Design of a Drug-Eluting Subcutaneous Implant of the Antiretroviral Tenofovir Alafenamide Fumarate.

PURPOSE: Sexual transmission of HIV has been clinically proven to be preventable with a once-daily oral tablet; however, missed doses dramatically increase the risk of HIV infection. Long-acting subcutaneous implants do not allow the user to miss a dose. A desirable long-acting drug-eluting implant can deliver a constant amount of drug, adjust the delivered dose, and be readily manufactured. We present a long-acting, subcutaneous implant design composed of tenofovir alafenamide hemifumarate (TAF) pellets loaded in a sealed polyether urethane tube for the prevention of HIV transmission. METHODS: Implants were prepared with pressed drug pellets and extruded polyurethane tubing. In vitro release rate of implants using different pellet formulations, rate-controlling membranes, and geometries were measured. RESULTS: Tenofovir alafenamide release appeared to be governed by a pseudo-steady state and followed a mass transport model of release from a cylindrical drug reservoir. Implant seal integrity was tested and confirmed using mechanical testing. The inclusion of sodium chloride in the pellet increased the release rate and reduced initial lag. The release was sustained for 100 days. CONCLUSIONS: The release rate of tenofovir alafenamide mechanistically varied with geometry and rate controlling membrane composition. The polyether urethane implant presented herein is modular and tunable to adjust the release rate and duration of the TAF release.

The road to market implantable drug delivery systems: a review on US FDA's regulatory framework and quality control requirements.

The scope of Implantable Drug Delivery Systems (IDDSs) comprehends a variety of sterile therapeutic implements placed inside the body to exert a certain therapeutic action for extended duration. They are classified under different categories from pharmaceutical science and regulatory perspectives. The novelty and variety of IDDSs prevent the application of a uniform regulation for all IDDS products; therefore, sponsors face regulatory challenges to register and market their products. This review investigates pharmaceutical science literature and the United States Food and Drug Administration (US FDA) regulatory guidance to find how any IDDS is classified, regulated, and introduced in the market. The regulatory classification of any IDDS, as a 'drug', 'medical device' or a 'combination product', is the cornerstone in determining the regulatory pathway, which decides the quality control requirements preceding the marketing approval. IDDSs are generally recognized as combination products as they consist of two or more regulated components (drugs, medical devices or biological products) combined prior to use to function as a single entity. Although robust and defined US FDA regulatory pathways exist for each component independent of one another, the regulatory pathways for combination products are less formalized.

The interprocess NIR sampling as an alternative approach to multivariate statistical process control for identifying sources of product-quality variability.

We are presenting a new approach of identifying sources of variability within a manufacturing process by NIR measurements of samples of intermediate material after each consecutive unit operation (interprocess NIR sampling technique). In addition, we summarize the development of a multivariate statistical process control (MSPC) model for the production of enteric-coated pellet product of the proton-pump inhibitor class. By developing provisional NIR calibration models, the identification of critical process points yields comparable results to the established MSPC modeling procedure. Both approaches are shown to lead to the same conclusion, identifying parameters of extrusion/spheronization and characteristics of lactose that have the greatest influence on the end-product's enteric coating performance. The proposed approach enables quicker and easier identification of variability sources during manufacturing process, especially in cases when historical process data is not straightforwardly available. In the presented case the changes of lactose characteristics are influencing the performance of the extrusion/spheronization process step. The pellet cores produced by using one (considered as less suitable) lactose source were on average larger and more fragile, leading to consequent breakage of the cores during subsequent fluid bed operations. These results were confirmed by additional experimental analyses illuminating the underlying mechanism of fracture of oblong pellets during the pellet coating process leading to compromised film coating.

Application of quality by design (QbD) to formulation and processing of naproxen pellets by extrusion-spheronization.

The aim of this research was to apply quality by design (QbD) to the development of naproxen loaded core pellets which can be used as the potential core for colon-specific pellets. In the early stages of this study, prior knowledge and preliminary studies were systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA) and fishbone diagram. Then Plackett-Burman design was used to screen eight potential high risk factors (spheronization speed, spheronization time, extrusion speed, drying method, CCMC-Na concentration, lactose concentration, water concentration and Tween 80 concentration) obtained from the above risk assessment. It was discovered that out of the eight potential high risk factors only three factors (spheronization speed, extrusion speed and CCMC-Na concentration) had significant effects on the quality of the pellets. This allowed the use of Box-Behnken design (BBD) to fully elucidate the relationship between the variables and critical quality attribute (CQA). Finally, the final control space was established within which the quality of the pellets can meet the requirement of colon-specific drug delivery system. This study demonstrated that naproxen loaded core pellets were successfully designed using QbD principle.

New york city physicians' views of providing long-acting reversible contraception to adolescents.

PURPOSE: Although the US adolescent pregnancy rate is high, use of the most effective reversible contraceptives-intrauterine devices (IUDs) and implantable contraception-is low. Increasing use of long-acting reversible contraception (LARC) could decrease adolescent pregnancy rates. We explored New York City primary care physicians' experiences, attitudes, and beliefs about counseling and provision of LARC to adolescents. METHODS: We conducted in-depth telephone interviews with 28 family physicians, pediatricians, and obstetrician-gynecologists using an interview guide based on an implementation science theoretical framework. After an iterative coding and analytic process, findings were interpreted using the capability (knowledge and skills), opportunity (environmental factors), and motivation (attitudes and beliefs) conceptual model of behavior change. RESULTS: Enablers to IUD counseling and provision include knowledge that nulliparous adolescents are appropriate IUD candidates (capability) and opportunity factors, such as (1) a clinical environment supportive of adolescent contraception, (2) IUD availability in clinic, and (3) the ability to insert IUDs or easy access to an someone who can. Factors enabling motivation include belief in the overall positive consequences of IUD use; this is particularly influenced by a physicians' perception of adolescents' risk of pregnancy and sexually transmitted disease. Physicians rarely counsel about implantable contraception because of knowledge gaps (capability) and limited access to the device (opportunity). CONCLUSION: Knowledge, skills, clinical environment, and physician attitudes, all influence the likelihood a physician will counsel or insert LARC for adolescents. Interventions to increase adolescents' access to LARC in primary care must be tailored to individual clinical practice sites and practicing physicians, the methods must be made more affordable, and residency programs should offer up-to-date, evidence-based teaching.

Development of a PAT tool for monitoring the Wurster coater performance.

Real-time process analytical technology (PAT) is proposed as an effective approach for monitoring the performance of a Wurster coater. The coater was used for coating of 0.78 mm pharmaceutical pellets. The coating solution consisted of Hydroxypropyl methylcellulose/Poly ethylene glycol. During the coating process, small amounts of pellets (∼2 g) were sampled at 10 min. intervals and the pressure fluctuations were recorded at the same time. The signals were analyzed using the wavelet transform (WT) and decomposed into different sub-signals. Principal component analysis (PCA) was employed to the energies of these sub-signals, whose outliers were eliminated using the Mahalanobis distance method. The reference coating thickness data were obtained via spectrophotometry during the coating process. The partial least squares (PLS) regression was incorporated with the PCA for the development of a model for prediction of the coating thickness. The PLS regression revealed that the pressure fluctuations can be used to evaluate the thickness with a good precision. This study demonstrated the applicability of pressure fluctuations for the prediction of the coating thickness. This method can be regarded as a new robust, fast and non-intrusive PAT approach for monitoring the coating process which can be easily used by engineers and practitioners.

The evolving process of European combination product review, Part I.

A new European guideline on drug-eluting stents (DES) introduces for the first time detailed information that European drug authorities should review concerning the medicinal substance that is incorporated into this type of drug-device combination product. Part I of this article discusses European requirements that apply to DES. Part II will discuss the new guideline, other stent guidelines and evolving process of drug-device regulatory review in Europe.

[Optimatization of pellet preparation is CF-granulator with factorial design]. / CF-granulátorral történo pelletkészítés optimalizálása kísérlettervezéssel.

Lithium carbonate-containing pellets were made in a laboratory-scale centrifugal granulator in order to investigate the effects of the process parameters (rotor rotation speed, slit airflow rate and spray air rate) on the pellet shape and size distribution. The size distribution and the shape parameters (roundness, roughness, rectangularity and sphericity) of the pellets were measured, and an optimization parameter was then calculated from these shape parameters. The experiment was carried out and evaluated according to a 2(3) full factorial design. All three variables were found to exert a significant effect on the pellet shape. With use of the signs and magnitudes of the coefficients of the variables in the fitted linear model, the direction of the gradient was determined; two control measurements were made. These proved the accuracy of the applied model and the direction of the gradient. Overall, a high rotor rotation speed and low slit airflow rate and spray air rate furnished the best value of the optimization parameter.

[Off-label use of drug-eluting coronary stents]. / Verwendung von Medikamente freisetzenden Koronarstents in Off-Label-Situationen.

Current recommendations of the German Cardiac Society on percutaneous coronary interventions (PCI) summarise the database available for the use of drug-eluting stents (DES) for the treatment of symptomatic coronary artery stenoses. This analysis concludes that the safety and efficacy of drug-eluting stent platforms have been shown in on- and off-label situations. However, stenting with DES should be critically examined and evaluated in each patient. The decision to use a DES depends on the analysis of the individual morbidity, history of cardio-vascular disease and the specific coronary morphology. Patients characterised by a high risk of restenosis following PCI benefit in particular from DES use. In these cases, the off-label implantation of DES is indicated and necessary.

Experience with the Histrelin Implant in Pediatric Patients.

The histrelin implant has emerged as a therapeutic option for the treatment of central precocious puberty that has been favorably received by patients and providers. Inserted subcutaneously, the 50-mg implant provides continuous release of the potent gonadotropin-releasing hormone analog (GnRHa) histrelin. Profound suppression of the hypothalamic-pituitary-gonadal (HPG) axis occurs within 1 month of its placement resulting in pubertal arrest, attenuation of skeletal advancement and a progressive increase in predicted adult height. Although marketed for annual use, suppression lasting 2 years from a single implant has been demonstrated. Placing and removing the device is a minor outpatient procedure easily accomplished by a pediatric surgeon using local anesthesia. The major downside to the implant is a ∼25% rate of breakage upon removal. Information about the recovery of the HPG axis following histrelin explantation is limited but suggests an average time to menarche comparable with depot GnRHa formulations albeit with wide individual variation.

Local drug delivery via a coronary stent with programmable release pharmacokinetics.

BACKGROUND: Fixed drug release kinetics and vessel wall partitioning may limit the effectiveness of drug-eluting stents. We report preliminary experience using a new coronary stent with programmable pharmacokinetics. METHODS AND RESULTS: A newly designed metallic stent contains honeycombed strut elements with inlaid stacked layers of drug and polymer. In vitro studies evaluated recipes for loading paclitaxel to establish the parameters for controlling drug release. Manipulation of the layers of biodegradable polymer and drug allowed varying of the initial 24-hour burst release of paclitaxel from 69% to 8.6% (P<0.0001). Late release of drug could be adjusted dependently or independently of early burst release. A biphasic release profile was created by the addition of blank layers of polymer within the stack. In the 30-day porcine coronary model (n=17 pigs), there was a 70% reduction in late loss (0.3+/-0.5 versus 1.0+/-0.5 mm, P=0.04), a 28% increase in luminal volume (132+/-12 versus 103+/-21 mm(3), P=0.02), and a 50% decrease in histological neointimal area (2.0+/-0.5 versus 4.0+/-1.6 mm(2); P<0.001) compared with bare metal controls. Temporal and regional variations in vascular healing were seen histologically. CONCLUSIONS: Layered polymer/drug inlay stent technology permits flexible and controllable pharmacokinetic profiles. Programmable, complex chemotherapy using this approach may be feasible for the treatment of cardiovascular disease.

Progestin-only contraceptive rings.

Several progestin-only long acting contraceptives are currently available in the form of implants or injectables. Vaginal rings are another contraceptive option in the final stages of development. These steroid-containing polymer rings are placed in the vagina, providing relatively constant drug release, thus allowing for lower effective doses. Vaginal rings have the advantage of being user-controlled and non-provider dependent, and their use is non-coital related. The first clinical study with medroxyprogesterone acetate vaginal rings was published in 1970. Since then numerous clinical trials testing different steroids and doses have followed. A large Phase III multicenter clinical trial with a levonorgestrel ring, releasing 20 microg/day, was coordinated and sponsored by WHO. The cumulative one-year pregnancy rate was 4. 5%. The principal reasons for discontinuation were menstrual disturbances (17.2%), followed by frequent expulsion of the ring (7. 1%), and vaginal symptoms (6.0%). The finding of erythematous lesions in the vagina in some women has led to the development of a more flexible device. Collaboration with industry should facilitate the manufacture of a redesigned levonorgestrel ring with a higher release rate. The Population Council is also developing a vaginal ring containing Nestorone for 6 months of continuous use. Ovulation inhibition was achieved in over 97% of the segments studied, with rings releasing either 50, 75, or 100 microg/day. No pregnancies occurred in women using the low-dose ring, while one pregnancy each occurred in the intermediate- and high-dose ring groups for a 6-month cumulative pregnancy rate of 0.0, 1.9, and 2.1%. Bleeding irregularities were common. Nestorone is orally inactive; therefore this ring is also excellent for use in lactating women.

Progestin implants.

Progestin implants for contraception are highly effective, safe, and the most convenient choice for many women. Progestin implants currently on the market, preparing for launch, or under investigation are reviewed here. Their basic galenic and pharmacokinetic features, as well as their contraceptive effectiveness, are described. The first progestin-only contraceptive implant placed on the market was Norplant, a multiunit system. Since then, several single- and double-rod implants have been developed, each using one of four different progestins: levonorgestrel, etonogestrel, Nestorone and nomegestrol acetate. Jadelle is similar to Norplant but consists of only two, rather than six, Silastic rods to simplify insertion and removal; nevertheless, levonorgesterel serum levels are identical, and performance is the same for both systems. The single implant systems reviewed here are: Implanon with a 3-year duration; Nestorone implants for breast feeding and non-breast feeding women lasting up to 2 years; and Uniplant, which is effective for 1 year. The advantages and disadvantages of progestin implants, the importance of counseling for increasing user satisfaction, and the future outlook for this contraceptive method are also discussed.

The levonorgestrel intrauterine system: therapeutic aspects.

Use of the levonorgestrel-releasing intrauterine system (LNG IUS) is associated with a strong reduction in the number of days of bleeding and menstrual blood loss. This effect is based on the marked local action of the intrauterine release of levonorgestrel (LNG) on the endometrium. In suppressed endometrium the production of many highly active compounds ceases. On the other hand, LNG stimulates the synthesis of some regulatory proteins in the endometrium. Reduction of menstrual blood loss results in improvement of the body iron balance and in an increase in hemoglobin concentration. The LNG IUS has been used in the prevention and treatment of iron deficiency anemia. Many studies have demonstrated that the LNG IUS is effective in the treatment of menorrhagia. Reduction of excessive blood loss is seen as soon as the first menstruation after insertion, and at 1 year the reduction is more than 90%. The therapeutic effect is maintained for more than 5 years after first placement of the LNG IUS in the uterine cavity. Correct insertion is essential, and complications and side effects are rare; fertility is preserved, and invasive procedures such as endometrial ablation or hysterectomy and hospitalization are avoided. The third major indication for therapeutic use is in protection of the endometrium in estrogen replacement therapy during peri- and postmenopausal years. A fundal position of the system in the uterine cavity results in reduction of bleeding, and an increasing number of women have no bleeding at all during use of the IUS. Acceptance and continuation of use of the LNG IUS in hormone replacement therapy (HRT) have been high.

The levonorgestrel intrauterine system in contraception.

The levonorgestrel intrauterine system (LNG IUS) releases 20 microg/24 h of levonorgestrel from a polymer cylinder mounted on a T-shaped frame and covered with a release rate-controlling membrane. It is approved for 5-year use. The most outstanding features of LNG IUS are its high contraceptive efficacy and reduction of menstrual blood flow. No single mode of action can account for its contraceptive efficacy. The endometrium becomes thin and inactive, and the cervical mucus turns scanty and viscous. Although ovulation may be disturbed to some degree, estradiol production continues normally. The Pearl index for LNG IUS from large clinical trials is 0.1. Extrauterine pregnancies occur in 1 in 5000 users per year. Both the volume of menstrual blood loss and the number of bleeding days are reduced. During the first year of use, 20% of women become amenorrheic. There is an initial increase in the mean number of bleeding and spotting days, but in 3 to 6 months the number of bleeding and spotting days is the same as observed in copper IUD-users. The variation between individuals is wide and unpredictable. There are also additional health benefits secondary to the inactivation of the endometrium: increased hemoglobin, decreased dysmenorrhea, a possible decrease in pelvic inflammatory disease. LNG IUS may also decrease the growth of fibroids. LNG IUS is well accepted by users, with typical annual continuation rates above 80% in clinical studies.

Vaginal rings for contraception in lactating women.

Contraceptive methods for breastfeeding women should be safe for the mother and infant and should not interfere with lactation. Progestin-only methods meet these conditions and can be used from the sixth week postpartum. Because all progestins are excreted in milk, those that are insufficiently active by the oral route are preferable to avoid any possible effect on the baby. These steroids, however, must be administered to the mother by a non-oral route. Initially, progesterone was administered subdermally to test this concept. Subsequently, a progesterone vaginal ring was developed to be used continuously for 3 to 4 months and replaced with a new device, as needed, until weaning. Clinical trials have shown a high contraceptive efficacy (over 98.5%) and safety. The gross continuation rate of this method is approximately 40% at 12 months of use, with use-related problems being the main reason for discontinuation (26.8%). Currently, a Nestorone vaginal ring is under development, delivering 50 microg of Nestorone per day. It may be used continuously for up to one year, even if weaning occurs earlier. Both of these progestin-only rings prolong lactational amenorrhea to 10 to 12 months, which represents a health benefit and convenience for many women. The registration of the progesterone vaginal ring, developed as a contraceptive method to be used exclusively during lactation, has been approved in Chile and Perú. The fact that it is a user-controlled long-term contraceptive that delivers a natural hormone makes it an attractive option for many women.

Polymeric sustained local drug delivery system for the prevention of vascular intimal hyperplasia.

Anastomotic intimal hyperplasia (IH) is a major cause of both autologous vein and synthetic vascular graft failure. We have previously published data suggesting that cyclosporin may reduce the development of IH in a canine model. However, systemic administration of cyclosporin could create serious adverse effects. Therefore, it is our long-term goal to test the hypothesis that the controlled local release of cyclosporin from a polymeric vascular wrap will prevent the development of IH. To test this hypothesis, we developed a controlled release vascular wrap (sheet/ring) using a poly(ethylene glycol) (PEG) hydrogel. Sterilization of the polymers was performed using the ethylene oxide and hydrogen peroxide sterilization methods. It was found that except for one combination (8000 molecular weight and 1:1 crosslinking ratio), the differences in the swelling ratios for the sterilized and unsterilized hydrogels were not statistically significant. Release studies from unsterilized and ethylene oxide-sterilized PEG hydrogels were conducted. It was found that release lasted for approximately 50 h for sterilized as well as unsterilized PEG hydrogels. Acute animal studies, to test the deployment of both the polymeric sheets and rings to the adventitial surface of native arteries and veins, were completed successfully.

Assessing the acceptability of Norplant contraceptive in four patient populations.

The object of this study was to review the experience of Norplant implants insertion at the University of Colorado Health Sciences Center with specific attention to the potential impact of source of care and/or clinic site of of insertion. Norplant implants were inserted at four different office sites, namely, adolescent-teen, resident, certified nurse midwife, and faculty physician. The charts of all patients who had Norplant implants inserted between April 1991 and September 1992 were reviewed and we attempted to contact each patient by telephone to assess clinical course and acceptability of Norplant contraceptive. We were able to contact 254 of 414 women (61%) who had Norplant implants inserted. The average length of time since Norplant implants insertion was 13.2 months. The only significant demographic difference between groups was that the adolescent-teen patients were younger, of lower parity, less educated, and were more likely to be single than the other three groups. The overall removal proportion was 14.6%, and removal proportions were not significantly different between any of the four groups. The primary reason for removal was unacceptable bleeding (32% of removers). Only 59% of patients returned for follow-up care. Faculty physician patients were significantly more compliant with follow-up compared to adolescent-teen and resident patients (p < 0.01). Patient retention of Norplant contraceptive is unrelated to age or the clinic setting in which the device was inserted. Since similar side effects are experienced by retainers and removers, it is unclear what other factors prompt women to seek removal. Particularly in the teen and resident groups, follow-up is poor.

PIP: To refine understanding of the acceptability of Norplant in the US on the basis of different target populations and sources of care, the experiences of four groups of clients who had the implants inserted at University of Colorado Health Sciences Center between April 1991 and September 1992 and could be reached for a postinsertion telephone interview were compared. The 254 women interviewed (61% of total acceptors over this period) were drawn from four clinics: adolescent, resident, certified nurse midwife, and faculty physician. The average length of time since insertion was 13.2 months. As expected, adolescent patients were significantly more likely to be younger, single, less educated, and of lower parity than women in the three other groups. The overall removal rate was 14.6%, with no significant difference among groups or in terms of factors such as age, race, or socioeconomic status; the mean time to removal was 10.2 months. The most common reason for removal (32%) was unacceptable bleeding; however, abnormal bleeding was not significantly associated with the decision to discontinue the method. Weight gain and headache were the only side effects reported significantly more frequently by removers than retainers. Only 150 (59%) women returned for a scheduled postinsertion follow-up visit; compliance was lowest among teens (41%) and highest among patients of faculty (77%). 10 of the 37 women who opted for removal had this procedure performed at another clinic site; this finding suggests that clinic-based studies may underestimate the actual Norplant discontinuation rate.

The power-consumption-controlled extruder: a tool for pellet production.

Based on the assumption that there is a link between power consumption of an extruder and pellet properties, a control circuit for power consumption was developed. Powder and granulation liquid are fed separately into a twin-screw extruder. The power consumption is controlled by varying the pump rate at a given powder-feed rate; consequently each level of power consumption results in a specific water content of the extrudate for a particular formulation. The shape of pellets depends almost entirely on the level of power consumption irrespective of formulation. The size of dry pellets is additionally affected by a shrinking factor which depends on the water content. The power-consumption-controlled extruder is an appropriate tool for the production of pellets. The system is able to adapt the water content for a formulation automatically.