Richard Süverkrüp

Pharmaceutical spray freeze drying

Pharmaceutical spray-freeze drying (SFD) includes a heterogeneous set of technologies with primary applications in apparent solubility enhancement, pulmonary drug delivery, intradermal ballistic administration and delivery of vaccines to the nasal mucosa. The methods comprise of three steps: droplet generation, freezing and sublimation drying, which can be matched to the requirements given by the dosage form and route of administration. The objectives, various methods and physicochemical and pharmacological outcomes have been reviewed with a scope including related fields of science and technology.

Dose uniformity of ophthalmic suspensions

Purpose: To quantify the rate of redispersion of three commercially available ophthalmic preparations as well as the drug content of single drops during the course of emptying a full container of suspension eyedrops. Setting: Department of Ophthalmology, University of Köln, and Department of Pharmaceutical Technology, University of Bonn, Germany. Methods: In a computer‐controlled test apparatus used to simulate the shaking and dropping behavior of humans under strictly reproducible conditions, we studied the rate of redispersion of three ophthalmic suspensions: 50 mg indomethacin, 50 mg prednisolone‐21‐acetate, and 50 mg dexamethasone in 5 mL of aqueous fluid. The degree of shaking intensity essential for the redispersion of the ophthalmic suspensions was quantified in healthy persons and patients by an acceleration sensor. Results: The mean dose delivered and the coefficient of variation of prednisolone were satisfactory. However, only 25% of the dexamethasone was available for administration; the rest remained in the bottle as a cake of sediment. Also, the variability of the drug content between drops was unacceptably high. The mean dose of indomethacin was adequate, but the between‐drop variability was excessive. Conclusion: The dose uniformity of suspension eyedrops depends on their homogeneity immediately before administration. Among the formulation factors studied, particle size appears to be the most important. The various redispersion rates of the three drugs underline their clinical profile.

Dry Drops: a new preservative-free drug delivery system.

Abstract · Purpose: We compared the tolerability and safety of a lyophilisate (Dry Drops) with conventional eye drops containing the same polymer and electrolytes. In Dry Drops the active ingredient is incorporated in a drop of hydrophilic polymer solution freeze-dried on the tip of a soft hydrophobic carrier strip. Upon contact with tear film and/or conjunctiva the lyophilisate immediately rehydrates and detaches from the carrier. · Methods: Dry Drops containing HPMC as active ingredient and a preservative-free tear film substitute were applied to 64 eyes of 32 healthy volunteers according to a 2² factorial design in an open-label, cross-over, randomised study. Tolerability and safety were quantified and qualified at 0.5, 2, 5 and 10 min after administration via slit-lamp biomicroscopy, questionnaire and visual analogue scales. · Results: The differences between Dry Drops and conventional eye drops were not statistically significant. The initial sensation of Dry Drops was slightly less uncomfortable than that of the conventional ophthalmic solution. None of the eyes showed any clinical findings with safety implications. · Conclusion: The safety and tolerability of a new application form were demonstrated in this phase I study. The improved chemical stability, exact dosing, reduced risk of lesions to the eye surface and good tolerability suggest that the new application device has promise for treatment in ophthalmology as well as in other medical subspecialties.

Dose uniformity and redispersibility of pharmaceutical suspensions. I: Quantification and mechanical modelling of human shaking behaviour.

Precision and uniformity of single doses are required for most dosage forms including suspensions for oral and ophthalmic administration. Therefore, solids forming sediments or aggregates must be distributed homogeneously immediately before use. If settling occurs, leading pharmacopoeias require that suspensions be redispersible by shaking, but a standardised testing procedure for this property is not available. Obviously, such a test will have to be based upon observations of human shaking patterns. We report the results of a study in which human shaking acceleration profiles were measured and the shaking intensity characterised by the area under the frequency spectrum obtained by Fourier transform of the autocorrelation function. We also present a prototype of a mechanical redispersibility tester, which is more flexible and simulates human shaking behaviour more closely than its pneumatic forerunner, which was described earlier.

Protein spheres prepared by drop jet freeze drying

In spray freeze drying (SFD) solutions are frozen by spraying into a very cold environment and subsequently dried by sublimation. In contrast to conventional freeze drying, spray freeze drying has the possibility to produce flowable lyophilizates which offers a variety of new pharmaceutical applications. Here, a drop jet nozzle is proposed as liquid dispenser that is able to produce droplets with a very narrow size distribution compared to standard methods. The drop jet nozzle is mounted in a spray tower designed to prevent direct contact of the product with the freezing medium. Various formulations have been tested containing lysozyme as model protein and stabilizers such as bovine serum albumin, polyvinylpyrrolidone or dextran in various concentrations and mannitol. Excellent free flowing and nearly monodispersed, porous particles are produced where particle properties can be controlled by formulation and process conditions. The particle diameter varied between 231 ± 3 μm and 310 ± 10 μm depending on the formulation composition. The lysozyme activity was >94 ± 5% for all formulations exhibiting a full preservation of enzyme activity. This new method is very promising for the production of nearly monodisperse particulate lyophilizates in various therapeutic applications.

DOSE UNIFORMITY AND REDISPERSIBILITY OF PHARMACEUTICAL SUSPENSIONS 2: ASSESSMENT OF THREE COMMERCIAL ERYTHROMYCIN ETHYL SUCCINATE ORAL LIQUIDS

The content of active ingredient of single doses of a suspension depends to a large extent upon the redispersibility of the product. Mathematical and technical aspects of a procedure to test this property have been discussed in a preceding article. Here, the method is applied to three commercial erythromycin ethylsuccinate suspensions obtained from community pharmacies in Germany. Three specimens of each product were tested in parallel. For approximately two weeks, samples were taken t.i.d. at 9 am, 1 pm and 5 pm after shaking the bottles on a prototype testing apparatus with an intensity of 134m(2)/s(3) per cycle corresponding to the 25th percentile of a group of 79 subjects, whose shaking habits had been assessed previously. In order to minimize volumetric errors, 2.5ml samples were drawn using a syringe. They were assayed by HPLC with electrochemical detection using oleandomycin as an internal standard. While one of the products performed satisfactorily and one showed moderate shortcomings, the dose uniformity of two specimens of the third product was clearly deficient. The problem seems to be associated with poor wetting behaviour of the solids.

The ophthalmic lyophilisate carrier system (OLCS): development of a novel dosage form, freeze-drying technique, and in vitro quality control tests.

The ophthalmic lyophilisate carrier system (OLCS) is a novel dosage form for delivery of pharmacologically active ingredients or other substances improving the structure of the tear film to the eye. A drop of lyophilisate containing the drug and bulk forming water-soluble or swelling excipients is attached to a flexible hydrophobic carrier. Placebo OLCS and OLCS containing several drugs commonly used in ophthalmology were compared to conventional eye drops containing the same ingredients. A novel lyophilization procedure for the production of this dosage form is described, which allows stricter control of the freezing and drying conditions and shortens the production cycle by at least an order of magnitude. In clinical studies it was found that OLCS are easy to administer and well tolerated if the force of adhesion between lyophilisates and carrier strips and the structural firmness of the lyophilisates themselves are well controlled. These parameters are critical for convenient administration and complete delivery of the dose of active ingredients incorporated, therefore suitable in vitro tests were developed with which their values can be determined for the purpose of process validation. A study of fluorescein OLCS in humans indicated that concentration profiles in the cornea and anterior chamber are significantly higher than after administration of equal doses of the diagnostic in conventional eye drops.

Collisions in fast droplet streams for the production of spherolyophilisates

Standard spray freeze drying usually leads to highly polydisperse particles, while a fast jet method allows for the preparation of lyophilisates with low polydispersity which is beneficial for a homogeneous drying process. Droplets of a monodisperse stream generated by Rayleigh disintegration of a fast liquid jet exiting from a piezoelectric dispenser are apparently subject to uncontrolled collisions. The process has been visualized by high-speed stroboscopic imaging, laser diffraction spectroscopy and image analysis of the footprint on a target moving at constant velocity across the spray plume. The analyses of the data sets obtained by these complementary methods yield an integrated picture of the processes leading to the loss of monodispersity and increased median size of droplets from 90 μm up to 264 ± 29 μm. Droplets collided and merged together which has in case of spray freeze drying to the same extent a direct impact on particle size and size distribution. These observations suggest utilizing measures to reduce the collision-related product changes.

Modelling ocular pharmacokinetics of fluorescein administered as lyophilisate or conventional eye drops.

ObjectiveThe objective of this evaluation was to model ocular pharmacokinetics of fluorescein administered as conventional eye drops and as lyophilisate to healthy volunteers in order to assess the relative bioavailability of the lyophilisate formulation.MethodsA total of 44 healthy subjects received equivalent doses of fluorescein as lyophilisate to one eye and as eye drops to the fellow eye in three individual studies. Fluorescein concentrations in the cornea and anterior chamber were measured by fluorophotometry. Data were analyzed by noncompartmental methods (WinNonlin software) and by compartmental population pharmacokinetic methods (NONMEM software).ResultsCompared to eye drops, both maximum fluorescein concentrations (Cmax) and the areas under the concentration-time curve (AUC0-t) values of fluorescein in the cornea and anterior chamber for lyophilisate were increased in the noncompartmental analysis: mean lyophilisate Cmax in the studies was 6.3- to 14.6-fold higher and mean AUC0–t was 4.7- to 8.9-fold higher for ocular concentrations in the three studies. A three-compartment open model with first-order elimination from the anterior chamber adequately described population data. Estimated fluorescein systemic bioavailability (F) via the ocular route from lyophilisate relative to eye drops was 3.7-fold higher (95% CI 2.6–4.8).ConclusionThe data clearly show a considerably superior intraocular bioavailability of fluorescein when given as lyophilisate compared to conventional eye drops. There is a clear pharmacokinetic advantage of the lyophilisate preparation.

Jet-vortex spray freeze drying for the production of inhalable lyophilisate powders.

&NA; Spray‐freeze‐dried powders were suggested for nasal, epidermal (needle‐free injection) or pulmonary application of proteins, peptides or nucleic acids. In spray‐freeze‐drying processes an aqueous solution is atomized into a refrigerant medium and subsequently dried by sublimation. Droplet‐stream generators produce a fast stream of monodisperse droplets, where droplets are subject to collisions and therefore the initial monodispersity is lost and droplets increase in diameter, which reduces their suitability for pulmonary application. In jet‐vortex‐freezing, a droplet‐stream is injected into a vortex of cold process gas to prevent droplet collisions. Both the injection position of the droplet‐stream and the velocity of the cold gas vortex have an impact on the size distributions of the resulting powders. A model solution containing mannitol (1.5% m/V) and maltodextrin (1.5% m/V) was sprayed at 5 droplet‐stream positions at distances between 1 mm and 30 mm from the gas jet nozzle and 5 gas velocities (0.8–6.8 m/s) at a process temperature of −100 °C. Mean geometric diameters of the highly porous particles (bulk density: 0.012 ± 0.007 g/cm3) ranged between 55 ± 4 and 98 ± 4 &mgr;m. Evaluation of the aerodynamic properties by Next‐Generation‐Impactor (NGI) analysis showed that all powders had high emitted doses (98 ± 1%) and fine‐particle fractions ranged between 4 ± 1% and 21 ± 2%. It was shown that jet‐vortex freezing is a suitable method for the reproducible production of lyophilized powders with excellent dispersibility in air, which has a high potential for nasal and pulmonary drug delivery. Graphical abstract Figure. No caption available.