-
Obstetrics and Gynecology Apr 2022To evaluate topiramate and etonogestrel pharmacokinetic interactions in contraceptive implant users.
OBJECTIVE
To evaluate topiramate and etonogestrel pharmacokinetic interactions in contraceptive implant users.
METHODS
We conducted a prospective, noninferiority study with healthy women using etonogestrel implants continuously for 12-36 months. We measured baseline serum etonogestrel concentrations and then began a 6-week titrated topiramate regimen to standard migraine (100 mg/day) and epilepsy (400 mg/day) dosages. We repeated serum etonogestrel concentrations at 3 weeks (100 mg/day), 4 weeks (200 mg/day), and 6 weeks (400 mg/day) of topiramate therapy. We measured etonogestrel using a validated liquid chromatography-tandem, mass-spectrometry assay and tested for noninferiority (less than 30% decrease) in serum etonogestrel concentrations from baseline.
RESULTS
We enrolled 48 total participants; 32 completed 3 weeks, 31 completed 4 weeks, and 27 completed all follow-up visits. Participants' median age was 25.3 years (range 18.3-37.2), median body mass index (BMI) was 25.5 kg/m2 (range 18.7-42.2), and median duration of implant use was 24 months (range 12-36). Median etonogestrel concentrations were 142 pg/mL (range 76.2-771) at baseline, 126 pg/mL (range 72.4-585) at 3 weeks, 119 pg/mL (range 65.6-542) at 4 weeks, and 105 pg/mL (46.2-859) at 6 weeks. The 95% CIs for mean percent change in serum etonogestrel concentrations from baseline were [-37.3%+16.9%], [-45.4%+5.2%], and [-66.8%+24.8%] at 3 weeks, 4 weeks, and 6 weeks, respectively. Excluding one participant who had a serum etonogestrel concentration less than 90 pg/mL at baseline, 30.8% of participants (8/26, 95% CI 14.3-51.8%) had a serum etonogestrel concentration less than 90 pg/mL at 6 weeks.
CONCLUSION
Though only a mild enzyme-inducing antiepileptic drug, concomitant topiramate use led to inferior serum etonogestrel concentrations among implant users, with a significant proportion reaching etonogestrel concentrations below the threshold for ovulatory suppression when taking antiepileptic dosages of topiramate.
FUNDING SOURCE
This study was primarily funded through an Investigator-Initiated Study grant from Merck Sharp & Dohme Corp [MISP#57073]. This work was also supported by NIH/NCATS CTSA Grant Number UL1 TR001082 and NICHD K12 Women's Reproductive Health Research Scholar Program (grant number 5K12HD001271-18).
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT03335163.
Topics: Adolescent; Adult; Contraceptive Agents, Female; Desogestrel; Drug Implants; Female; Humans; Prospective Studies; Topiramate; Young Adult
PubMed: 35594123
DOI: 10.1097/AOG.0000000000004697 -
European Journal of Pharmaceutics and... Feb 2021In the field of drug delivery, the most commonly used treatments have traditionally been systemically delivered using oral or intravenous administration. The problems... (Review)
Review
In the field of drug delivery, the most commonly used treatments have traditionally been systemically delivered using oral or intravenous administration. The problems associated with this type of delivery is that the drug concentration is controlled by first pass metabolism, and therefore may not always remain within the therapeutic window. Implantable drug delivery systems (IDDSs) are an excellent alternative to traditional delivery because they offer the ability to precisely control the drug release, deliver drugs locally to the target tissue, and avoid the toxic side effects often experienced with systemic administration. Since the creation of the first FDA-approved IDDS in 1990, there has been a surge in research devoted to fabricating and testing novel IDDS formulations. The versatility of these systems is evident when looking at the various biomedical applications that utilize IDDSs. This review provides an overview of the history of IDDSs, with examples of the different types of IDDS formulations, as well as looking at current and future biomedical applications for such systems. Though there are still obstacles that need to be overcome, ever-emerging new technologies are making the manufacturing of IDDSs a rewarding therapeutic endeavor with potential for further improvements.
Topics: Delayed-Action Preparations; Drug Approval; Drug Compounding; Drug Implants; Drug-Eluting Stents; History, 20th Century; History, 21st Century; Humans; United States; United States Food and Drug Administration
PubMed: 33338604
DOI: 10.1016/j.ejpb.2020.12.005 -
Pharmaceutics Oct 2022The robustness of the pellet coating process with and without the use of an in-process coating thickness analyzer (PATVIS APA) was investigated. Pellets containing model...
The robustness of the pellet coating process with and without the use of an in-process coating thickness analyzer (PATVIS APA) was investigated. Pellets containing model drug were coated with a prolonged release film coating, using different process conditions. In the first set of experiments film coating was performed as process repetitions with unintentional variation of process parameters, and in the second set, controlled changes (inlet air humidity, gap between distribution plate and Wurster partition, starting pellet load) were made. Within the first set of experiments, the coating process endpoint was determined either via gravimetric consumption of coating dispersion or by means of in-line coating thickness monitoring. The release profiles of the pellets were analyzed and the density of coating calculated. Both methods of the process endpoint determination can be relatively robust in batch processing, if key factors influencing drug release profile are under control. PATVIS APA was shown to be a useful tool to better understand the coating process and can be helpful if coating process interruptions are encountered. Water content was shown to be the key factor influencing the drug profile, presumably by influencing the structure and thickness of the coating applied.
PubMed: 36365093
DOI: 10.3390/pharmaceutics14112274 -
Therapeutic Delivery Oct 2019Uveitis is a major cause of ocular morbidity, potentially leading to significant visual impairment. The recent adoption of alternative drug delivery options has led to... (Review)
Review
Uveitis is a major cause of ocular morbidity, potentially leading to significant visual impairment. The recent adoption of alternative drug delivery options has led to the development of new sustained-delivery corticosteroid systems, able to manage successfully chronic noninfectious posterior uveitis. The treatment goal is to target the site of inflammation with low dose of corticosteroids, delivered over an extended period of time, to minimize the cumulative damage resulting from repeated recurrences, reducing both injections frequency and ocular side effects. This article will review the pharmacology and preliminary clinical data of the 0.18 mg fluocinolone acetonide intravitreal implant (YUTIQ™), to show its efficacy and safety in the treatment of noninfectious posterior uveitis.
Topics: Chronic Disease; Clinical Trials, Phase III as Topic; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Implants; Drug Liberation; Fluocinolone Acetonide; Glucocorticoids; Humans; Randomized Controlled Trials as Topic; Treatment Outcome; Uveitis, Posterior
PubMed: 31663454
DOI: 10.4155/tde-2019-0051 -
Journal of Orthopaedics 2022Cartilage-derived chondroprogenitors have been reported to possess the biological potential for cartilage repair. However, its inherent chondrogenic potential in pellet...
Assessment of the inherent chondrogenic potential of human articular cartilage-derived chondroprogenitors in pellet culture using a novel whole pellet processing approach.
PURPOSE
Cartilage-derived chondroprogenitors have been reported to possess the biological potential for cartilage repair. However, its inherent chondrogenic potential in pellet culture needs evaluation. In-vitro cartilage regeneration models based on pellet cultures have been employed to evaluate the chondrogenic potential of stem cells. Evaluation of the degree of differentiation routinely involves paraffin embedding, sectioning, and immunohistochemical staining of the pellet. However, since chondrogenic differentiation is commonly non-uniform, processing random sections could lead to inaccurate conclusions. The study aimed at assessing the inherent lineage bias of chondroprogenitors with and without chondrogenic induction, using a novel whole pellet processing technique.
METHODS
Human chondroprogenitors (n=3) were evaluated for MSC markers and processed in pellet cultures either with stromal medium (uninduced) or chondrogenic differentiation medium (induced) for 28 days. The whole pellets and the conventional paraffin-embedded sectioned pellets were subjected to Collagen type II immunostaining and assessed using confocal laser microscopy. The staining intensities of the whole pellet were compared to the paraffin sections and revalidated using qRT-PCR for COL2A1 expression.
RESULTS
Uninduced and induced pellets displayed Collagen type II in all the layers with comparable fluorescence intensities. COL2A1 expression in both pellets was comparable to confocal results. The study demonstrated that uninduced chondroprogenitors in pellet culture possess promising inherent chondrogenic potential. Confocal imaging of whole pellets displayed different degrees of chondrogenic differentiation in the entire pellet, thus its probable in-vivo behavior.
CONCLUSION
The novel approach presented in this study could serve as an efficient in-vitro alternative for understanding translational application for cartilage repair.
PubMed: 35368732
DOI: 10.1016/j.jor.2022.03.007 -
International Journal of Pharmaceutics Mar 2024Multiple-unit dosage forms prepared by compacting pellets offer important manufacturing and compliance advantages over pellet-filled capsules. However, compaction may...
Multiple-unit dosage forms prepared by compacting pellets offer important manufacturing and compliance advantages over pellet-filled capsules. However, compaction may negatively affect the release control mechanism of pellets, and subunits may not be readily available after intake. Application of a cushioning layer to the starting units is here proposed as a strategy to obtain tablets with satisfactory mechanical strength, rapid disintegration and maintenance of the expected release profile of individual subunits while avoiding the use of mixtures of pellets and excipients to promote compaction and limit the impact of the forces involved. Cushion-coating with PEG1500, a soft and soluble material, was proved feasible provided that the processing temperature was adequately controlled. Cushioned gastro-resistant pellets were shown to consolidate under relatively low compaction pressures, which preserved their inherent release performance after tablet disintegration. Adhesion problems associated with the use of PEG1500 were overcome by applying an outer Kollicoat® IR film. Through design of experiment (DoE), robustness of the proposed approach was demonstrated, and the formulation as well as tableting conditions were optimized. The tableted cushion-coated pellet systems manufactured would allow a relatively high load of modified-release units to be conveyed, thus setting out a versatile and scalable approach to oral administration of multiple-unit dosage forms.
Topics: Excipients; Delayed-Action Preparations; Drug Implants; Tablets; Administration, Oral
PubMed: 38316318
DOI: 10.1016/j.ijpharm.2024.123874 -
Current Diabetes Reports Nov 2019The aim of this review is to summarize the development of the photoactivated depot (PAD) approach for the minimally invasive and continuously variable delivery of... (Review)
Review
PURPOSE OF REVIEW
The aim of this review is to summarize the development of the photoactivated depot (PAD) approach for the minimally invasive and continuously variable delivery of insulin.
RECENT FINDINGS
Using an insulin PAD, we have demonstrated that we can release native, bioactive insulin into diabetic animals in response to light signals from a small external LED light source. We have further shown that this released insulin retains bioactivity and reduces blood glucose. In addition, we have designed and constructed second generation materials that have high insulin densities, with the potential for multiple day delivery. The PAD approach for insulin therapy holds promise for addressing the pressing need for continuously variable delivery methods that do not rely on pumps, and their myriad associated problems.
Topics: Animals; Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Drug Implants; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Light; Photosensitizing Agents
PubMed: 31696345
DOI: 10.1007/s11892-019-1233-3 -
Animals : An Open Access Journal From... Oct 2022During the processing of compound feed for broilers, several changes occur that affect the physical and probably the nutritional properties of pellets, influencing...
During the processing of compound feed for broilers, several changes occur that affect the physical and probably the nutritional properties of pellets, influencing animal performance. The effects of mill type, particle size (PS) and expander conditioning prior to pelleting (E + P) were combined to generate pellets. A 2 × 3 × 2 factorial arrangement was designed with two mill types (a hammer mill (HM) or roller mill (RM)), three PSs (0.8, 1.2 or 1.6 mm) and two E + Ps (with or without expander processing prior to pelleting), with six replications of 12 unsexed Ross 308 broilers each. All the processing lines reduced the PS from mash to finished pellets via secondary grinding, by 2.35 times on average. However, RM grinding required less electric power (p < 0.001). The intended PS (0.8, 1.2 or 1.6 mm) did not affect this energy consumption. E + P and the PS interacted for the pellet durability index (PDI) (p = 0.006). The worst PDI in the pellets was observed when a PS of 1.6 mm without E + P was used. Only E + P positively affected starch (p < 0.001) and amino acids’ ileal apparent digestibility (p < 0.01). Organic matter (OM) (p = 0.02) and fat (p < 0.001) digestibility, as well as AMEN (p = 0.005) content, were influenced by the PS (main effect), whereas E + P and mill type interacted with these values (p < 0.005). Lower OM digestibility and AMEN content were observed when RM without E + P was used (p = 0.001). The feed conversion ratio (FCR) was enhanced and feed intake (FI) was improved with E + P. The combination of the RM mill, a 1.6 mm mean PS, and E + P improved FCR (three-way interaction, p = 0.019)), showing that for a higher PS, E + P is necessary for animal performance. Carcass yield was, on average, 80.1%. No effects on commercial cuts (breast, legs and wings) were observed. In contrast, abdominal fat was affected by mill type * PS (p = 0.012) and E + P * PS (p = 0.048) in a two-way interaction. The highest abdominal fat indicated an imbalance in the amino acid (AA)-to-AMEN ratio. Coarse PS promoted heavier gizzards (p = 0.02) but E + P tended to reduce them (p = 0.057). The processing steps improved pellet quality and feed efficiency associated with RM, coarse PS and E + P, highlighting the positive effects of E + P on abdominal fat and AMEN content, which should be adjusted to AA or reduced at formulation. However, these results are for an experimental processing plant and may not necessarily apply to larger plants, so the use of these data and methods should be considered as guidelines for replication at production sites.
PubMed: 36230448
DOI: 10.3390/ani12192707 -
Nature Communications May 2021Polymeric drug carriers are widely used for providing temporal and/or spatial control of drug delivery, with corticosteroids being one class of drugs that have...
Polymeric drug carriers are widely used for providing temporal and/or spatial control of drug delivery, with corticosteroids being one class of drugs that have benefitted from their use for the treatment of inflammatory-mediated conditions. However, these polymer-based systems often have limited drug-loading capacity, suboptimal release kinetics, and/or promote adverse inflammatory responses. This manuscript investigates and describes a strategy for achieving controlled delivery of corticosteroids, based on a discovery that low molecular weight corticosteroid dimers can be processed into drug delivery implant materials using a broad range of established fabrication methods, without the use of polymers or excipients. These implants undergo surface erosion, achieving tightly controlled and reproducible drug release kinetics in vitro. As an example, when used as ocular implants in rats, a dexamethasone dimer implant is shown to effectively inhibit inflammation induced by lipopolysaccharide. In a rabbit model, dexamethasone dimer intravitreal implants demonstrate predictable pharmacokinetics and significantly extend drug release duration and efficacy (>6 months) compared to a leading commercial polymeric dexamethasone-releasing implant.
Topics: Adrenal Cortex Hormones; Animals; Cells, Cultured; Delayed-Action Preparations; Dexamethasone; Dimerization; Disease Models, Animal; Drug Delivery Systems; Drug Implants; Drug Liberation; Polymers; Rabbits; Rats; Uveitis
PubMed: 34001908
DOI: 10.1038/s41467-021-23232-7 -
Drug Delivery Dec 2022The traditional systemic chemotherapy through intravenous infusion of doxorubicin (DOX) has many side effects. The aim of this study was to develop a PLGA-based...
The traditional systemic chemotherapy through intravenous infusion of doxorubicin (DOX) has many side effects. The aim of this study was to develop a PLGA-based DOX-loaded implant and to evaluate the efficacy and drug metabolism distribution of the implant in intratumoral chemotherapy for osteosarcoma (OS). In this study, implants containing DOX, poly(d,l-lactide-co-glycolide), and polyethylene glycol 4000 were prepared by melt-molding method. Then, the antitumor activity and systemic drug distribution of the implants were tested in a K7M2 OS bearing mouse model. The scanning electron microscope images showed that DOX was uniformly dispersed in the polymer matrix. Both the and release profiles of implants are characterized by three-phase release. Implantation of DOX-loaded implants into tumors can inhibit tumor growth in a dose-dependent manner. The pharmacokinetic behavior shows that intratumor chemotherapy through implants has a much higher drug concentration in tumors than in normal tissues, which may be the reason for improving antitumor activity and reducing systemic side effects. In summary, the drug release of the implants prepared in this study is sustained and stable, which promotes long-term local accumulation of drugs in tumors, improves the efficacy of chemotherapy and has low toxicity to normal tissues.
Topics: Animals; Animals, Outbred Strains; Antibiotics, Antineoplastic; Bone Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Implants; Drug Liberation; Female; Male; Mice; Mice, Inbred BALB C; Osteosarcoma; Polyethylene Glycols; Polylactic Acid-Polyglycolic Acid Copolymer; Random Allocation; Rats, Sprague-Dawley; Technology, Pharmaceutical; Xenograft Model Antitumor Assays; Rats
PubMed: 35147071
DOI: 10.1080/10717544.2022.2032878