Endogenous release of female hormones from co-microencapsulated rat granulosa and theca cells.

Deficiency of female hormones is the principal cause of menopausal syndrome. The aim of this study was to establish a co-microencapsulation model of ovarian granulosa cells (GCs) and theca cells (TCs), and to investigate its endogenous release of female hormones. Rat ovarian GCs and TCs were isolated and co-microencapsulated in alginate-chitosan-alginate microcapsules. The effects of cell number ratio of GCs/TCs on syntheses of estradiol (E2) and progesterone (P4) were investigated in vitro. Serum levels of E2 and P4 in ovariectomized rats were measured for 60 days after the co-microencapsulated GCs and TCs were transplanted. It was showed that E2 synthesis in vitro was influenced by cell number ratio of GCs/TCs and the ratio for the maximum synthesis was 1:2. Serum E2 and P4 levels could be maintained normal for 60 days by the co-microencapsulated GCs/TCs. Transplantation of co-microencapsulated GCs/TCs may be a promising approach to provide endogenous female hormones for menopausal syndrome.

Solubility-modulated monolithic osmotic pump tablet for atenolol delivery.

A method for the preparation of monolithic osmotic pump tablet was obtained by modulating atenolol solubility with acid. Tartaric acid was used as solubility promoter, sodium chloride as osmotic agent and polyvinyl pyrrolidone as retardant agent. Ethyl cellulose was employed as semipermeable membrane containing polyethylene glycol 400 as plasticizer. The formulation of atenolol monolithic osmotic pump tablet was optimized by orthogonal design and evaluated by similarity factor (f(2)). The optimal monolithic osmotic pump tablet was found to be able to deliver atenolol at the rate of approximate zero-order up to 24h, independent of release media and agitation rate. The approach of solubility-modulated by acid-alkali reaction might be used for the preparation of osmotic pump tablet of other poorly water-soluble drugs with alkaline or acid groups.

Preparation of bilayer-core osmotic pump tablet by coating the indented core tablet.

In this paper, a bilayer-core osmotic pump tablet (OPT) which does not require laser drilling to form the drug delivery orifice is described. The bilayer-core consisted of two layers: (a) push layer and (b) drug layer, and was made with a modified upper tablet punch, which produced an indentation at the center of the drug layer surface. The indented tablets were coated by using a conventional pan-coating process. Although the bottom of the indentation could be coated, the side face of the indentation was scarcely sprayed by the coating solution and this part of the tablet remained at least partly uncoated leaving an aperture from which drug release could occur. Nifedipine was selected as the model drug. Sodium chloride was used as osmotic agent, polyvinylpyrrolidone as suspending agent and croscarmellose sodium as expanding agent. The indented core tablet was coated by ethyl cellulose as semipermeable membrane containing polyethylene glycol 400 for controlling the membrane permeability. The formulation of core tablet was optimized by orthogonal design and the release profiles of various formulations were evaluated by similarity factor (f(2)). It was found that the optimal OPT was able to deliver nifedipine at an approximate zero-order up to 24 h, independent on both release media and agitation rates. The preparation of bilayer-core OPT was simplified by coating the indented core tablet, by which sophisticated technology of the drug layer identification and laser drilling could be eliminated. It might be promising in the field of preparation of bilayer-core OPT.

Delivery of prazosin hydrochloride from osmotic pump system prepared by coating the core tablet with an indentation.

The preparation of an osmotic pump tablet was simplified by elimination of laser drilling using prazosin hydrochloride as the model drug. The osmotic pump system was obtained by coating the indented core tablet compressed by the punch with a needle. A multiple regression equation was achieved with the experimental data of core tablet formulations, and then the formulation was optimized. The influences of the indentation size of the core tablet, environmental media, and agitation rate on drug release profile were investigated. The optimal osmotic pump tablet was found to deliver prazosin hydrochloride at an approximately constant rate up to 24 hr, and independent on both release media and agitation rate. Indentation size of core tablet hardly affected drug release in the range of 0.80-1.15 mm. The method that is simplified by elimination of laser drilling may be promising for preparation of an osmotic pump tablet.

Improved dissolution of oleanolic acid with ternary solid dispersions.

The purpose of this study was to enhance the dissolution of oleanolic acid by solid dispersions consisting of the drug, a polymeric carrier, and a surfactant. Binary solid dispersions consisting of oleanolic acid and polyvinylpyrrolidone were prepared for comparison. Polysorbate 80, a nonionic surfactant, was incorporated into binary solid dispersions as the third component to prepare ternary solid dispersions. Solid dispersions were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and dissolution tests. The crystallinization of OA was prohibited in solid dispersions. Both the binary and ternary solid dispersions enhanced the dissolution of OA. Moreover, the dissolution of ternary solid dispersion was faster compared with that of binary solid dispersion. Polysorbate 80 played an important positive role in dissolution of the solid dispersion.

Conformal microcapsules encapsulating microcarrier-L02 cell complexes for treatment of acetaminophen-induced liver injury in rats.

Transplantation of hepatocyte microcapsule is considered to be a promising therapy for liver injury. In view of long diffusion distances in existing cell microcapsules, transport efficiencies of nutrients, metabolic wastes, and therapeutic secretions are greatly restricted. In this study, a novel conformal microcapsule was established with L02 cells cultured on Cytodex-3 microcarriers designed as the core and alginate-chitosan-alginate (ACA) polyelectrolyte layers as the shell. When L02 cells on Cytodex-3 microcarriers grew to the late exponential phase, they were microencapsulated with thin conformal coatings by an aqueous two-phase emulsification method to ensure short and about the same distance for transport of nutrients, metabolic wastes, and therapeutic secretions between all encapsulated cells and the transplantation site. Selective permeability, mechanical stability, surface roughness and hepatic functions were characterized. It was demonstrated that conformal microcapsules enclosing microcarrier-L02 cell complexes could produce urea and human albumin continually in vitro. When the microcapsules were transplanted into rats with liver injury induced by acetaminophen, serum total bilirubin, alanine transaminase and albumin levels in vivo could be maintained normal for 60 days. Cell survival was improved and the strategy for cell microencapsulation may be promising in controlled release of therapeutic secretions for relevant diseases.

Preparation of monolithic osmotic pump system by coating the indented core tablet.

A method for the preparation of monolithic osmotic pump tablet was obtained by coating the indented core tablet compressed by the punch with a needle. Atenolol was used as the model drug, sodium chloride as osmotic agent and polyethylene oxide as suspending agent. Ethyl cellulose was employed as semipermeable membrane containing polyethylene glycol 400 as plasticizer for controlling membrane permeability. The formulation of atenolol osmotic pump tablet was optimized by orthogonal design and evaluated by similarity factor (f2). The optimal formulation was evaluated in various release media and agitation rates. Indentation size of core tablet hardly affected drug release in the range of (1.00-1.14) mm. The optimal osmotic tablet was found to be able to deliver atenolol at an approximately constant rate up to 24h, independent of both release media and agitation rate. The method that is simplified by coating the indented core tablet with the elimination of laser drilling may be promising in the field of the preparation of osmotic pump tablet.

Preparation and characterization of inclusion complexes of prazosin hydrochloride with beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.

The slightly water-soluble drug prazosin hydrochloride (PRH) and its inclusion with either beta-cyclodextrin (betaCD) or hydroxypropyl-beta-cyclodextrin (HPbetaCD) were investigated. The phase solubility profiles of PRH with betaCD and HPbetaCD were classified as B(s)- and A(L)-types, respectively. Stability constants with 1:1 molar ratio were calculated from the phase solubility diagrams and the solubility of PRH could be enhanced by 27.6% for betaCD and 226.4% for HPbetaCD, respectively. Binary systems of PRH with betaCD or HPbetaCD prepared by various methods were characterized by differential scanning calorimetry and Fourier transformation-infrared spectroscopy. It could be concluded that PRH could form inclusion complex with either betaCD or HPbetaCD. The dissolution profiles of inclusion complexes were determined and compared with those of PRH alone and their physical mixtures. The dissolution rate of PRH was increased by betaCD and HPbetaCD inclusion complexation remarkably. Both the preparation technique and nature of the carriers played important roles in the dissolution performance of the systems. All the systems with HPbetaCD showed better performance than the corresponding ones with betaCD.

[Preparation of atenolol monolithic osmotic pump tablets].

AIM: The simplified preparative method and formulation for atenolol monolithic osmotic pump tablets were investigated. METHODS: The core tablets with an indentation were compressed by the punch with a needle. Osmotic pump tablets were prepared by coating the indented tablets. Similarity factor was used to evaluate formulation of osmotic pump tablets. RESULTS: The formulation of core tablets and the composition and thickness of coating membrane showed marked effects on drug release. Orifice size of core tablets in the range of 1.00 - 1.14 mm scarcely affected drug release. CONCLUSION: The preparation of osmotic pump tablets was simplified with the exempting of laser drilling. The atenolol monolithic osmotic pump tablets could deliver drug constantly for 24 h.

[Sandwiched osmotic pump tablet for controlled release of water-insoluble drug].

AIM: To study sandwiched osmotic pump tablet for delivering water-insoluble drug for 24 hours. METHODS: Sandwiched osmotic pump tablet was prepared using nifedipine as the model drug. The effects of various formulation variables and orifice size on drug release were studied. The mechanical properties of cellulose acetate membrane were also investigated. RESULTS: Polyethylene oxide of drug layer and potassium chloride of push layer showed marked positive effects on drug release. In the range of 0.50 mm to 1.40 mm, orifice size hardly affects drug release. Cellulose acetate membrane is strong enough to assure the integrity of osmotic pump tablet and could sustain an internal pressure ranging from 0.34 MPa to 2.85 MPa. CONCLUSION: Sandwiched osmotic pump tablet can deliver water-insoluble drug constantly for 24 hours. Release media and agitation rate scarcely affect drug release. Compared with the commercialized push-pull osmotic pump tablet, sandwiched osmotic pump tablet is easy in preparation with exempting identification of drug layer before drilling.

[Unitary-core osmotic pump tablet for controlled release of water-insoluble drug].

AIM: To study unitary-core osmotic pump tablet for delivering water-insoluble drug for 24 hours. METHODS: Unitary-core osmotic pump tablet was prepared using nifedipine as the model drug. The effects of various core formulation variables on drug release were studied. RESULTS: Polyethylene oxide and potassium chloride have comparable positive effects on drug release, whereas, nifedipine has markedly negative effect on drug release. CONCLUSION: Unitary-core osmotic pump tablet is very easy in preparation and it can deliver water-insoluble drug in substantially constant rate for 24 hours.

Female hormone release of microencapsulated Xenopus laevis ovarian cells.

Cell microencapsulation has potential for the treatment of endocrine diseases. This study aims to probe the feasibility of Xenopus laevis as an animal model for cell microencapsulation and transplantation and to evaluate the female hormone release of microencapsulated X. laevis ovarian cells. The cells were harvested, cultured and microencapsulated into alginate-chitosan-alginate microcapsules with an electrostatic generator. The estradiol and progesterone releases of the microencapsulated X. laevis ovarian cells were investigated both in vitro and in vivo. The results showed that the microencapsulated cells kept secreting estradiol and progesterone in vitro for 60 days. After transplantation, serum estradiol and progesterone levels in ovariectomized X. laevis remained elevated for 60 days. X. laevis has been proved to be a suitable animal model for cell microencapsulation and transplantation. Microencapsulated ovarian cells may be considered as a promising endogenous drug delivery system for the treatment of deficiency of female hormones.

An ovarian cell microcapsule system simulating follicle structure for providing endogenous female hormones.

The aim of this study was to create a microcapsule system simulating native follicle structure by introducing microcarrier culture to microencapsulation for providing endogenous female hormones. Granulosa and theca cells of rat follicles were isolated. Granulosa cells were grown on microcarriers and enclosed together with theca cells in alginate-chitosan-alginate microcapsules. The cell viability and female hormone secretion were investigated in vitro. The microcapsules were transplanted to ovariectomized rats and the serum levels of estradiol and progesterone were measured for 60 days. The microencapsulated granulosa cells growing on microcarriers exhibited enhanced viability and promoted secreting ability of estradiol and progesterone compared with those without the microcarriers. Co-microencapsulation of granulosa cells and theca cells markedly elevated estradiol secretion in vitro. Transplantation of co-microencapsulated granulosa cells on microcarriers and theca cells maintained serum estradiol and progesterone at normal levels for 60 days. Microcarrier cell culture has been proved to be an effective method to enhance the viability of granulosa cells in microcapsules. Moreover, the transplantation of microcapsules enclosing granulosa cells on microcarriers and theca cells may be promising to provide endogenous female hormones for menopausal syndrome treatment.