| 1. |
- Emilsson, Gustav, 1989, et al.
(författare)
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The In Vivo Fate of Polycatecholamine Coated Nanoparticles Is Determined by a Fibrinogen Enriched Protein Corona
- 2023
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Ingår i: ACS Nano. - 1936-086X .- 1936-0851. ; 17:24, s. 24725-24742
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Tidskriftsartikel (refereegranskat)abstract
- Polycatecholamine coatings have attracted significant attention in the past 10 years owing to their ability to functionalize a wide range of materials. Here we apply the use of such coatings to drug nanocrystals, made from a poorly soluble drug compound, to postfunctionalize the nanocrystal surface with the aim of providing steric stabilization and extending their circulation time after intravenous injection. We show that both polydopamine and polynorepinephrine can be used to successfully modify drug nanocrystals and subsequently incorporate end-functionalized PEG to the surface. Even though high grafting densities of PEG were achieved, we observed rapid clearance and increased liver uptake for polycatecholamine functionalized drug nanocrystals. Using both surface sensitive model systems and protein corona profiling, we determine that the rapid clearance was correlated with an increase in adsorption of proteins involved in coagulation to the polycatecholamine surface, with fibrinogen being the most abundant. Further analysis of the most abundant proteins revealed a significant increase in thiol-rich proteins on polycatecholamine coated surfaces. The observed interaction with coagulation proteins highlights one of the current challenges using polycatecholamines for drug delivery but might also provide insights to the growing use of these materials in hemostatic applications.
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| 2. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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A small structural change resulting in improved properties for product development
- 2015
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 41:5, s. 866-873
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Tidskriftsartikel (refereegranskat)abstract
- AZD9343 is a water-soluble gamma amino butyric acid (GABAB) agonist intended for symptomatic relief in gastroesophageal reflux disease (GERD) patients. The compound has good chemical stability in aqueous solutions, as well as in the solid state. Only one crystal modification has been observed to date. This polymorph is slightly hygroscopic (1.5% water uptake at 80% relative humidity (RH)), which is an improvement compared to the structurally similar agonist lesogaberan (AZD3355) which liquefies at 65% RH. Since the substance is very polar and lacks a UV chromophore, conventional separation and detection techniques cannot be used to characterize the substance and its impurities. The analytical techniques are described, focusing on the capillary electrophoresis method with indirect UV detection for assay and purity, the liquid chromatographic method for enantiomeric separation with derivatization with UV chromophore and three complementary nuclear magnetic resonance (NMR) approaches (P-31-NMR, C-13-NMR and H-1-NMR) for impurities. For oral solutions, it was important to select the right concentration of phosphate buffer for the specific drug concentration and routinely use small additions of EDTA. I.V. solutions containing physiological saline as tonicity modifier could not be stored frozen at -20 degrees C. Properties of AZD9343 will be discussed in light of experiences from the structurally similar lesogaberan and (2R)-(3-amino-2-fluoropropyl) sulphinic acid (AFPSiA).
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| 3. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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Co-administration of a nanosuspension of a poorly soluble basic compound and a solution of a proton pump inhibitor-the importance of gastrointestinal pH and solubility for the in vivo exposure
- 2011
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 37:9, s. 1036-1042
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Tidskriftsartikel (refereegranskat)abstract
- In Sigfridsson et al. (2011, Drug Dev Ind Pharm, 37: 243-251), there was no difference in plasma concentration of BA99 when administering the drug as nanosuspension or microsuspension and analyzing the blood samples by liquid chromatography-mass spectrometry. This was related to the dissolved amount of drug in the gastric tract, which was high enough to support fast absorption when the drug reached the small intestine. One single physicochemical property (pK(a), about 3 for BA99) abolished the benefit of small particles. These results were further confirmed in the present study, where a proton pump inhibitor, AZD0865, was used to elevate the gastric pH and then drastically decreased the gastric solubility. In this way, BA99 could be considered as a model compound for a neutral substance. By increasing the gastric pH to 5-6 and 8-9, respectively, in rats, the plasma concentrations of BA99, after administering nanosuspensions, were unchanged compared with untreated (i.e. no AZD0865) animals. For microsuspensions of the test compound, on the other hand, the exposure of BA99 was 2- to 3-fold lower than for nanosuspensions at both pHs. Moreover, the blood concentrations of BA99 administered as microsuspension were also 2- to 3-fold lower compared with untreated (no AZD0865) individuals receiving both nanoparticles and microparticles of BA99. Obviously, for neutral compounds, with similar physicochemical properties as the present compound, size reduction will be crucial for increased plasma exposure. For basic compounds, with similar physicochemical properties as the present compound, the crucial step for absorption is the dissolution and solubility in the gastric tract.
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| 4. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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Early development evaluation of AZD2738, a substrate for the NK receptors
- 2011
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 37:6, s. 719-726
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to investigate whether AZD2738, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development with an oral immediate release solid dosage form as a possible final product. The neutral form of AZD2738 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Mostly crystalline material of fumarate, maleate and chloride salt of AZD2738 were obtained. X-ray powder diffractometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the salts. Based on the physicochemical properties, the chloride salt is preferred for continued product development. The chloride salt of AZD2738 is an anhydrate, the crystallization is reproducible, the hygroscopicity is acceptable and just one polymorph was obtained. Notably is that the two obtained polymorphs of the fumarate salt of AZD2738 are monotropically related, whereas the two identified polymorphs for the maleate salt of the compound are enantiotropic. The dissolution behavior and the stability (in aqueous solutions, formulations and solid state) of the salts were also studied and found to be satisfactory, at least at pH >3. Liquid formulations should preferable be stored frozen at pH >3.
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| 5. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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Early development evaluation of AZD8081: a substrate for the NK receptors
- 2011
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 37:6, s. 702-713
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to find out if AZD8081, a dual neurokinin (NK)1/2 receptor antagonist, was suitable for development of an oral, solid immediate release (IR) formulation and in a further perspective also as an oral extended release (ER) formulation. AZD8081 is a base with pK(a) values
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| 6. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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Early pharmaceutical evaluation of a crystalline and hygroscopic GABA(B) receptor agonist
- 2013
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 39:10, s. 1573-1581
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Tidskriftsartikel (refereegranskat)abstract
- Lesogaberan is a potent gamma amino butyric acid agonist and has been evaluated for its utility in treatment of gastroesophageal reflux disease. Lesogaberan is a crystalline substance that absorbs considerable amounts of water above 65% relative humidity (RH) where it also liquifies. As a result of the hygroscopicity of the zwitterionic form an investigation of different salt forms was performed. Since the test compound is polar and lacks ultraviolet (UV) chromophore, conventional separation and detection techniques could not be used to characterise the test compound and the impurities. The analytical techniques are described, focusing on the capillary electrophoresis method with indirect UV detection for purity, the liquid chromatographic method for enantiomeric separation with derivatisation with UV chromophore and two complementary nuclear magnetic resonance (NMR) approaches (F-19-NMR and H-1-NMR) for impurities. The stability study in solution showed that solutions between pH 5 and 7 were the most stable ones, but after some time degradation occurred at room temperature. When bulk lesogaberan was stored at 25 degrees C/60% RH no chemical degradation was observed after 1 year. At 40 degrees C/75% RH, where the compound liquefies, a significant degradation was observed after 1 month. However, in a closed container (= 40 degrees C) or as a napsylate salt, no degradation of lesogaberan was observed at 40 degrees C/75% RH.
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| 7. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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Evaluation of exposure properties after injection of nanosuspensions and microsuspenions into the intraperitoneal space in rats
- 2013
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 39:11, s. 1832-1839
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Tidskriftsartikel (refereegranskat)abstract
- In the present paper, BA99 and AC88 were used as model compounds for intraperitoneal (i.p.) administration to Sprague-Dawley rats. A major problem for the compounds, like many others newly developed pharmaceutical drugs, is the poor solubility in water. To solve solubility related problems, development of nanosuspensions is an attractive alternative. Both compounds are suitable for nanosuspensions, using the milling approach. After 2 weeks in freezer, the nanoparticles aggregated to form particles in the 400-2000 nm interval. However, following a 20 s ultrasonication step, the original particle sizes (about 200 nm) were obtained. Adding 5% mannitol before the samples were frozen abolished aggregation. It is also possible to freeze-dry the nanosuspension in the presence of 5% mannitol and re-disperse the formulation in water. Nanosuspensions of both compounds were injected i.p. to rats at 5 and 500 mu moL/kg. At the low dose, also a microsuspension was administered. I. p. administration resulted in overall improved C-max for both AC88 and BA99 compared to s. c. and oral administration. I. p. is the preferred route of administration of tolerable drugs when a fast onset of action is desired and when a significant first passage metabolism occurs. The net charge of the active molecule appeared to affect the absorption kinetics. In the present work, the neutral molecule was favored over the negatively charged one.
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| 8. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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Evaluation of systemic exposure of nanoparticle suspensions subcutaneously administered to mice regarding stabilization, volume, location, concentration and size
- 2014
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:10, s. 1318-1324
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Tidskriftsartikel (refereegranskat)abstract
- Different routes of administration are likely to result in very different outcomes due to different availability or plasma profile. The objective of the present study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administration of nanoparticle suspensions of a lipophilic compound to mice. Pharmacokinetics of the selected test compound and the effect of drug concentration, particle size, location of administration, volume given and particle stabilizers were studied. Adding PEGylated lipids or pluronic F-127 to the negatively charged surface of the nanoparticles increased the stability of the particles and the bioavailability. The in vivo studies demonstrated linear absorption kinetics for the selected model compound up to at least 500 mu mol/kg. Absorption from upper-neck resulted in different systemic exposure compared to administration in the hip. The former was preferred if a prolonged C-max was desired while the latter ensured a flat profile for approximately 24 hours. Administering the double volume (but the same dose) had no effect on the pharmacokinetics, whereas smaller particle size significantly increased the exposure.
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| 9. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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Preformulation evaluation of AZD1305, an oxabispidine intended for oral and intravenous treatment
- 2012
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 38:1, s. 19-31
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Tidskriftsartikel (refereegranskat)abstract
- Aim: AZD1305 is a novel, water-soluble investigational antiarrhythmic agent for restoration and maintenance of sinus rhythm in atrial fibrillation patients. The present studies were performed to evaluate the possibility for further development of the compound.Methods: A set of technical approaches were used, including X-ray powder diffractometry, differential scanning calorimetry, thermogravimetrical analysis, dynamic vapor sorption, scanning electron microscopy, salt screen, and liquid chromatography.Results: AZD1305 is a crystalline oxabispidine and its neutral form is a base with a pK(a) of 9.9. The substance degrades with higher temperature and lower pH. The free base of the solid substance is stable at 25 degrees C (closed container), 40 degrees C/75% relative humidity (open container), and at 50 degrees C (closed container) for at least 3 months. The free base of AZD1305 is polymorphic with two known forms. Both forms are non-hygroscopic ansolvates with melting points of approximately 90 degrees C. No salt was found with overall improved properties. The substance had a strong odor, which was reduced by increased particle size.Conclusions: The free base of AZD1305 seemed to be the most suitable agent for product development even though it has a fairly low melting point and occurred as two different crystal forms. Form B was the most stable thermodynamically in the temperature interval of interest.
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| 10. |
- Sigfridsson, Kalle, 1964, et al.
(författare)
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Subcutaneous administration of nano- and microsuspensions of poorly soluble compounds to rats
- 2014
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:4, s. 511-518
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate and interpret the pharmacokinetic profiles of two compounds after subcutaneous (s.c.) administration. The compounds have similar physicochemical properties, but are a base (BA99) and an acid (AC88), respectively. The compounds were administered as nano- (5 and 500 mu mol/kg) and microsuspensions (5 mu mol/kg) s.c. to Sprague-Dawley rats. At the low dose, the exposure was higher for both compounds administered as nanocrystals compared to microparticles. The high dose of the compounds resulted in even higher exposure, but not in a dose-linear manner. The differences in exposure between nano- and microparticles were mainly ascribed to higher dissolution rate and improved solubility for smaller particles. In addition to differences in exposure, there were also differences in the elimination pattern. After s.c. injection of 5 mu mol/kg of BA99 as nano- and microsuspensions, the elimination profile was similar as observed earlier after oral administration. However, after injection of the higher dose of BA99 and all formulations of AC88, an extended elimination profile was observed, forming a maintained plateau under the investigated time-period. Essentially, constant plasma levels were caused by a balanced equilibrium between total body clearance of the drug and supply rate of drug from the formulations.
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