Development of Dissolution Tests on the Basis of Gastrointestinal Physiology

Sustained-release (SR) formulations may appear advantageous in first-in-human (FIH) study of innovative medicines. The newly developed SR matrix tablets require prolonged maintenance of API concentration in plasma and should be reliably assessed for the risk of uncontrolled release of the drug. In the present study, we describe the development of a robust SR matrix tablet with a novel G-protein-coupled receptor 40 (GPR40) agonist for first-in-human studies and introduce a general workflow for the successful development of SR formulations for innovative APIs. The hydrophilic matrix tablets containing the labeled API dose of 5, 30, or 120 mg were evaluated with several methods: standard USP II dissolution, bio-predictive dissolution tests, and the texture and matrix formation analysis. The standard dissolution tests allowed preselection of the prototypes with the targeted dissolution rate, while the subsequent studies in physiologically relevant conditions revealed unwanted and potentially harmful effects, such as dose dumping under an increased mechanical agitation. The developed formulations were exceptionally robust toward the mechanical and physicochemical conditions of the bio-predictive tests and assured a comparable drug delivery rate regardless of the prandial state and dose labeled. In conclusion, the introduced development strategy, when implemented into the development cycle of SR formulations with innovative APIs, may allow not only to reduce the risk of formulation-related failure of phase I clinical trial but also effectively and timely provide safe and reliable medicines for patients in the trial and their further therapy.

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Gastrointestinal Physiology Before and After Duodenal Switch with Comparisons to Unoperated Lean Controls: Novel Use of the SmartPill Wireless Motility Capsule

Obesity Surgery ◽

10.1007/s11695-021-05452-4 ◽

2021 ◽

Author(s):

Khalid Elias ◽

Per M. Hellström ◽

Dominic-Luc Webb ◽

Magnus Sundbom

Keyword(s):

Small Bowel ◽

Transit Time ◽

Duodenal Switch ◽

Rating Scale ◽

Gastrointestinal Symptoms ◽

Small Bowel Transit ◽

Gastrointestinal Physiology ◽

Time Points ◽

Small Bowel Transit Time ◽

Wireless Motility Capsule

Abstract Purpose Bariatric surgery alters gastrointestinal anatomy. In this exploratory study, the SmartPill® wireless motility capsule (WMC) was used to study changes in gastrointestinal physiology following biliopancreatic diversion with duodenal switch (BPD/DS). Material and Methods Twenty-eight BPD/DS patients (35 ± 11 years, 50% females, body mass index [BMI] 56 ± 5) were to be examined preoperatively and postoperatively. In addition to transit time, appetite control and gastrointestinal symptoms were studied by patient-scored questionnaires (visual analogue scale and Gastrointestinal Symptom Rating Scale (GSRS)). Data was compared to 41 lean unoperated controls. Results About 1.8 years postoperatively, 18 patients (BMI 35.8 ± 8.3) returned for a second WMC test. As expected, small bowel transit time was reduced, from 3.9 ± 1.6 h to 2.8 ± 2.0, p = 0.02, and at both these time points, it was shorter than in lean controls (5.4 ± 1.9 h, p = 0.001). Postoperatively, a trend towards reduced colon and whole gut transit times was seen in BPD/DS-patients, thus approaching those of lean controls. Surprisingly, BPD/DS patients scored higher satiety than controls preoperatively as well as increased hunger and desire to eat postoperatively. Compared to lean, BPD/DS patients reported a higher total GSRS score at both time points (1.2 ± 0.2 vs 1.7 ± 0.6 and 2.3 ± 0.5, p < 0.001). Postoperatively, the scores for diarrhea and indigestion increased. Conclusions The novel use of the SmartPill system in BPD/DS patients gave the expected readouts. Although small bowel transit time was further shortened after BPD/DS, whole gut transit time did not differ from controls. Typical gastrointestinal symptoms were reported postoperatively. Graphical abstract

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Physicochemical and Antifungal Properties of Clotrimazole in Combination with High-Molecular Weight Chitosan as a Multifunctional Excipient

Marine Drugs ◽

10.3390/md18120591 ◽

2020 ◽

Vol 18 (12) ◽

pp. 591

Author(s):

Bożena Grimling ◽

Bożena Karolewicz ◽

Urszula Nawrot ◽

Katarzyna Włodarczyk ◽

Agata Górniak

Keyword(s):

Molecular Weight ◽

High Molecular Weight ◽

Weight Ratio ◽

Scanning Calorimetry ◽

Minimal Inhibitory Concentrations ◽

Dissolution Tests ◽

Effective Combination ◽

The Impact ◽

High Molecular Weight Chitosan

Chitosans represent a group of multifunctional drug excipients. Here, we aimed to estimate the impact of high-molecular weight chitosan on the physicochemical properties of clotrimazole–chitosan solid mixtures (CL–CH), prepared by grinding and kneading methods. We characterised these formulas by infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffractometry, and performed in vitro clotrimazole dissolution tests. Additionally, we examined the antifungal activity of clotrimazole–chitosan mixtures against clinical Candida isolates under neutral and acid conditions. The synergistic effect of clotrimazole and chitosan S combinations was observed in tests carried out at pH 4 on Candida glabrata strains. The inhibition of C. glabrata growth reached at least 90%, regardless of the drug/excipient weight ratio, and even at half of the minimal inhibitory concentrations of clotrimazole. Our results demonstrate that clotrimazole and high-molecular weight chitosan could be an effective combination in a topical antifungal formulation, as chitosan acts synergistically with clotrimazole against non-albicans candida strains.

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Rabbit gastrointestinal physiology

Veterinary Clinics of North America Exotic Animal Practice ◽

10.1016/s1094-9194(02)00024-5 ◽

2003 ◽

Vol 6 (1) ◽

pp. 139-153 ◽

Cited By ~ 37

Author(s):

Ron Rees Davies ◽

Jennifer A.E Rees Davies

Keyword(s):

Gastrointestinal Physiology

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Gastrointestinal Physiology

JAMA ◽

10.1001/jama.1978.03280430081026 ◽

1978 ◽

Vol 239 (16) ◽

pp. 1665

Author(s):

R. Thomas Holzbach

Keyword(s):

Gastrointestinal Physiology

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Neptunium Speciation in Humic Acid-rich Clay Water upon Interaction With Radioactive Waste Glass Samples

MRS Proceedings ◽

10.1557/proc-757-ii7.1 ◽

2002 ◽

Vol 757 ◽

Cited By ~ 3

Author(s):

V. Pirlet ◽

P. Van Iseghem

Keyword(s):

Humic Substances ◽

Humic Acids ◽

Specific Interaction ◽

Waste Glass ◽

High Level Waste ◽

Boom Clay ◽

Dissolution Tests ◽

Vis Spectroscopy ◽

Doped Glasses ◽

High Level

ABSTRACTOrganic complexes of actinides are known to occur upon interaction of high level waste glass and Boom Clay which is a potential host rock formation for disposal of high level waste in Belgium. The solubility and mobility of 237Np, one of the most critical radionuclides, can be affected by the high dissolved organic carbon content of the Boom Clay porewater through complexation with the humic substances. The influence of humic substances on the Np behaviour is considered through dissolution tests of Np-doped glasses in Boom Clay water and through fundamental study of the specific interaction between Np(IV) and the humic acids using spectroscopic techniques. High Np(IV) concentrations are found in the glass dissolution tests. These concentrations are higher than what we should expect from the solubility of Np(OH)4, the solubility limiting solid phase predicted under the reducing conditions and pH prevailing in Boom Clay. Studying the specific interaction of Np(IV) with humic acids in Boom Clay porewater, high soluble Np concentrations are also measured and two main tetravalent Np-humate species are observed by UV-Vis spectroscopy. The two species are interpreted in terms of mixed hydroxo-humate complexes, Np(OH)xHA with x = 3 or 4. These species are the most likely species that can form according to the pH working conditions. Using thermodynamic simplified approaches, high complexation constants, i.e. log β131 and log β141 respectively equal to 46 and 51.6, are calculated for these species under the Boom Clay conditions.Comparing the spectroscopic results of the dissolution tests with the study of the interaction of Np(IV) with humic substances, we can conclude that the complexation of Np(IV) with the humic acids may occur and increases the solubility of Np(OH)4 upon interaction of a Np-doped glass and the Boom Clay porewater.

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Automation of dissolution tests

Journal of Automated Methods and Management in Chemistry ◽

10.1155/s1463924603000026 ◽

2003 ◽

Vol 25 (1) ◽

pp. 7-15 ◽

Cited By ~ 5

Author(s):

Rolf Rolli

Keyword(s):

Quality Control ◽

In Vitro Dissolution ◽

Pharmaceutical Companies ◽

Dissolution Testing ◽

Simultaneous Operation ◽

Task Forces ◽

The Core ◽

Dissolution Tests ◽

The 1960S

Dissolution testing of drug formulations was introduced in the 1960s and accepted by health regulatory authorities in the 1970s. Since then, the importance of dissolution has grown rapidly as have the number of tests and demands in quality-control laboratories. Recent research works lead to the development of in-vitro dissolution tests as replacements for human and animal bioequivalence studies. For many years, a lot of time and effort has been invested in automation of dissolution tests. There have been a number of in-house solutions from pharmaceutical companies and many have created task forces or even departments to develop automation. Robotic solutions with sequential operation were introduced as well as the simultaneous operation concept developed by SOTAX. Today, pharmaceutical companies focus their resources mainly on the core business and in-house engineering solutions that are very difficult to justify. Therefore, it is important to know the basic considerations in order to plan an automation concept and implement it together with a vendor.

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Difference in the Dissolution Behaviors of Tablets Containing Polyvinylpolypyrrolidone (PVPP) Depending on Pharmaceutical Formulation After Storage Under High Temperature and Humid Conditions

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3hw3q ◽

2016 ◽

Vol 19 (4) ◽

pp. 511 ◽

Cited By ~ 2

Author(s):

Yoh Takekuma ◽

Haruka Ishizaka ◽

Masato Sumi ◽

Yuki Sato ◽

Mitsuru Sugawara

Keyword(s):

High Temperature ◽

Benzoic Acid ◽

Dissolution Rate ◽

Simple Structure ◽

Pharmaceutical Formulations ◽

Magnesium Stearate ◽

Principal Agent ◽

Amino Groups ◽

Dissolution Tests ◽

Rosuvastatin Calcium

PURPOSE. Storage under high temperature and humid conditions has been reported to decrease the dissolution rate for some kinds of tablets containing polyvinylpolypyrrolidone (PVPP) as a disintegrant. The aim of this study was to elucidate the properties of pharmaceutical formulations with PVPP that cause a decrease in the dissolution rate after storage under high temperature and humid conditions by using model tablets with a simple composition. METHODS. Model tablets, which consisted of rosuvastatin calcium or 5 simple structure compounds, salicylic acid, 2-aminodiphenylmethane, 2-aminobiphenyl, 2-(p-tolyl)benzoic acid or 4.4’-biphenol as principal agents, cellulose, lactose hydrate, PVPP and magnesium stearate as additives, were made by direct compression. The model tables were wrapped in paraffin papers and stored for 2 weeks at 40°C/75% relative humidity (RH). Dissolution tests were carried out by the paddle method in the Japanese Pharmacopoeia 16th edition. RESULTS. Model tablets with a simple composition were able to reproduce a decreased dissolution rate after storage at 40°C/75% RH. These tablets showed significantly decreased water absorption activities after storage. In the case of tablets without lactose hydrate by replacing with cellulose, a decreased dissolution rate was not observed. Carboxyl and amino groups in the structure of the principal agent were not directly involved in the decreased dissolution. 2-Benzylaniline tablets showed a remarkably decreased dissolution rate and 2-aminobiphenyl and 2-(p-tolyl)benzoic acid tablets showed slightly decreased dissolution rates, though 4,4’-biphenol tablets did not show a decrease dissolution rate. CONCLUSIONS. We demonstrated that additives and structure of the principal agent were involved in the decreased in dissolution rate for tablets with PVPP. The results suggested that one of the reasons for a decreased dissolution rate was the inclusion of lactose hydrate in tablets. The results also indicated that compounds as principal agents with low affinity for PVPP may be easily affected by airborne water under high temperature and humid conditions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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