Controlled release of octreotide and assessment of peptide acylation from poly(D,L-lactide-co-hydroxymethyl glycolide) compared to PLGA microspheres.

PURPOSE: To investigate the in vitro release of octreotide acetate, a somatostatin agonist, from microspheres based on a hydrophilic polyester, poly(D,L-lactide-co-hydroxymethyl glycolide) (PLHMGA). METHODS: Spherical and non-porous octreotide-loaded PLHMGA microspheres (12 to 16 µm) and loading efficiency of 60-70% were prepared by a solvent evaporation. Octreotide release profiles were compared with commercial PLGA formulation (Sandostatin LAR(®)); possible peptide modification with lactic, glycolic and hydroxymethyl glycolic acid units was monitored. RESULTS: PLHMGA microspheres showed burst release (~20%) followed by sustained release for 20-60 days, depending on the hydrophilicity of the polymer. Percentage of released loaded peptide was high (70-90%); > 60% of released peptide was native octreotide. PLGA microspheres did not show peptide release for the first 10 days, after which it was released in a sustained manner over the next 90 days; > 75% of released peptides were acylated adducts. CONCLUSIONS: PLHMGA microspheres are promising controlled systems for peptides with excellent control over release kinetics. Moreover, substantially less peptide modification occurred in PLHMGA than in PLGA microspheres.

Hydrophilic polyester microspheres: effect of molecular weight and copolymer composition on release of BSA.

PURPOSE: To study the release of a model protein, bovine serum albumin (BSA), from microspheres of an hydroxylated aliphatic polyester, poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA). METHODS: BSA-loaded microspheres were prepared by a double emulsion solvent evaporation method. The effect of copolymer composition and the molecular weight of the copolymer on in vitro release and degradation were studied. The integrity of the released BSA was studied by fluorescence spectroscopy and size exclusion chromatography (SEC). RESULTS: Microspheres prepared from PLHMGA with 50% hydroxymethyl glycolic acid (HMG) showed a burst release followed by a sustained release in 5-10 days. PLHMGA microspheres prepared from a copolymer with 35% and 25% HMG showed a sustained release of BSA up to 80% for 30 and 60 days, respectively. The release of BSA was hardly affected by the molecular weight of the polymer. Fluorescence spectroscopy and SEC showed that the released BSA preserved its structural integrity. Microspheres were fully degradable, and the degradation time increased from approximately 20 days to 60 days when the HMG content decreased from 50% to 25%. CONCLUSIONS: Taking the degradation and release data together, it can be concluded that the release of BSA from PLHMGA microspheres is governed by degradation of the microspheres.

Peripheral and axial substitution of phthalocyanines with solketal groups: synthesis and in vitro evaluation for photodynamic therapy.

Phthalocyanines (Pcs) are a class of photosensitizers (PSs) with a strong tendency to aggregate in aqueous environment, which has a negative influence on their photosensitizing ability in photodynamic therapy. Pcs with either peripheral or axial solketal substituents, that is, ZnPc(sol)8 and Si(sol)2Pc, respectively, were synthesized and their tendency to aggregate as well as their photodynamic properties in 14C and B16F10 cell lines were evaluated. The results were compared to more hydrophilic silicon Pcs, that is, Si(PEG750)2Pc and Pc4. The order of cellular uptake was Pc4 > ZnPc(sol)8 > Si(PEG750)2Pc > Si(sol2)Pc. In contrast, Si(sol2)Pc showed the highest photocytotoxicity, while ZnPc(sol)8 did not show any photocytotoxicity up to a concentration of 10 microM in both cell types. UV/vis spectroscopy showed that Si(sol)2Pc is less prone to aggregation than ZnPc(sol)8, which can explain the lack of photoactivity of the latter. Si(sol)2Pc was predominantly located in lipid droplets, whereas Si(PEG750)2Pc was homogeneously distributed in the cytosol, which is probably the main cause of their difference in photoactivity. The very high photodynamic efficacy of Si(sol)2Pc makes this PS an interesting candidate for future studies.

Polyurethane-based drug delivery systems.

Polyurethanes (PUs) are formed by a reaction between isocyanates and diols to yield polymers with urethane bonds (-NH-COO-) in their main chain. A great variety of building blocks is commercially available that allows the chemical and physical properties of PUs to be tailored to their target applications, particularly for the biomedical and pharmaceutical fields. This article reviews the synthesis and characterization of PUs and PU-copolymers, as well as their in vitro and in vivo biodegradability and biocompatibility. Particular emphasis is placed on the use of PUs for the controlled release of drugs and for the (targeted) delivery of biotherapeutics.

Perceived diabetes status is independently associated with glucose monitoring behaviour among type 2 diabetes mellitus patients.

AIMS: To investigate if patients' perceptions of their diabetes status is related to blood glucose self-monitoring (SMBG) behaviour, independent of self-reported disease severity. METHODS: The setting of this study was a cross-sectional study among 1561 patients, 18 years or older, who filled at least two prescriptions for any glucose lowering drug between March 2002 and 2003 in the Netherlands. Using a 30-item self-administered questionnaire, data on self-monitoring behaviour (frequency of test strip use and objective of self-monitoring), perceived diabetes status and disease severity were gathered. Type 1 diabetes mellitus patients were excluded. We used logistic regression to calculate odds ratios (OR) and their 95% confidence intervals (CI). RESULTS: About 54% of the patients (n=841) returned evaluable questionnaires. After exclusion of 97 type 1 diabetes mellitus patients, 744 type 2 diabetes mellitus patients were included. Practising SMBG was more common among patients who rated their diabetes status as poorly or moderately controlled compared to those who rated it (very) well-controlled (OR 1.93; 95% CI: 1.20-3.12). A better perceived diabetes status was more likely in those who performed SMBG infrequently compared to those who performed SMBG frequently (p-value for trend=0.001). Self-reported factors of disease severity and personalized objectives did not affect these associations considerably. CONCLUSIONS: Among type 2 diabetes mellitus patients, SMBG behaviour is associated with patients' perceptions of diabetes status, irrespective of the self-reported disease severity.

Differences in the association between structural factors and diabetes self-monitoring support.

OBJECTIVE: To determine if the association between the level of community pharmacy diabetes services and six of its reported determinants is influenced by the definition of these services. METHOD: Cross-sectional survey among 97% of all Dutch community pharmacies (1,642) registered in 2004. Seven definitions of self-monitoring support (support to patients performing self-monitoring of blood glucose) were constructed: one based on the Dutch pharmacy practice guideline (containing five activities related to patient counselling, calibration and dispensing), one based on patient counselling activities only and five definitions based on each separate activity. Multivariable models of self-monitoring support according to the different definitions were compared. MAIN OUTCOME MEASURE: Associations between determinants and the different definitions of self-monitoring support, expressed as odds ratio (OR) and 95% confidence intervals (95% CI). All definitions were compared to the practice guideline definition. RESULTS: The ORs of 14 of the 48 possible comparisons of different definitions were significantly different from one. The standardized difference ranged from 1.42 (95% CI: 1.01-1.90) to 3.05 (95% CI: 1.51-4.61). Three out of six predictive models retained different determinants compared to the multivariable model of self-monitoring support based on the guideline. CONCLUSION: The association between self-monitoring support and its determinants depend on the definition of self-monitoring support. This underlines the importance for pharmacy practice research to unambiguously describe the characteristics and the setting of an intervention. Only with a complete description of the intervention, the likelihood for success of implementation in another setting can be determined.

Methacrylamide polymers with hydrolysis-sensitive cationic side groups as degradable gene carriers.

Water-soluble polymers with hydrolyzable cationic side groups (structure of the monomers are shown in Figure 1) were synthesized and evaluated as DNA delivery systems. The polymers, except for pHPMA-NHEM, were able to condense plasmid DNA into positively charged nanosized particles. The rate of hydrolysis at 37 degrees C and pH 7.4 of the side groups differed widely; the fastest rate of hydrolysis was observed for HPMA-DEAE (half-life of 2 h), while HPMA-DMAPr had the lowest rate of hydrolysis (half-life of 70 h). In line with this, pHPMA-DEAE-based polyplexes showed the fastest destabilization of the polyplexes at 37 degrees C and pH 7.4. Polyplexes based on pHPMA-DEAE, pHPMA-DMAE, and pHPMA-MPPM showed release of intact DNA within 24, 48, and 48 h, respectively, after incubation at 37 degrees C and pH 7.4. PHPMA-DEAE and pHPMA-MPPM based polyplexes showed the highest transfection activity (almost twice as active as pEI). Importantly, the pHPMA-DEAE, pHPMA-MPPM, and pHPMA-BDMPAP polyplexes preserved their transfection activity in the presence of serum proteins. All polymers investigated showed a substantial lower in vitro cytotoxicity than pEI. In conclusion, pHPMA-based polyplexes are an attractive class of biodegradable vectors for nonviral gene delivery.

Regional influences on the dispensing of glucose test strips in Dutch community pharmacies.

BACKGROUND: Pharmacy practice guidelines promote the role of community pharmacies in self-monitoring of blood glucose. However, variations between Dutch pharmacies exist in the proportion of patients to whom test strips are dispensed. OBJECTIVE: To assess whether variations between community pharmacies in dispensing of blood glucose test strips can be explained by differences in patient characteristics and the region in which the pharmacy is located. SETTING: PHARMO-Record Linkage System containing drug dispensing histories from 40 community pharmacies of about 450,000 patients in the Netherlands. METHOD: We performed a retrospective cohort study. Data on prescription of all drugs and medical aids between 1991 and 2001 were extracted for all new users of antidiabetic drugs. Patients were excluded if the dispensing history did not allow classification of the type of diabetes or if the dispensing pharmacy could not be determined. The data were analysed using a Cox proportional hazard model. MAIN OUTCOME MEASURE: Time to first test strips dispensed. RESULTS: We identified 8,233 starters of antidiabetic drugs. During a median follow-up of 2.1 years, 20% of the patients were dispensed test strips at least once. Community pharmacy was significantly associated with the dispensing of test strips after adjustment for patient characteristics. This association was less apparent when stratified for the geographical location of the pharmacy. CONCLUSION: Community pharmacy is an independent determinant of the start of use of test strips. Differences in dispensing of test strips between pharmacies are dependent on geographical region. This suggests that implementing practice guidelines for diabetes care in community pharmacy requires different approaches in different regions.

Collaborative services among community pharmacies for patients with diabetes.

BACKGROUND: Patients performing self-monitoring of blood glucose (SMBG) may benefit from community pharmacy services. However, wide-scale implementation of these services is limited. Many pharmacy characteristics (eg, physical layout of the pharmacy, knowledge and competence of the pharmacy team) are reported to be relevant when implementing these services. Still, the importance of local agreements on the division of roles with, for example, local general practitioners or diabetes nurses, is less clear. OBJECTIVE: To study the association between local collaboration and the level of services provided by community pharmacies to patients performing SMBG. METHODS: In 2004, we performed a cross-sectional survey among all 1692 Dutch community pharmacies. Data were gathered on provision of services for SMBG, local agreements, and pharmacy characteristics. Data were analyzed using logistic regression. Associations were adjusted for pharmacy characteristics. RESULTS: About 44% (724) of the community pharmacies returned the questionnaire. Pharmacies that were not involved in local collaborative services on patient counseling reported to provide fewer services compared with those that were involved in such agreements (OR 0.26, 95% CI 0.13 to 0.53). Similar findings were observed for agreements on calibration of SMBG equipment (0.17, 0.04 to 0.71). The associations remained after adjusting for pharmacy characteristics. CONCLUSIONS: Local collaboration on the division of roles in diabetes care between healthcare professionals is independently associated with the number of pharmacy services provided to patients performing SMBG.

Dispensing glucose test materials in Dutch community pharmacies.

OBJECTIVE: To assess the proportion of diabetic patients who collect self-monitoring equipment for glucose testing in Dutch community pharmacies. METHODS: Data were used from the PHARMO-Record Linkage System, containing pharmacy dispensing records from 1991 to 1998. The study population consisted of patients who received at least two prescriptions of insulin and/or oral hypoglycemic agents. Information was collected on patient demographics, antidiabetic drug use and self-monitoring equipment (blood glucose meters and test strips). Type of diabetes was determined for all incident users of antidiabetic drugs. MAIN OUTCOME MEASURE: The proportion of patients per community pharmacy, who were dispensed self-monitoring equipment at least once. RESULTS: The study population consisted of 11,358 diabetic patients. The number of incident patients was 5,050, of whom 91.7% had type 2 diabetes. Twenty-nine pharmacies were included. The mean proportion of patients per pharmacy who received test strips at least once was 30.1% (SD = 6.7%), range 19-46%. The proportion of patients who were dispensed test strips was almost three times higher among type 1 than among type 2 patients (54% vs. 17%). CONCLUSION: In comparison to other countries' published data, Dutch community pharmacies dispense relatively few glucose test materials to diabetic patients. There are substantial differences between pharmacies in dispensing test strips. Further research is needed into the determinants governing the use of test strips at both patient and pharmacy level.

Direct-to-consumer communication on prescription only medicines via the internet in the Netherlands, a pilot study. Opinion of the pharmaceutical industry, patient associations and support groups.

OBJECTIVE: Investigation of the current application of direct-to-consumer (DTC) communication on prescription only medicines via the Intemet in the Netherlands. METHOD: Questionnaires were sent by e-mail to 43 Dutch innovative pharmaceutical industries and 130 Patient Association and Support Groups (PASGs). RESULTS: In this pilot study, the response of the pharmaceutical industry was rather low but the impression is that they were willing to invest in DTC communication. The majority of the websites of PASGs did not link to websites of pharmaceutical companies. The PASGs had no opinion whether patients can make a good distinction between DTC advertising and information on websites of the pharmaceutical industry nor about the quality. PASGs did not think unambiguously about the impact on the patient-doctor relationship. CONCLUSION: The impact of DTC communication on prescription only medicines via the internet is not yet clear in the Netherlands.