Biomedical subjects

P Jarho

Publications and source records attributed to P Jarho.

12 recordsLinked to original sources

PubMed2006

In vitro evaluation of the effect of cyclodextrin complexation on pulmonary deposition of a peptide, cyclosporin A.

The effect of hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD) complexation on in vitro pulmonary deposition of a cyclic peptide cyclosporin A (CsA) was studied. In addition, the effect of storage (32 days, 40 degrees C, 75% RH) on CsA/HP-alpha-CD complexes was studied. The complexation of CsA with CDs was evaluated by a phase-solubility method. Solid CsA/HP-alpha-CD complexes were prepared by freeze drying. Three inhalation formulations were prepared: CsA/lactose reference formulation (LF) (drug:carrier 1:364, w/w), CsA/HP-alpha-CD complex formulation (CDF) (drug:CD 1:269, w/w) and CsA/HP-alpha-CD complex/lactose formulation (CDLF) (complex:carrier 100:114, w/w). The inhalation studies were performed in vitro using Andersen Sampler (Ph. Eur.) and Taifun multi-dose dry powder inhalers (DPIs). Before the storage, the respirable fraction value (RF%) of CsA was 19.8+/-0.7%, 33.0+/-7.0% and 34.6+/-1.1% (mean+/-S.D., n=4 x 20) with LF, CDF and CDLF, respectively. When exposed to moisture (storage in a permeable polystyrene tube), the RF% values of CsA from formulations containing CsA/HP-alpha-CD complexes were lower than before the storage. However, when stored in the Taifun DPI, the RF% value of CsA from any of the formulations did not decrease. In conclusion, an acceptable RF% value of a peptide CsA from freeze-dried, simply micronized CsA/HP-alpha-CD complex powder was achieved before and after storage in the DPI.

Administration, Inhalation↗

PubMed2001

Complexation with tolbutamide modifies the physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin.

The physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and its tolbutamide (TBM) complex were studied. The kinetics of TBM/HP-beta-CD inclusion complex formation in solution were determined by the phase solubility method. Solid complexes were prepared by freeze-drying and spray-drying. Water sorption-desorption behaviour of the materials were studied and compacts were made using a compaction simulator. TBM and HP-beta-CD formed 1:1 inclusion complexes in aqueous solution with an apparent stability constant of 63 M(-1). HP-beta-CDs and TBM/HP-beta-CD complexes were amorphous whereas the freeze-dried and spray-dried TBMs were polymorphic forms II and I, respectively. Sorption-desorption studies showed that HP-beta-CDs were deliquescent at high relative humidities. TBM/HP-beta-CD complexes had slightly lower water contents at low relative humidities than the physical mixtures. However, at high humidities their water sorption and desorption behaviours were similar to those of corresponding physical mixtures, indicating a glass transition of the complexed materials. TBM/HP-beta-CD complexes demonstrated a worse compactability than similarly prepared HP-beta-CDs or physical mixtures. Also particle properties that resulted from these preparation methods affected the compactability of the materials. In conclusion, the physicochemical and tableting properties of HP-beta-CD were modified by complexation it with TBM.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2000

Cyclodextrin-catalyzed deacetylation of spironolactone is pH and cyclodextrin dependent.

The complexation of spironolactone (SP) with cyclodextrins (CDs) and the effect of pH on the CD catalyzed deacetylation of SP was studied in the presence of beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), sulfobutylether-beta-cyclodextrin ([SBE](7m)-beta-CD), gamma-cyclodextrin (gamma-CD), and sulfobutylether gamma-cyclodextrin (SBE-gamma-CD). The complexation of SP with beta-CD and the mechanism of deacetylation was confirmed using NMR. The complexation of SP with CDs was determined by means of the phase-solubility method at pH 2, in which chemical degradation was minimal. The phase-solubility diagrams were classified as A(L)-type and the apparent stability constants (K(1:1)) for 1 : 1 inclusion complex were calculated to be 9939 M(-1), 10,976 M(-1), 15,816 M(-1), 4792 M(-1) and 4118 M(-1) for beta-CD, HP-beta-CD, (SBE)(7m)-beta-CD, gamma-CD, and SBE-gamma-CD, respectively. The effect of pH on the degradation rate of SP was studied in the presence and absence of 4.4 mM CD solutions at pH 4, 5, 6, 7, and 8 (25 degrees C). The stability studies showed that CD-catalyzed degradation of SP can be decreased by lowering the pH. The pH-rate profiles of SP degradation with different CDs gave slopes of 1.0. Because no buffer catalysis was observed, the reaction appears to be specific-base catalyzed. The catalytic activity of CDs was as follows: SBE-gamma-CD < (SBE)(7m)-beta-CD < HP-beta-CD approximately gamma-CD < beta-CD. NMR studies confirmed that SP forms an inclusion complex with beta-CD and complexation occurs by means of the secondary face. The NMR studies also showed that during the deacetylation of SP, the secondary hydroxyl groups of beta-CD at the 2- and 3-position were acetylated. The decrease of catalytic activity of CDs at low pH values and the CDs differing ability to catalyze the degradation of SP correlated qualitatively with the ionization state of the CD hydroxyl groups, which were lower in SBE-CDs. The site of binding differences and the number of hydroxyl groups present probably also contribute to the differences.

Acetylation↗

PubMed1998

Hydroxypropyl-beta-cyclodextrin and its combination with hydroxypropyl-methylcellulose increases aqueous solubility of delta9-tetrahydrocannabinol.

Delta9-tetrahydrocannabinol (THC) is the main psychoactive constituent of Cannabis sativa L. and its therapeutic effects are currently under intensive study. However, THC has a very low aqueous solubility (1-2 microg/mL), which restricts its use as a pharmaceutical. The present study demonstrates that THC forms a drug-cyclodextrin complex in an aqueous solution of hydroxypropyl-beta-cyclodextrin (HP-beta-CD), resulting in a thousand-fold increase in THC solubility. This improvement in solubility can be further increased by adding 0.1% hydroxypropylmethylcellulose to the HP-beta-CD solution. The present results suggest that the use of cyclodextrins might be a simple and useful method to overcome the poor water solubility of THC.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1998

Co-administration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms.

PURPOSE: The aim of this study was to investigate the effect of cyclodextrins (beta-CD, HP-beta-CD and (SBE)7m-beta-CD), and co-administration of a water-soluble polymer (HPMC) and cyclodextrins, on the oral bioavailability of glibenclamide in dogs. METHODS: Effects of cyclodextrins on the aqueous solubility of glibenclamide, with and without hydroxypropylmethylcellulose (HPMC), were determined by a phase-solubility method. Solid inclusion complexes were prepared by freeze-drying. Glibenclamide was administered orally and intravenously to beagle dogs. RESULTS: Aqueous solubility of glibenclamide increased as a function of cyclodextrin concentration, showing an AL-type diagram for beta-CD and an Ap-type diagrams for both of the beta-CD derivatives studied. HPMC enhanced the solubilising effect of cyclodextrins, but did not affect the type of phase-solubility diagram. Orally administered glibenclamide and its physical mixture with HP-beta-CD showed poor absolute bioavailability, while orally administered glibenclamide/cyclodextrin-complexes significantly enhanced the absolute bioavailability of glibenclamide. Orally administered glibenclamide/beta-CD/HPMC and glibenclamide/(SBE)7m-beta-CD/HPMC complexes showed similar absolute bioavailability compared to formulations not containing HPMC, even though 80% (in the case of (SBE)7m-beta-CD) or 40% (in the case of beta-CD) less cyclodextrin was used. CONCLUSIONS: The oral bioavailability of glibenclamide was significantly increased by cyclodextrin complexation. HPMC increased the solubilising effect of cyclodextrins and, therefore, the amount of cyclodextrin needed in the solid dosage form was significantly reduced by their co-administration. In conclusion, the pharmaceutical usefulness of cyclodextrins in oral administration may be substantially improved by co-administration of a water-soluble polymer.

Administration, Oral↗

PubMed1997

Effects of topical alpha-substituted anandamides on intraocular pressure in normotensive rabbits.

PURPOSE: Anandamides have been observed to lower intraocular pressure in the rabbit eye, preceded by a period of hypertension. Amidases are thought to catabolize these compounds into their component parts, including arachidonic acid. Direct application of arachidonic acid has been observed to cause a marked rise of intraocular pressure. Thus, anandamide analogs resistant to catabolism were thought possibly devoid of this initial hypertension, and their effects on rabbit IOP investigated. METHODS: A series of chiral alpha-substituted anandamides were synthesized and studied for their effect on the intraocular pressure (IOP) of normotensive pigmented rabbits. Each test compound was dissolved in an aqueous 2-hydroxypropyl-beta-cyclodextrin solution (containing 3% polyvinyl alcohol) and administered (62.5 micrograms) unilaterally to the eye. RESULTS: The most promising compounds caused a statistically significant reduction of IOP (vs. vehicle) in the treated eyes. Of these, the R-alpha-isopropyl compound exhibited the best activity tested. Unlike the alpha-unsubstituted analogs previously studied, hypotensive effects were not preceded by an initial elevation of IOP and indomethacin pre-treatment (12.5 mg, s.c.) did not eliminate the IOP response, as demonstrated by administered R-alpha-isopropyl anandamide. CONCLUSIONS: Catabolism of alpha-unsubstituted anandamides may account for their observed intraocular hypertensive effects. The physiological mechanism by which alpha-substituted anandamides work apparently differs from that of the more easily metabolized alpha-unsubstituted compounds.

Animals↗

PubMed1996

Hydroxypropyl-beta-cyclodextrin increases aqueous solubility and stability of anandamide.

Anandamide (arachidonylethanolamide; AEA) is an endogenous ligand for the cannabinoid receptor and its pharmacological effects are under intensive study. However, AEA has a low aqueous solubility and stability which may restrict its use and may eventually endanger the reliability of the obtained results. In the present study, it was found that AEA forms inclusion complexes with cyclodextrins (CDs), resulting in greater aqueous solubility and stability of AEA as AEA/CD complex. Aqueous solubility increased 1 000 to 30 000-fold, depending on the type of CD (10% solution) used. The half-life of AEA in aqueous hydroxypropyl-beta-cyclodextrin solution (10%) at 50 degree C was 2.9 years. These results suggest that CD-technology will be a very useful method to overcome the solubility and stability problems of AEA.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1996

Effects of topical anandamides on intraocular pressure in normotensive rabbits.

A series of anandamide-type compounds were synthesized and studied for their effect on the intraocular pressure (IOP) of normotensive pigmented rabbits. Each test compound was dissolved in an aqueous 2-hydroxypropyl-beta-cyclodextrin solution and administered (31.25 - 62.5 micrograms) unilaterally to the eye. The most promising anandamides caused a statistically significant reduction of IOP in treated eyes, usually preceded by an initial transient elevation of IOP, compared to saline controls. In the contralateral untreated eyes, only a marginal or short hypotensive response was observed. Indomethacin pre-treatment (12.5 mg, s.c.) eliminated the IOP response to administered anandamides and arachidonic acid.

Administration, Topical↗

PubMed1996

Modified beta-cyclodextrin (SBE7-beta-CyD) with viscous vehicle improves the ocular delivery and tolerability of pilocarpine prodrug in rabbits.

The complexation of pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, with various beta-cyclodextrin (beta-CyD) derivatives was studied by the phase solubility method. The effects of coadministered sulphobutyl ether beta-CyD (SBE7-beta-CyD) with and without poly(vinyl alcohol) (PVA) on the miotic response and eye irritation of the prodrug were investigated in pigmented rabbits. The pilocarpine prodrug formed 1:1 inclusion complexes with variably substituted sulphobutyl ether derivatives of beta-CyD (SBE4-beta-CyD and SBE7-beta-CyD), and 1:1 and 1:2 complexes with hydroxypropyl-beta-CyD (HP-beta-CyD) at pH 7-4. Coadministered SBE7-beta-CyD eliminated the eye irritation due to the pilocarpine prodrug, but also decreased the miotic response. Ocular absorption of the prodrug was improved by increasing the viscosity of prodrug/SBE7-beta-CyD solution with PVA without inducing any eye irritation. Eye irritation due to viscous prodrug/SBE7-beta-CyD solutions was comparable with isotonic NaCl solution. We conclude that administration of pilocarpine prodrug in viscous SBE7-beta-CyD solution decreases substantially eye irritation while ocular absorption is not affected.

Animals↗

PubMed1995

Hydroxypropyl-beta-cyclodextrin increases the aqueous solubility and stability of pilocarpine prodrugs.

PURPOSE: The effects of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the aqueous solubility and stability of two lipophilic bispilocarpine prodrugs were investigated at pH 7.4. METHODS: The solubility of prodrugs was studied by phase-solubility method (0-72.5 mM HP-beta-CD). The stability of one of the prodrugs was investigated as a function of temperature (40 degrees C-70 degrees C) and HP-beta-CD concentration (0-72.5 mM). The apparent rate constants (k1, k2) for degradation of prodrug in 1:1 and 1:2 inclusion complexes and apparent stability constants (K1:1, K1:2) were calculated by the curve-fitting method. RESULTS: The phase-solubility diagrams were classified as Ap-type and the apparent stability constants (K1:1, K1:2) for 1:1- and 1:2-inclusion complexes were calculated to be 143-815 M-1 and 29-825 M-1, respectively. The stability of prodrug increased as a function of HP-beta-CD concentration over the studied temperature range. The shelf-life (t90%, calculated by the Arrhenius equation) of the prodrug in 72.5 mM HP-beta-CD solution increased 5.1-fold and 6.1-fold at 25 degrees C and 4 degrees C, respectively. CONCLUSIONS: The solubility of the prodrugs was shown to increase markedly in phase-solubility studies. The degradation rate of prodrug in stability studies was shown to be slower in the 1:2-complex than in the 1:1-complex and the relative amounts of complex species were found to be dependent on CD concentration.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1995

Ophthalmic arachidonylethanolamide decreases intraocular pressure in normotensive rabbits.

Arachidonylethanolamide (AEA) was the first anandamide to be identified as an endogenous ligand for the cannabinoid receptor of porcine brain. Since cannabinoids have shown some value in the reduction of ocular hypertension, the title compound was evaluated in normotensive rabbits as a possible topically applied agent for reducing intraocular pressure. AEA was dissolved in an aqueous solution of 2-hydroxy-propyl-beta-cyclodextrin. Single eyedrops (25 microliters) containing 3.13, 6.25, 31.25, 62.5 or 125.0 micrograms of AEA were instilled unilaterally into eyes of normotensive albino and pigmented rabbits. The intraocular pressures (IOPs) of these rabbits were then measured at fixed time intervals. The effect of AEA on IOP in treated and untreated (contralateral) eyes was similar in both types of rabbits. Administration of 31.25 micrograms of AEA caused an immediate IOP reduction in the treated eyes. AEA doses of 62.5 micrograms caused an initial increase and subsequent decrease of IOP in the treated eyes. In the untreated eyes, a marginal ocular hypotensive response of limited duration occurred immediately after administration of AEA at doses 31.25 or 62.5 micrograms. A significant increase (without subsequent decrease below baseline) in IOP occurred in treated eyes after a dose of 125.0 micrograms. The lowest dose (3.13 micrograms) did not have an effect on IOP. This study constitutes the first published demonstration that topical, unilateral administration of AEA significantly decreases IOP in normotensive albino and pigmented rabbits. Although the mechanism of action by which this compound produces its hypotensive effect in the eye is not known, the results suggest that AEA may prove useful in the investigation of glaucoma therapy.

Animals↗

PubMed1989

Electrochemical detection of indole alkaloids of Catharanthus roseus in high-performance liquid chromatography.

Hydrodynamic voltammograms for indole and five indole alkaloids with different amino functions were obtained in order to evaluate the applicability of high-performance liquid chromatography (HPLC) with coulometric detection to these compounds. With the exception of serpentine, which has a quaternary nitrogen in its structure, all the compounds were oxidised and gave net signals of greater than 25 nA pmol(-1) at potentials of between +0.2 and +0.85 V versus a solid Pd electrode in an acetate-buffered (pH 6.5) water-methanol-acetonitrile system. An HPLC assay for quantifying picomole amounts of catharanthine and ajmalicine in Catharanthus roseus cell culture samples is described.

Alkaloids↗