Release and elimination of 14C‐fluphenazine enanthate and decanoate esters administered in sesame oil to dogs

doi:10.1002/jps.2600650407

Journal of Pharmaceutical Sciences

Volume 65, Issue 4, April 1976, Pages 502-507

https://doi.org/10.1002/jps.2600650407 Get rights and content

Abstract

The rates of release of ¹⁴C‐fluphenazine enanthate and ¹⁴C‐fluphenazine decanoate were compared in two groups of five male dogs. Each dog was given a single dose (2 mg/kg im) of either the enanthate or decanoate ester in sesame oil. The times required to attain maximum concentrations of radioactivity in plasma were 3.8 ± 0.5 days (±SE) for the enanthate ester and 10.6 ± 1.1 days for the decanoate ester (p < 0.001); maximum concentrations of radioactivity in the plasma at these times were 16.7 ± 1.1 and 11.1 ± 1.2 ng/ml, respectively (p < 0.01). However, 35 days after dosing, the concentrations of radioactivity in plasma were greater for the decanoate ester than for the enanthate ester. The times required for 50% of the dose to be excreted in the urine and feces were 7.8 ± 0.5 days for the enanthate ester and 22.6 ± 4.4 days for the decanoate ester (p < 0.05). The total amounts excreted in 35 days were 85.4 ± 1.8 and 68.8 ± 6.6% of the dose for the enanthate and decanoate esters, respectively; the average halftimes for the rates of release of radioactivity from depot and body, as calculated from the data for total excretion, were 5.55 days for the enanthate ester and 15.4 days for the decanoate ester. Thirty‐five days after dosing, the amount of the dose present in the injection site was 4.6 ± 1.6% for the enanthate ester and 18.6 ± 5.7% for the decanoate ester. Two groups of six dogs each were protected against the emetic effects of apomorphine more than twice as long by the decanoate ester than by the enanthate ester after the subcutaneous administration of single 8‐mg/kg doses of either drug in sesame oil (p < 0.05). Based on measurements of total radioactivity, it was concluded that the decanoate ester was released from the depot at less than one‐half the rate of the enanthate ester.

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The rate constants for transfer of a homologous series of nicotinic acid esters from oil vehicles to aqueous buffer phases were determined using a rotating dialysis cell. The chemical stability of butyl nicotinate has been investigated at 60°C over pH range 0.5–10. Maximum stability occurs at pH 4–5 and an inflection point was seen around the pK_a. For the nicotinic acid esters, a linear correlation was established between the first-order rate constant related to attainment of equilibrium, k_obs and the apparent partition coefficient, P_app: log k_obs=−0.83 log P_app+0.26 (k_obs in h⁻¹, n=9). For hexyl nicotinate with a true partition coefficient of 4 it was possible to determine k_obs by decreasing pH in the aqueous release medium to 2.05. Thus, under the latter experimental conditions estimation of the relative release rates for the esters were performed. The ratio between the specific rate constant k_ow, related to the transport from oil vehicle to aqueous phase, for ethyl and hexyl nicotinate was 139. The hydrophobic substituent constant for a methylene group, π(CH₂), was determined for nicotinic acid esters in different oil/buffer partitioning systems to 0.54–0.58. Addition of hydroxypropyl-β-cyclodextrin to the aqueous release medium did not enhance the transport rate of the esters from the oil phase.
Addition of hydrogen bond donating excipients to oil solution: Effect on in vitro drug release rate and viscosity
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In oily vehicles containing different hydrogen bond donating excipients rates of transfer of the weak electrolytes naproxen and lidocaine from the oil phase to the aqueous medium were measured by using the rotating dialysis cell. A logarithmic linear correlation was established between the apparent partition coefficient, P_app, and the first-order rate constant related to attainment of equilibrium between the two phases, k_obs, which fitted well with results from former publications. Further, release data for the non-electrolyte testosterone were found to fit into this linear correlation. Apparent partition coefficients were determined between oil vehicles containing various amounts of hydrogen bond donating excipients and phosphate buffer, pH 6.00, revealing a rise in log P_app with increasing concentration of excipient. Viscosity was measured for castor oil containing vehicles showing a linear relationship between percentage (v/v) castor oil and log viscosity (mPa s) of the mixed vehicle.
Modification of in vitro drug release rate from oily parenteral depots using a formulation approach
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Rate constants for transfer of naproxen and lidocaine from different oils and oil mixtures to aqueous buffer, pH 6.00, were determined using the rotating dialysis cell. Significantly different first-order rate constants related to attainment of equilibrium, k_obs, were derived depending on the type of oil/oil mixtures used in the release experiments. For the drugs a linear correlation was found between log k_obs and the logarithm of the partition coefficient P_app: log k_obs=−0.68 log P_app−0.25 (k_obs in h⁻¹, n=26). A linear relationship was observed between the calculated and experimentally determined P_app values for the oil mixtures investigated. The specific rate constants, k_ow and k_wo, related to the partition process were derived from the determined k_obs and P_app values. The rate constant k_ow representing the rate of transfer of the solute from the oil phase to the aqueous buffer was shown to be strongly dependent on the partition coefficient according to the relationship: log k_ow=−0.68 log P_app−log(P_app+1)−0.25 (k_ow in h⁻¹, n=26). In particular, diminished release rates were seen for oil mixtures containing castor oil most likely afforded by hydrogen bonding between the solute and the hydroxy groups of the latter vegetable oil. In this study it has been possible to alter P_app for a specific compound up to a factor of 10 by variation of the composition of the oil vehicle. Such a span of P_app values results in in vitro release rates differing a factor of 37. Thus, by proper design of the oil vehicle composition it should be possible to modify the release rate for a specific compound within certain limits.
The in vivo release of cortisone esters from liposomes and the intramuscular clearance of liposomes
1984, International Journal of Pharmaceutics
Studies are reported in which multilamellar liposomes (MLVs) are used as a vehicle to administer cortisone esters by the intramuscular route. The following conclusions were reached.
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- 2.
  (2) No detectable removal of intact MLVs from the injection site occurs.
- 3.
  (3) No spreading of the MLVs at the injection site occurs over the period of 1 h to 7 days post-injection.
- 4.
  (4) The [¹³¹I]lecithin complex is stable in vivo.
- 5.
  (5) Encapsulation in DPPC liposomes has been shown to significantly prolong the absorption of cortisone hexadecanoate from the i.m. site.
- 6.
  (6) In vitro data cannot give precise information about the in vivo performance of liposome formulations.
- 7.
  (7) It is possible that the primary release mechanism of cortisone prodrug clearance is diffusion from liposomal material at the i.m. site. However, the presence of secondary depots cannot be completely discounted.
Drug release from lipid-based dosage forms. I
1980, International Journal of Pharmaceutics
Fluphenazine enanthate and fluphenazine decanoate: Intramuscular injection and esterification as requirements for slow‐release characteristics in dogs
1976, Journal of Pharmaceutical Sciences
14C‐Fluphenazine base was administered intramuscularly in sesame oil to five male beagles (2 mg/kg). The concentration of radioactivity in plasma and the excretion of radioactivity in urine and feces were measured for 14 days. Maximum concentrations of radioactivity were found in plasma 2 hr after administration. These levels declined with elimination half‐lives of 3.20 hr during the 2‐12‐hr interval after dosing and of 4.02 days during the 2‐14‐day interval. Most administered radioactivity was excreted during the first 2 days after dosing, predominantly in the feces. An average of 0.43% of the dose was present at the injection site 14 days after dosing; some residual radioactivity was found in the liver and in the ocular portion consisting of the combined retina, choroid, and sclera. ¹⁴C‐Fluphenazine and its enanthate and decanoate esters were each administered intravenously to three different groups of intact dogs at doses of 1 mg/kg. Regardless of which compound was administered, concentrations of radioactivity in the plasma of these dogs were comparable. Thirty minutes after these dogs had been dosed with ¹⁴C‐fluphenazine enanthate or ¹⁴C‐fluphenazine decanoate, most radioactivity in the plasma was present as ¹⁴C‐fluphenazine base and other unidentified metabolites; at this time, at least 79% of either of the two ¹⁴C‐fluphenazine esters had been biotransformed. The excretion of radioactivity by these same three groups of dogs was very similar, regardless of which of the three compounds was given. In 7 days, an average of only 3–4% of the dose was excreted in urine; the remainder was excreted in feces. ¹⁴C‐Fluphenazine and its enanthate and decanoate esters (1 mg/kg) were administered intravenously to dogs whose bile ducts had been cannulated. The amounts of radioactivity excreted in the urine and bile in 8 hr were very similar, as were the residual amounts of radioactivity present in selected tissues. Comparison of the data obtained from dogs given these three compounds intravenously (unformulated) or intramuscularly in sesame oil points to the following conclusions: (a) fluphenazine base per se does not provide slow‐release characteristics unless it has been esterified, for example, with heptanoic or decanoic acid, and (b) intramuscular rather than intravenous administration of these two esters is responsible for producing their slow‐release characteristics.

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: The authors thank Mr. Peter Egli for synthesizing the radiolabeled fluphenazine esters, Mr. Carmen Mondi and Mrs. Louise Carter for excellent technical assistance, Dr. Morton Goldberg and Ms. Rita Fand for evaluating the duration of action studies with apomorphine, and Mr. Sal Meloni for preparing the illustrations.

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ArticleRelease and elimination of 14C‐fluphenazine enanthate and decanoate esters administered in sesame oil to dogs

Abstract

J. Pharm. Sci

Ibid

J. Pharmacol. Exp. Ther

Psychopharmacologia

Anal. Biochem

Applied Regression Analysis

Practical Nonparametric Statistics

Introduction to Statistical Analysis

Article
Release and elimination of ¹⁴C‐fluphenazine enanthate and decanoate esters administered in sesame oil to dogs