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WO2007057468A1 - Procede et systeme complet destines au developpement de formes et a leurs tests in vitro presentant une bonne previsibilite de l'absorption in vivo, un rendement eleve et de faibles exigences en ce qui concerne la substance active - Google Patents

Procede et systeme complet destines au developpement de formes et a leurs tests in vitro presentant une bonne previsibilite de l'absorption in vivo, un rendement eleve et de faibles exigences en ce qui concerne la substance active Download PDF

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Publication number
WO2007057468A1
WO2007057468A1 PCT/EP2006/068682 EP2006068682W WO2007057468A1 WO 2007057468 A1 WO2007057468 A1 WO 2007057468A1 EP 2006068682 W EP2006068682 W EP 2006068682W WO 2007057468 A1 WO2007057468 A1 WO 2007057468A1
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WO
WIPO (PCT)
Prior art keywords
active substance
solid
testing
release
formulations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2006/068682
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English (en)
Inventor
Rolf-Stefan Brickl
Julia Boni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of WO2007057468A1 publication Critical patent/WO2007057468A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0848—Specific forms of parts of containers
    • B01L2300/0851—Bottom walls
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions

Definitions

  • the present invention relates to a rational method of developing galenic formulations, preferably oral galenic formulations, based on a dissolution method with a high throughput and low consumption of active substances, as well as the apparatus required therefor, consisting of a specific combination of pieces of equipment, some of which are already known.
  • the poor solubility can be determined as follows:
  • Table 1 shows by way of example an active substance which is readily soluble in an acidic medium but poorly soluble at a higher pH. Up to pH 3 total dissolution occurs at the dosage of 150 mg / person taken, whereas at pH 6 less than 1 % of the dose dissolves, i.e. in an anacid stomach considerable absorption problems can be expected.
  • Substantially total absorption may be achieved by the addition of suitable excipient combinations which eliminate the solubility problems. This applies to both instant and delayed-release formulations, while particularly when developing delayed-release formulations on the one hand the formulation must ensure that the active substance also dissolves completely in the lower sections of the bowel, but on the other hand an optimum delayed-release is also achieved in each case.
  • suitable excipient combinations which eliminate the solubility problems.
  • Formulations are currently produced in conventional apparatus for various technologies and then tested in vitro using dissolution methods. Admittedly, in recent years, a number of manufacturers have put equipment on the market designed for smaller batch sizes, but with the apparatus currently on sale the smallest amounts of formulations that can be produced therewith are generally 10 - 50 g, as shown in Table 2.
  • test is carried out under so-called “sink conditions” , i.e. the active substance has to dissolve completely in the test medium;
  • Standard commercial release apparatus made by various manufacturers is used (e.g. Sotax Varian etc.), which is complicated to clean in each case, on account of the complex structure (temperature-controlled bath, 6-8 release pots, complex hose system for pumping round into the measuring cells of the photometer etc.) , i.e. the throughput is relatively low.
  • These test methods are admittedly highly suitable for the quality control of formulations, but do not allow any reliable pronouncements to be made regarding in vivo absorption in the case of formulations of poorly soluble active substances, as the sink conditions are not achieved.
  • the currently conventional manufacturing and testing methods have major disadvantages for poorly soluble active substances, as they require large amounts of active substance, allow only a low throughput and the test methods have little predictive power for the absorption in the patient.
  • substantially total absorption if largely total release of the active substance is achieved in vitro within 15 to 30 minutes at all the pH values that occur physiologically and the active substance remains dissolved for approx. 10 - 30 minutes. If these conditions are met, substantially total absorption is virtually guaranteed with theoretically good absorbability of the active substance, i.e. the absolute bioavailability is reduced only by first pass effects, but not by incomplete absorption. If this goal is not achieved entirely, for example because insufficient supersaturation has been obtained or because other aspects such as stability, dose or safety had to be taken into account, good absorption may still be obtained, but the risk of "absorption failure" occurring is increased. Particularly careful in vivo testing (e.g. making the test subjects anacid, testing on older patients), while taking account of the later patient situation, is essential in these cases.
  • the release of the active substance must be achieved at all the physiologically occurring pH values in the intestinal tract and the active substance must remain in solution long enough to ensure absorption even in the case of longer diffusion paths at lower sections of the bowel.
  • the aim of the present invention is to provide a rational method for developing galenic formulations, preferably oral galenic formulations, based on a dissolution method which has the advantages of a high throughput, the use of small amounts of active substance or formulation and good predictability for the absorption in the patient, as well as the apparatus required for this purpose.
  • a low consumption of active substance is of considerable advantage, as at the early stages of the development of new active substances ("new chemical entities", NCEs) because of the often very time-consuming processes for synthesising increasingly more complex molecules generally only small amounts of active substance are available.
  • the invention relates to a Method A for developing galenic formulations, preferably solid oral preparations, characterised by the parallel combinatory preparation of a number of liquid formulations or solutions on a tiny scale, and testing the supersaturation characteristics.
  • a preferred embodiment B of the invention comprises in one step testing the supersaturation behaviour of solutions instead of the otherwise conventional dissolution tests on solid forms, particularly testing the stability of a supersaturated active substance solution by adding buffer at the pH of minimal solubility of the active substance.
  • a second preferred embodiment C of the invention comprises in one step the production of a thin solid film of a solid formulation by eliminating the liquid constituents from a liquid formulation and investigating the dissolution characteristics of the solid film, particularly testing the dissolution characteristics of the solid film produced directly by evaporation in the release vessels, instead of the otherwise conventional dissolution tests on solid forms.
  • a third preferred embodiment D of the invention comprises in one step testing the release characteristics in an in vitro release model using physiological volumes, the testing preferably being carried out at the pH of the minimum solubility of the active substance, if this is in the physiological range.
  • a further object E of the invention is a special microtitre plate, consisting of a plate with a plurality of regularly arranged, preferably cylindrical recesses, formed in this plate from above, which differs from conventional microtitre plates in that instead of the complete bore each recess (well) comprises an elevation formed in the recess from the underside of the plate, preferably in the form of an inner cylinder which is lower than the bore and terminates at the top in a UV-permeable quartz disc (cf. Figure 7, Appendix).
  • These special microtitre plates may for example be milled from a piece of plastics, the quartz disc is pressed tightly into a ring of precisely the correct size.
  • these special microtitre plates may for example also be produced by injection moulding from UV-permeable plastics.
  • layer thicknesses above the quartz plate which are suitable for direct UV measurements (e.g. 0.8 - 2 mm leading to extinction values in the range from 0.5 to 2).
  • Highly accurate layer thicknesses can be obtained by means of a precisely fitting mating piece with an inverse structure (lock and key principle), which fits directly into the special microtitre plate and when pushed fully together results in the desired layer thickness.
  • microtitre plate and "well plate” are to be taken as synonymous for the purposes of the present invention, the term “well” referring to the depressions in the microtitre plate.
  • the expression "on a tiny scale” refers to the use of small amounts of active substance as well as small volumes of the liquid components, the ratio of active substance to release volume always being chosen so that the highest human dose would be released in a volume of 200 ml.
  • the reduction in the amount of active substance is determined by the small release volumes, i.e. the saving of active substance can be estimated directly using the volume ratios shown in Table 3: If a dosage range of from 1 to 500 mg is taken as the human dose, then for each measurement 1 to 500 mg active substance are needed using standard methods, whereas with the methods according to the invention an amount of 2.5 ml of release medium needs only 0.0027 mg or 1.333 mg, 0.22 ml release medium requires only 0.0002 mg or 0.12 mg, i.e. less than 1/1000 of the original dose.
  • the recipes are produced directly in the release vessel, e.g. in a 96 well plate on a tiny scale (1 - 10 mg active substance/mixture) by pipetting together pre-prepared, usually aqueous solutions (excipient and active substance) or suspensions. If necessary the active substance may also be dissolved in small amounts of organic, water-miscible solvent. Suitable devices for this purpose are pipetting robots. Solutions of active substance and excipient are placed in 96 wells (normal height with 250 ⁇ l/well microtitre plates or deep well plates containing 2.5 ml/well in each case).
  • BCS Biopharmaceutics classification system.
  • the throughput is also higher by powers often: Whereas in the preparation of solid recipes generally approx 1 to 5 per day are possible, here 96 recipes can be produced in a few minutes.
  • FIG. 1 An example of the subdivision of a microtitre storage plate, with which a simple pipetting programme can be carried out, is shown in Figure 1 (Appendix).
  • Wa water; Wi: active substance solution;
  • the next test plates would contain the remaining mixtures of the acids 2 - 4 with the corresponding excipients.
  • the embodiment B of the invention comprises in one step testing the supersaturation behaviour of the solutions prepared by Method A-, instead of the otherwise conventional dissolution tests on solid forms, particularly testing the stability of supersaturated active substance solutions by adding buffer at the pH of minimum solubility of the active substance.
  • One example of testing the supersaturation behaviour with various excipients is shown in the precipitation experiments illustrated in Figure 3 (Appendix) .
  • the excipient is found to have a significant influence in terms of supersaturation, the most suitable excipients keeping the active substance fully in solution.
  • Embodiment C relates to the production of a thin solid film of a solid formulation (preparation of "solid recipes in the test tube") by eliminating the liquid constituents of a liquid formulation prepared by Method A, for example, and investigating the dissolution characteristics of the solid film, particularly testing the dissolution characteristics of the solid film produced directly by evaporation in the release vessels, instead of the otherwise conventional dissolution tests on solid forms.
  • the recipe is first of all produced as described hereinbefore with reference to Method A, preferably using specially made 24 or 12 well plates instead of 96 well plates.
  • the recipes thus obtained (total volume ⁇ 1 ml) are then evaporated down, for example, under reduced pressure, possibly in the Rotavapor, wherein the aqueous solutions contained in the special microtitre plate are evaporated down with agitation and heating, while a film only a few microns thick is formed on the walls of the wells. This can then be used immediately for the release so as to determine the dissolution characteristics.
  • the only important factor here is the speed of dissolution of the recipe, but not the breakdown of a larger solid preparation, which in conventional solid forms such as tablets would be superimposed on the dissolution process and in some circumstances would even dominate it.
  • This procedure requires only small amounts of active substance and excipients, can be carried out exceptionally quickly and also has the following important advantage: aAs the recipe is "applied” to the test tube wall in a very thin layer, the "breakdown time" of the recipe plays only a minor part, i.e. the intrinsic properties of the excipients with regard to dissolving the active substance and keeping it in solution can be determined directly.
  • Embodiment D of the invention relates to testing the release characteristics of solid galenic formulations, for example the solid films of embodiment C, in an in vitro release model using physiological volumes, while the relationship between the highest dose of active substance and the volume of release medium is guided by the amount drunk in the human trial or in the patient.
  • an assumed dose of approx. 120 mg dose and a drink volume of approx. 240 ml in the test approx. 0.5 mg of active substance are used to approx. 1 ml of release volume.
  • This is preferably done at the "least favourable pH "-, i.e. the pH of minimum solubility of the active substance, if this is in the physiological range, instead of using pH values which correspond to sink conditions, i.e.
  • physiologically acceptable buffers of low buffer capacity in the range from 0.05 - 0.005 are preferably used, which roughly correspond to the physiological conditions, e.g. phosphate, citrate or carbonate buffers.
  • the testing is preferably carried out by direct UV measurement in the release medium in 12, 24 or 96 well plates instead of large-capacity release vessels, without centrifugation or filtration, so as to avoid false-negative release values.
  • the UV measurement in the release medium is preferably carried out at a number of characteristic wavelengths which allow the true UV signal and the turbidity fraction to be evaluated by computation.
  • the computation is preferably carried out by computerised determination of the extinction and turbidity fraction using the Excel Solver. It is advantageous to compress the release data onto characteristic values which allow rapid evaluation of the supersaturation behaviour of a plurality of formulations and thus permit a quick decision as to further formulation steps.
  • Preferred test strategies within embodiment D may be summarised under the following headings:
  • physiological volumes i.e. the relationship between the maximum dose of active substance and the volume of release medium should be similar to the amount of drink in the human trial or in the patient (e.g. at a dose of 120 mg and a drink volume of 240 ml, 0.5 mg of active substance should be used per 1 ml of release volume);
  • Moderate buffer strengths in the range from 0.1 to 0.001, preferably 0.05 to 0.005;
  • New well plates for direct measurement of the release or for precipitation tests instead of the transfer from the test well plate into the measuring well plate it is also possible to use a specially developed 12 or 24 well plate which allows direct measurement with small layer thicknesses. This is usually only possible with expensive fibre optics, which have come onto the market in recent years for the dissolution method.
  • Object E of the invention is a special well plate (special microtitre plate), consisting of a plate with a plurality of regularly arranged preferably cylindrical depressions formed in this plate from above, which differs from conventional microtitre plates in that instead of the full bore each depression (well) has an elevation formed in the depression from the underside of the plate, preferably in the form of an inner cylinder which is lower than the bore and terminates at the top with a UV permeable quartz disc (cf. Figure 7, Appendix).
  • These special microtitre plates may for example be milled from a piece of plastics, the quartz disc is pressed tightly into a ring of precisely the correct size.
  • these special microtitre plates may for example also be produced by injection moulding from UV-permeable plastics.
  • layer thicknesses above the quartz plate which are suitable for direct UV measurements (e.g. 0.8 - 2 mm leading to extinction values in the range from 0.5 to 2).
  • Highly accurate layer thicknesses can be obtained by means of a precisely fitting mating piece with an inverse structure (lock and key principle), which fits directly into the special microtitre plate and when pushed fully together results in the desired layer thickness.
  • Object E of the invention may for example be a 12 or 24 well plate, as shown in Figure 7 (Appendix), and have the structure described as follows:
  • the external dimensions and the dimensions of the wells correspond to commercially obtainable well plates, which means that all the otherwise conventional equipment such as agitators, Elisa readers etc can be used without the need for modification.
  • UV measurement with small layer thicknesses is made possible by an inner cylinder which terminates at the top in a UV permeable quartz disc.
  • the desired layer thickness can be adjusted by means of the amount of buffer packed in. Even greater precision is achieved by a low-rise mating part (cover) of analogous construction which fits according to the lock and key principle.
  • the plate may be used both for precipitation tests and for dissolving solid forms.
  • a particular advantage of solid forms is that the still solid fractions are in the bottom annular part and thus do not interfere with the measurement.
  • the plate is agitated in a temperature-controlled agitator and then measured in an Elisa reader at the respective measuring times.
  • Figure 1 shows an example of the subdivision of a microtitre storage plate which enables a simple pipetting programme to be carried out.
  • Figure 2 shows an example of the subdivision of a 96-well microtitre test plate. All the wells also contain active substance solution.
  • Figure 3 shows an example of testing the supersaturation behaviour with various excipients by precipitation tests according to embodiment B of the invention. The differing supersaturation characteristics caused by various excipients can be detected.
  • Figure 4 shows UV spectra of an active substance in the dissolution test, in which the supersaturation of the active substance is destroyed by centrifuging.
  • Figure 5 shows measured and theoretical UV spectra of a dissolved active substance and the turbidity suspensions thereof.
  • Figure 6 shows the correlation of the data sets of "true” extinction values calculated with Excel Solver with the theoretical values known from the mixing ratio for dissolved active substance and the turbidity suspensions thereof.
  • Figure 7 shows, as an example of a special well plate according to the invention (special microtitre plate milled from one piece; Object E of the invention), a 12 well plate for direct UV measurement, shown once in longitudinal sectional view along an axis A-A, and once in plan view, and in photographic view from diagonally above. All the measurements are given in mm and are intended solely by way of example.
  • Reference numeral: 1 UV permeable quartz disc
  • Example 1 Testing the supersaturation with various excipients for an active substance which is readily soluble in the acidic range but virtually insoluble at pH values above 5; assumed human dose 100 mg, assumed volume in humans is 200 ml
  • the operational steps for a semiautomatic apparatus are as follows: •
  • the active substance solution used is a solution of 11.5 mg/ml active substance in In hydrochloric acid, the excipients are dissolved in water in the concentrations 11.5 mg/ml, 3.45 mg/ml, 11.5 mg/ml and 0.345 mg/ml; • active substance and excipient solutions are transferred into a 96 deep-well plate analogously to Figure 1 as the storage well and placed in an automatic pipetting apparatus at the "storage plate" position;
  • Example 2 Testing the supersaturation with various excipients for an active substance which is readily soluble in the acidic range but virtually insoluble at pH values above 5; assumed human dose 100 mg, assumed volume in humans is 200 ml
  • the active substance solution used is a solution of 11.5 mg/ml active substance in 1 n hydrochloric acid, the excipients are dissolved in water at concentrations of 11.5 mg/ml, 4.45 mg/ml, 1.15 mg/ml and 0.5 mg/ml;
  • Example 3 Testing the dissolution characteristics of small-particled solid forms for an active substance which is readily soluble in an acidic and/or basic medium, but poorly soluble at pH values from 4 - 8 (assuming a human dose of 100 mg active substance)
  • the 24-well plate is placed in the automatic pipetting apparatus and 20 ⁇ l aliquots are transferred into a 384 well measuring plate (or 50 ⁇ l aliquots are transferred into a 96-well measuring plate) and then in each case measured in a multichannel Elisa reader at 5 different wavelengths;
  • Example 4 Testing the dissolution characteristics of small-particled solid forms for an active substance which is readily soluble in an acidic or basic medium, but poorly soluble at pH values from 4 - 8 (assuming a human dose of 100 mg active substance) using the special well plate according to the invention
  • Example 5 Description of the evaluation of the "true extinction" with the aid of the Excel solver using the example of a turbidity with linear dependency on the wavelength:
  • the absorption is measured at a number of wavelengths, e.g. with a UV spectrum as shown in Figure 5, at the maximum (300nm) and minimum (270nm) of the UV spectrum of the active substance and at values at which the dissolved active substance exhibits little (330nm) or no (360 + 400 nm) absorption
  • the turbidity characteristic which is most suitable for the particular problem can be determined: it is the method which has the lowest total sum of all the distance squares after a complete measuring series has been carried out.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un procédé destiné au développement de formes galéniques, idéalement des préparations orales solides, qui se caractérise par la préparation combinée en parallèle d'une pluralité de formes ou de solutions liquides à petite échelle, des procédés de détermination du comportement de sursaturation des solutions et des caractéristiques de libération des formes solides, ainsi qu'une plaque spéciale de microtitrage à cupules qui peut être utilisée dans le procédé susmentionné et qui est tout à fait indiquée pour mesurer le rayonnement ultraviolet.
PCT/EP2006/068682 2005-11-21 2006-11-20 Procede et systeme complet destines au developpement de formes et a leurs tests in vitro presentant une bonne previsibilite de l'absorption in vivo, un rendement eleve et de faibles exigences en ce qui concerne la substance active Ceased WO2007057468A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP05111011.2 2005-11-21
EP05111011 2005-11-21

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WO2007057468A1 true WO2007057468A1 (fr) 2007-05-24

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PCT/EP2006/068682 Ceased WO2007057468A1 (fr) 2005-11-21 2006-11-20 Procede et systeme complet destines au developpement de formes et a leurs tests in vitro presentant une bonne previsibilite de l'absorption in vivo, un rendement eleve et de faibles exigences en ce qui concerne la substance active

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008062303A3 (fr) * 2006-11-23 2008-07-17 Uni Degli Studi Del Piemonte O Micropuits à fond convexe

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59116250A (ja) * 1982-12-24 1984-07-05 Hiroyuki Nohira 光学活性α―ｐ―トリルエチルアミンの製造方法
WO1998046981A1 (fr) * 1997-04-14 1998-10-22 Ljl Biosystems Microplateau comportant des puits avec des fonds sureleves
WO1999013986A1 (fr) * 1997-09-17 1999-03-25 Glaxo Group Limited Dispositif de realisation d'essais photometriques
US6180138B1 (en) * 1999-01-29 2001-01-30 Abbott Laboratories Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption
WO2004032971A1 (fr) * 2002-10-08 2004-04-22 Fresenius Kabi Deutschland Gmbh Conjugues d'oligosaccharide pharmaceutiquement actifs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59116250A (ja) * 1982-12-24 1984-07-05 Hiroyuki Nohira 光学活性α―ｐ―トリルエチルアミンの製造方法
WO1998046981A1 (fr) * 1997-04-14 1998-10-22 Ljl Biosystems Microplateau comportant des puits avec des fonds sureleves
WO1999013986A1 (fr) * 1997-09-17 1999-03-25 Glaxo Group Limited Dispositif de realisation d'essais photometriques
US6180138B1 (en) * 1999-01-29 2001-01-30 Abbott Laboratories Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption
WO2004032971A1 (fr) * 2002-10-08 2004-04-22 Fresenius Kabi Deutschland Gmbh Conjugues d'oligosaccharide pharmaceutiquement actifs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008062303A3 (fr) * 2006-11-23 2008-07-17 Uni Degli Studi Del Piemonte O Micropuits à fond convexe

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