apparent at either site.

Transdermal delivery of narcotic analgesics : pH, anatomical and subject influences on cutaneous permeability of fentanyl and sufentanil

The permeation of fentanyl and sufentanil through cadaver skin membranes was investigated using in vitro diffusion cell techniques. Neither drug influenced the permeation of the other when they were concurrently applied to the skin membrane. With respect to transdermal delivery, short diffusion lag times of less than 0.5 hr were observed for each compound. Their permeation rates through heat-isolated epidermis and dermatomed (200- to 250-µm) skin sections were essentially the same. However, when the stratum corneum was removed by tape stripping, the respective permeability coefficients were increased >30-fold, establishing the stratum corneum as the principal barrier to their skin permeation. Permeation was also studied as a function of pH. From pH 4 to pH 8 the permeability coefficients of both fentanyl and sufentanil, calculated from the total solution concentration regardless of ionization, increased exponentially. The free base is thus responsible for the relatively facile skin permeation of these drugs. Factoring of the independent permeability coefficients of the ionized and free-base forms was possible, with the latter being over two log orders larger than seen for the protonated species. Permeability coefficients of fentanyl and sufentanil through skin sections obtained from different cadavers varied four- to fivefold. Neither gender nor age was a flux-determining variable for either drug. The permeability coefficients of the drugs through skin sites as diverse as the sole of the foot, chest, thigh, and abdomen were remarkably similar. Their fluxes were sufficient for transdermal administration.

Transfollicular Drug Delivery

The hair follicle, hair shaft, and sebaceous gland collectively form what is recognized as the pilosebaceous unit. This complex, three-dimensional structure within the skin possesses a unique biochemistry, metabolism and immunology. Recent studies have focused on the hair follicle as a potential pathway for both localized and systemic drug delivery. Greater understanding of the structure and function of the hair follicle may facilitate rational design of drug formulations to target follicular delivery. Targeted drug delivery may enhance current therapeutic approaches to treating diseases of follicular origin. Presented here is a review of follicular drug delivery and a discussion of the feasibility of the pilosebaceous unit as a target site.

Influence of liposomal drug entrapment on percutaneous absorption

Abstract Results of permeation experiments involving finite dose diffusion cells with hairless mouse skin as the membrane indicate that neither intact liposomes nor the phospholipid of which they are comprised diffuses across the skin. Lipophilic drugs like progesterone and hydrocortisone, which are intercalated within the bilayer structure of the phospholipid in multilamellar liposomes, seem to pass through the skin with comparable facility to free drug (comparable mass transfer coeficients). On the other hand, highly polar glucose entrapped in the aqueous compartments of the liposome is poorly available for transport. The results of in vitro release rate studies and theoretical calculations indicate that the very slight flux of liposomally incorporated glucose seen experimentally is attributable to a slow release rate of glucose out of the liposome followed by relatively rapid skin permeation of the free solute. On the other hand, for hydrophobic progesterone and hydrocortsone the experimental results and supportive theoretical analysis suggest direct transfer of drug from liposome to the skin. Considering this mechanism and owing to increased soluble payloads of lipophilic drugs through liposomal incorporation, n ore total drug may be delivered through skin via liposomes relative to simple aqueous solutions.

Transdermal Delivery of Narcotic Analgesics: Comparative Permeabilities of Narcotic Analgesics Through Human Cadaver Skin

Relationships between the in vitro permeation rates of select narcotic analgesics through human skin and their physicochemical properties were investigated by following the permeation kinetics of six representative compounds in small diffusion cells. The relative permeability coefficients of three phenylpiperidine analogues, meperidine, fentanyl, and sufentanil, all measured on a single piece of skin, were 3.7 × 10−3, 5.6 × 10−3, and 1.2 × 10−2 cm/hr, respectively. Using membranes from the same skin section, the permeability coefficients of three opioid alkaloids, morphine, codeine, and hydromorphone, were considerably lower, at 9.3 × 10−6, 4.9 × 10−5, and 1.4 × 10−5 cm/hr, respectively. The high permeability coefficients of the former compounds are due to their highly lipophilic nature as reflected in high octanol/water partition coefficients and low solubility parameters. Generally, the permeability coefficients of the narcotics increase as the lipophilicity increases. When viewed in literature perspective, the data suggest that aqueous tissue control of transport is approached in the case of the phenylpiperidine analogues, all of which have Koctanol/water values greater than 40. Permeability coefficients of fentanyl and sufentanil were also determined as a function of pH over the pH range 7.4 to 9.4, in this instance with membranes prepared from additional samples of skin. The permeability coefficients of each drug varied less than threefold over the pH range, a behavior consistent with the highly hydrophobic natures of the compounds. The low permeability coefficients of morphine, codeine, and hydromorphone coupled with their low potencies make these drugs poor transdermal candidates. It appears that fentanyl and sufentanil can be successfully transdermally delivered.

Solubility and Related Physicochemical Properties of Narcotic Analgesics

AbstractThe physicochemical properties of select opioid and anilinopiperidine narcotic analgesics were investigated. The solubilities of the narcotics in hexane and water and, for morphine, in other organic solvents were determined. Regular solution theory seems to be applicable to the solubility behavior of morphine in solvents that lack strong dipoles and hydrogen bonds. A best-fit solubility parameter of 13.2 (cal/cm3)

Topical and Transdermal Drug Products

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Solubility Behavior of Narcotic Analgesics in Aqueous Media: Solubilities and Dissociation Constants of Morphine, Fentanyl, and Sufentanil

for morphine was determined from its solubilities in London solvents and its ideal solubility. Calculation of morphines solubility parameter from its hexane solubility alone and its melting properties gave a corresponding δ2 value. These measured solubility parameters were appreciably larger than the solubility parameter estimated from molar attraction constants. Solubility parameters of hydromorphone, codeine, fentanyl, and sufentanil were also calculated from respective hexane solubilities, melting points, and heats effusion and were 11.7, 10.9, 9.8, and 9.7 (cal/cm3)