WO2002016941A2 - Methode combinatoire de criblage rapide de preparations d'administration de medicaments - Google Patents

Methode combinatoire de criblage rapide de preparations d'administration de medicaments Download PDF

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WO2002016941A2
WO2002016941A2 PCT/US2001/026473 US0126473W WO0216941A2 WO 2002016941 A2 WO2002016941 A2 WO 2002016941A2 US 0126473 W US0126473 W US 0126473W WO 0216941 A2 WO0216941 A2 WO 0216941A2
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donor
membrane
test
skin
formulation
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PCT/US2001/026473
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WO2002016941A3 (fr
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Samir Mitragotri
Pankaj Karande
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The Regents Of The University Of California
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Priority to AU2001286725A priority Critical patent/AU2001286725A1/en
Priority to US10/344,961 priority patent/US20040023841A1/en
Publication of WO2002016941A2 publication Critical patent/WO2002016941A2/fr
Publication of WO2002016941A3 publication Critical patent/WO2002016941A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays

Definitions

  • the field of the invention is screening methods for drug delivery.
  • a typical drug formulation may contain anywhere from 3-15 components.
  • a formulation containing six components, including the drug In order to optimize the concentration of these components, an experimental design is required, for example, five levels of concentration of each component. In order to determine the optimal concentration of these components, 5 6 experiments are required; that is, about 15,000. Note that in a typical formulation development project testing of a system containing more than six components is not unusual. Thus, the number of experiments required for optimization is extremely large. This problem is circumvented by reducing the parameter space by either eliminating some of the components or by reducing the levels of each component in the experimental design. Although this process reduces the number of experiments needed to be done, it greatly increases the likelihood of "missing" important formulations.
  • a typical transdermal transport experiment lasts for at least 24 hours and uses about a 2 cm piece of skin. It is customary to run about 15-20 transport experiments at a time. At this rate, it would take hundreds of days to screen all 15,000 combinations. Thus, it is extremely difficult to perform these many experiments. Hence, intuition is used to eliminate a majority of these combinations. Although this decreases the number of experiments, it increases the risk of not finding a valuable formulation.
  • the disclosed invention offers a method that greatly increases the efficiency of formulation screening.
  • the method for performing high throughput assays of drug delivery formulations includes the steps of: i) securing a test membrane to a device comprising a donor plate, which includes a plurality of donor wells formed by donor holes passing through the donor plate; ii) introducing a formulation into each donor well, the formulation including a test substance and an inert medium; and iii) evaluating a characteristic of the test substance that remains in the donor well or migrates into the test membrane.
  • the test membrane is preferably mammalian skin or mucosa.
  • the device may also include a receiver plate having a plurality of receptor wells corresponding to the donor wells of the donor plate, so that the test membrane is secured between the donor plate and the receiver plate.
  • the device may further comprise two electrodes to measure current across the membrane.
  • the donor holes have a diameter of about 40 microns to about 10 mm and the volume of the donor wells is about 1 to 500 ⁇ l..
  • Formulations for testing include a test substance within an inert medium.
  • the test substance is a drug or its analog.
  • a preferred drug analog is a molecule of similar size and chemical properties to the drug, which is also a radioactive or fluorescent substance.
  • Preferred formulations also include one or more permeability enhancers
  • the inert medium can be an ointment, cream, gel, solution or lotion.
  • the concentration of test substance that remains in the donor well can be determined by conventional assays, such as HPLC, UV spectroscopy and the like.
  • a test substance that migrates into the test membrane can be monitored by its radioactivity, fluorescence or enhancement of membrane conductivity.
  • Such evaluating steps can recur at one or more periodic intervals over a period of about 24 hrs. Preferably the evaluating step occurs no later than 8 hours after introducing the formulation to the donor well.
  • the present invention also includes a device for conducting high throughput assays of drug formulations, which includes a donor plate having a plurality of donor wells formed by donor holes passing through the donor plate; means for securing a test membrane to the donor plate, whereby one or more donor wells are sealed at one end of the well and transfer of one or more substances to the membrane can occur; and one or more electrodes to measure current across a portion of the test membrane, said portion sealing an individual donor well.
  • Fig. 1 is a schematic representation of the device used for formulation testing
  • Fig.lA is a side view of the disc used for screening transdermal formulations
  • Fig. IB is a top-view representation of the disc of Fig. 1 A;
  • Fig. 2 is a schematic representation of the skin and the stratum corneum (SC) layer;
  • Fig. 3 is a graph showing the loss of drug from the donor hole into the skin
  • Fig. 4 is a graph showing the relationship between the percent drug lost from the donor hole versus permeabilities measured by traditional methods that use diffusion cells;
  • Fig. 5 is an image of the skin obtained during the experiment performed using the device shown in Figure 1;
  • Fig. 6 is a graph representing sulforhodamine delivery with varying ratios of SLS and dodecyl pyridinium chloride, corresponding to the image shown in Figure 5;
  • FIG. 7A shows a top view of a 10 x 10 High Throughput Array assembly, where the top and bottom plate are held together by a set of four screws;
  • Fig. 7B shows and oblique view of the 10 x 10 High Throughput Array assembly, .
  • Fig. 8 shows Conductivity Enhancement for SLS using 10 x 10 High Throughput array
  • Fig. 9 shows Conductivity Enhancement for TDAB using 10 x 10 High Throughput array
  • Fig. 10 shows Transport Enhancement for SLS and TDAB using 10 x 10 High Throughput array at the end of 7 Hrs;
  • Fig. 11 shows Conductivity Enhancement for SLS using 5 x 5 High Throughput array
  • Fig. 12 shows Conductivity Enhancement for TDAB using 5 x 5 High Throughput array
  • Fig. 13 shows Transport Enhancement for SLS and TDAB using 5 x 5 High Throughput array at the end of 7 Hrs;
  • Fig. 14 shows Conductivity Enhancement for SLS using Franz Diffusion cells
  • Fig. 15 shows Conductivity Enhancement for TDAB using Franz Diffusion cells
  • Fig. 16 shows Transport Enhancement for SLS and TDAB using Franz Diffusion cells at the end of 7 Hrs;
  • Fig. 17 shows the Effectiveness ratio (SLS: TDAB) for Franz diffusion cell and 10 x 10 HTP array at 18 Hrs and 25 Hrs;
  • Fig. 18 shows Average conductivity enhancement for SLS over three different geometries
  • Fig. 19 shows Average conductivity enhancement for TDAB over three different geometries
  • Fig. 20 shows Average transport enhancement for SLS and TDAB over three different geometries.
  • Fig. 21 shows Conductivity (current per unit area) in Franz Diffusion cells and High Throughput array (10 x 10).
  • FIG. 1 A A schematic representation of a device for screening transdermal formulations is shown in Figure 1 A and Figure IB.
  • Figure 1A shows a cross-sectional view of the device that will be used in the disclosed method.
  • the device as shown in Figure 1A, consists of a disc, which can be made from teflon, polycarbonate, silicon or other material; about 5 cm in diameter and about 0.5-2 mm in height.
  • the disc contains about 600 holes, each hole having a diameter of about 2 mm, as shown in a top-view in Figure IB.
  • the disc is placed on the skin. The holes are subsequently filled with formulations to be tested.
  • HTP screening array which mimics the Franz diffusion cells on a miniature scale, consists of two polycarbonate plates each 0.5 inches thick.
  • the top plate (donor plate) has through holes (wells) drilled in it, each of which acts as an isolated donor chamber similar to the donor chamber in the Franz diffusion cells.
  • the bottom plate (receiver plate) also has holes (wells) drilled in the same pattern as the donor plate and simulates the receiver compartment of the diffusion cells. All wells are isolated from each other for all practical purposes and each well acts like an individual diffusion cell.
  • the skin is placed between the donor and receiver plate and the plate assembly is clamped using four screws as shown in the figure (Fig. 7A)
  • the wells in the receiver plate are filled with PBS.
  • the skin is placed on the receiver plate with the stratum corneum (SC) facing the donor plate.
  • SC stratum corneum
  • the donor plate is then placed on the skin and the entire assembly is clamped tightly using four screws.
  • a mild vacuum is then applied to remove any excess PBS that may be pushed in to the wells in the receiver plate.
  • this method can extend to other drug delivery methods including oral delivery.
  • this method can be used to screen formulations for oral drug delivery by replacing the skin with mucosal membrane.
  • the test membrane can be any of a variety of membranes suitable for use in the diffusion experiments, such as hairless mouse skin, porcine skin, guinea pig skin, human skin, or alternatively, a synthetic membrane may be used, such as an elastomeric membrane, or any of a number of endothelial or epithelial cell culture barriers, such as those described in Audus, K. L., et al., Pharmaceutical Research, 1990, 7 (5), p 435 . Screening of formulations for transdermal delivery is most preferably conducted using pigskin.
  • a typical transdermal transport experiment lasts for at least 24 hours and uses about a 2 cm 2 piece of skin.
  • the method of the present invention uses as little as 0.03 cm 2 of skin per experiment, which is a much smaller area compared to the traditional methods that use about 1-2 cm 2 of skin.
  • the cost of experiments is also reduced as well as the amount of chemicals used for screening.
  • a typical drug formulation may contain anywhere from 3-15 components.
  • a formulation generally includes a test substance, typically a drug or a drug analog, within a an inert medium.
  • the drug analog can be a molecule of about the same size and chemical properties of the drug, which may include a radioactive tracer or fluorescent dye for ease of detection.
  • the inert media can include any of a number of solvents, carriers, binders, gelling agents, and so forth, for an active agent to be delivered.
  • Media for topical delivery include ointments, creams, gels, solutions and lotions. While ointments are composed of mostly high molecular weight hydrocarbons, creams, gels, solutions and lotions typically comprise up to 90 percent of fairly volatile solvents, such as water, ethanol and propylene glycol.
  • the formulation will include one or more permeability enhancers.
  • Over 250 enhancers have been used for enhancing transdermal drug transport. These enhancers have been classified into several categories based on their structure or their effect on permeability:
  • Surfactants are amphiphilic molecules with a hydrophilic head and a hydrophobic tail group.
  • the tail length and the chemistry of the head group play an important role in determining their effect on skin permeability.
  • Surfactants can be categorized into four groups, cationic, anionic, non-ionic, and zwitter-ionic depending on the charge on the head group.
  • Prominent examples of surfactants that have been used for transdermal delivery include: Brij (various chain lengths), HCO-60 surfactant, Hydroxypolyethoxydodecane, Lauroyl sarcosine, Nonionic surface active agents, Nonoxynol, Octoxynol, Phenylsulfonate, Pluronic, Polyoleates (nonionic surfactants) Rewopal HVIO, Sodium laurate, Sodium oleate, Sorbitan dilaurate, Sorbitan dioleate, Sorbitan monolaurate, Sorbitan monooleates, Sorbitan trilaurate, Sorbitan trioleate, Span 20, Span 40, Span 85, Synperonic NP, Triton X-100, Tweens, Sodium alkyl sulfates, and alkyl ammonium halides.
  • Brij variable chain lengths
  • HCO-60 surfactant Hydroxypolyethoxy
  • Azone and related compounds are also amphiphilic and possess a nitrogen molecule in their head group (preferable in the ring). The presence of a nitrogen atom makes these surfactants very peculiar in terms of their interactions with skin. Examples of such compounds include N-Acyl-hexahydro-2-oxo-lH-azepines, N-Alkyl- dihydro- 1 ,4-oxazepine-5 ,7-diones, N-Alkylmorpholine-2,3-diones, -Alkylmorpholine-3 ,5 - diones, Azacycloalkane derivatives (-ketone, -thione).
  • Solvents and related compounds are solubility enhancers. Some of them also extract lipids, thereby increasing skin permeability.
  • solvents include Acetamide and derivatives , Acetone, n-Alkanes (chain length between 7 and 16) , Alkanols, diols, short-chain fatty acids , Cyclohexyl-l,l-dimethylethanol , Dimethyl acetamide, Dimethyl formamide, Ethanol, , Efhanol/d-limonene combination , 2-Ethyl-l,3- hexanediol, Xylene, DMSO and related compounds.
  • Thse molecules are classic bilayer fluidizers. These correspond to one of the most investigated class of enhancers. Examples of these enhancers include Aliphatic alcohols, Decanol, Lauryl alcohol (dodecanol), Linolenyl alcohol, Nerolidol, 1-Nonanol, n-Octanol, Oleyl alcohol, Butyl acetate, Cetyl lactate, Decyl N,N-dimethylamino acetate, Decyl N,N-dimethylamino isopropionate, Diethyleneglycol oleate, Diethyl sebacate, Diethyl succinate, Diisopropyl sebacate, Tetradecyl N,N-dimethylamino, Sodium deoxycholate, Sodium taurocholate, Sodium tauroglycocholate.
  • formulations corresponding to these combinations are then prepared by mixing the components in the desired concentrations. About one to about 500 microliters of each formulation is placed in each donor well.
  • the diffusion test is typically run for a period of 24 hours or more; over the course of the study, samples are periodically withdrawn from a receiver receptacle to evaluate the flux of drug through the skin over time.
  • the present invention may be designed so that the permeation experiment is run to a pre-determined end point, i.e., less than about eight hours.
  • the formulation will typically remain on the membrane for several hours, which is referred to as contact time.
  • a sample may be taken from the donor wells by an automated process and transferred to a detection device.
  • Donor samples may be periodically withdrawn from their respective wells, typically by aspiration, and assayed by an appropriate analytical method.
  • the samples can be assayed by any of a number of analytical test methods, such as HPLC (high performance liquid chromatography), UN (ultraviolet spectrometry), GC (gas chromatography), LC (liquid chromatography) or, if the samples are radiolabeled, scintillation counting.
  • disruption of the lipid bilayer which also disrupts transport of ions, may be monitored by measuring the conductivity of skin.
  • one embodiment of the present invention uses electrodes to measure the conductivity of the skin, which is proportional to permeability. The conductivity measurements may be conveniently taken at periodic intervals without having to remove the formulation or disassemble the screening device.
  • the receiver assembly is detached from the donor assembly upon termination of the diffusion experiment, and the membrane is assayed by fluorescence or liquid scintillation counting.
  • Stratum corneum the uppermost layer of the skin, is the rate limiting step in transdermal transport.
  • Stratum corneum consists of about 15 layers of keratin-filled cells called keratinocytes. In between the keratinocytes are lipid bilayers, as shown in Figure 2.
  • Low permeability of the SC is due to the low permeability of its lipid bilayers; see Mitragotri, et al., infra.
  • the SC consists of layers of keratinocytes and intracellular spaces filled with lipid bilayers; see Elias, et al., infra. Transdermal transport of drugs, especially hydrophobic drugs, occurs through these lipid bilayers. Hence, only a small fraction of the area is available for drug transport. Furthermore, the drug has to follow a tortuous path to cross the SC. So the effective SC thickness for solute transport is ⁇ * L, where, L is the SC thickness and /is the effective tortuosity factor.
  • V PBS is the thickness of the formulation layer on the SC.
  • Figure 3 is a typical plot of the left hand side of Eq. [4].
  • Figure 3 shows that the amount of drug lost from the donor hole increases with time before achieving equilibrium at times greater than 50 hours.
  • the equations described above [Eq.l - 4] are used to determine the effectiveness of formulations via three methods.
  • the effectiveness of the formulation is determined by the loss of the drug from the formulation in a given amount of time. Specifically, the higher the loss of the drug from the formulation in a given amount of time, the higher the penetration of the drug into the skin.
  • the amount of drug delivered into the skin is measured by radioactivity, fluorescence or conductivity assays.
  • the third method which corresponds to the traditional method, the amount of drug delivered across the skin is measured and used to determine the most effective formulation.
  • the HTP method can be at least 50-400 fold more efficient as compared to conventional Franz diffusion cells on basis of skin area utilized, sampling volume and hold up times. Moreover, there is no physical, experimental or fundamental limit on the size of wells used in the HTP array. We can scale down to a smaller well diameter and correspondingly further increase the efficiency of the HTP screening method. Once we have established the efficacy of an enhancer in increasing conductivity of the skin, we can find out the actual amount of drug transported across the skin using Franz diffusion cells. Knowing the relative efficiency of one enhancer over another from HTP screening, it is sufficient to repeat transport experiments in Franz diffusion cells for only one enhancer at one concentration. Thus we conclude that the novel HTP screening method we propose is a much more efficient way of screening enhancers. It is not only useful as a tool for identifying the right vehicle for transdermal drug delivery but also a means to answer some fundamental underlying issues of transdermal transport.
  • the following example describes a method where the amount of drug measured in the skin can be used to screen formulations.
  • a device shown in Figure 1 was prepared using plexi glass. The device was configured in a square shape. The device consisted of two plates each having 400 holes each with a diameter of about 700 micron. A sample of pigskin was sandwiched between the two plates and the plates were clamped. The holes were filled with formulations to be tested for drug delivery. Two model drugs (fluorescein and sulforhodamine) were used to assess the efficacy of the enhancers. Two model enhancers, sodium lauryl sulfate and dodecyl pyridinium chloride, were used in these experiments.
  • Figure 6 shows that the formulation, a mixture of sodium lauryl sulfate and dodecyl pyridinium chloride (4:6 parts), is most effective in delivering drugs.
  • the disclosed method allows discovery of new formulations for effective drug delivery.
  • This array is built as a pattern of 10 x 10 matrix. This corresponds to 100 test wells, each well 3 mm in diameter. a. LA. Conductivity Measurements.
  • the formulations to be tested are filled in the donor compartments. Each formulation is filled in 4 wells and each well can hold about 85 ⁇ L of the test formulation.
  • Two 22 G 1 Vz needles are used as electrodes to measure current across the skin. One needle is stuck into the dermis and acts as the common electrode while the other needle is sequentially placed in each well to measure current. Current measurements are made across the skin periodically over a span of 25 hrs. The current, measured at 100 Hz and 143mNpp, varied between 1 ⁇ A at time 0 to 10-12 ⁇ A at time 25 hrs.
  • Conductivity enhancement for SLS (Fig 8) and TDAB (Fig 9) is plotted at various times for different concentrations between 0% (w/v) to 2% (w/v).
  • the conductivity enhancement increases with increasing SLS or TDAB concentration and reaches a maximum after which it starts decreasing. This effect gets more pronounced at larger times.
  • the location of the maximum on the enhancement curve is a function of time.
  • Radiolabelled mannitol was added to all formulations prepared in PBS at a concentration of 10 ⁇ Ci/mL.
  • the donor compartments were filled with these formulations with each formulation filled in 4 wells.
  • the skin was then incubated for 7 hrs.
  • the solutions from the donor compartment were removed at the end of incubation period.
  • the skin was then gently rinsed to free any mannitol that could be sticking to the surface of the sldn.
  • the sldn was then cut and dissolved in 0.5 M Solvable, a tissue and gel solubilizer from Packard Chemicals, at 60°C overnight.
  • a 500 ⁇ L sample was then taken and concentration of radiolabeled mannitol in this sample was then measured using a scintillation counter (Packard Tricarb 2000 CA).
  • the transport enhancement at different test formulations is then calculated
  • This array is built as a pattern of a 5 x 5 matrix. This corresponds to 25 test wells, each well 7.5 mm in diameter. It consists of two polycarbonate plates each 0.5 inches thick.
  • the top plate (donor plate) has 25 through holes (wells), diameter 7.5 mm, drilled in it, each of which acts as an isolated donor chamber similar to the donor chamber in the Franz diffusion cells.
  • the bottom plate (receiver plate) also has holes (wells) drilled in a similar pattern as the donor plate and simulates the receiver compartment of the diffusion cells. All wells are isolated from each other for all practical purposes and each well acts like an individual diffusion cell.
  • the skin is placed between the donor and receiver plate and the plate assembly is clamped using four screws as shown in the figure.
  • Screening of the formulations is performed using pigskin.
  • the wells in the receiver plate are filled with PBS.
  • the skin is placed on the receiver plate with the stratum corneum (SC) facing the donor plate.
  • SC stratum corneum
  • the donor plate is then placed on the skin and the entire assembly is clamped tightly using four screws.
  • a mild vacuum is then applied to remove any excess PBS that may be pushed in to the wells in the receiver plate.
  • the formulations to be tested are filled in the donor compartments. Each formulation is filled in 2 wells and each well can hold about 500 ⁇ L of the test formulation.
  • Two 22 G V ⁇ needles are used as electrodes to measure current across the sldn. One needle is stuck into the dermis and acts as the common electrode while the other needle is sequentially placed in each well to measure current. Current measurements are made across the skin periodically over a span of 25 hrs. The current, measured at 100 Hz and 143mVpp, varied between 1 ⁇ A at time 0 to 25-30 ⁇ A at time 25 hrs.
  • I t is the current across the skin at time 'f and IQ is the current across the skin at time 0.
  • Conductivity enhancement for SLS (Fig 11) and TDAB (Fig 12) is plotted at various times for different concentrations between 0% (w/v) to 2% (w/v).
  • the enhancement increases as a function of the SLS or TDAB concentration and reaches a maximum. The position of the maximum is a function of time.
  • Radiolabelled mannitol was added to all formulations prepared in PBS at a concentration of 10 ⁇ Ci/mL.
  • the donor compartments were filled with these formulations each formulation was filled in 1 well.
  • the skin was then incubated for 7 hrs.
  • the solutions from the donor compartment were removed at the end of incubation period.
  • the skin was then gently rinsed to free any mannitol that could be sticking to the surface of the skin.
  • the sldn was then cut and dissolved in 0.5 M Solvable, a tissue and gel solubilizer from Packard Chemicals at 60°C overnight.
  • a 500 ⁇ L sample was then taken and concentration of radiolabeled mannitol in this sample was then measured using a scintillation counter (Packard Tricarb 2000 CA).
  • the transport enhancement at different test formulations is then calculated
  • Pigskin samples about 2-3 sq.cm, without any detectable scratches or abrasions were used for these experiments.
  • a small stir bar and an Ag/AgCl disk electrode (E242 Invivo Metrics) were added to the receiver chamber.
  • the receiver chamber was filled with PBS.
  • Pigskin was thawed and was mounted on the diffusion cell with the epidermis side facing up. The donor and the receiver compartments were clamped making sure there were no bubbles in the receiver chamber. Before each experiment, structural integrity of the skin was confirmed by measuring its conductivity.
  • Skin samples with a resistivity less than 20 Kohm-cm 2 were assumed to be defective and not used. Skin conductivity was measured throughout the experiment to assess the effect of the formulation on skin structure. Effect of different formulations at different surfactant concentrations in the range 0 to 2 % was tested on skin conductivity. Each formulation was prepared in PBS. Current across the skin was measured over a period of 24 hours. The enhancement of skin conductivity was calculated as
  • radiolabeled mannitol 3 H labeled was added to the formulation at a concentration of 10 ⁇ Ci/ml.
  • the skin was incubated in the cells for 7 hrs. At the end of 7 hrs the skin was removed from the cell and dissolved in 0.5M Solvable, a gel and tissue solubilizer from Packard Chemicals, at 60°C overnight. About 250 ⁇ L samples were then taken from the dissolved skin solution and concentration of radiolabeled mannitol was measured using a scintillation counter (Packard Tricarb 2000 CA).
  • E ⁇ C F /C C , where Cp is the radiation count for a particular formulation and Cc is the radiation count for the control which in this case is simply PBS with radiolabeled mannitol but no surfactant.
  • Transport enhancement for SLS and TDAB (Fig 16) is plotted at various times for different concentrations between 0% (w/v) to 2% (w/v). The amount of mannitol transported increases monotonously as a function of the surfactant concentration.
  • Mitragotri S. In Situ Determination of Partition and Diffusion Coefficients in the Lipid Bilayers of the Stratum Corneum. Pharm. Res. Submitted: (2000). Mitragotri, S., Johnson, M.E., D., B. and Langer, R. A Theoretical Analysis of Partitioning, Diffusion, and Permeation Across lipid bilayers. Biophys. J 77: 1268-1283 (1999).

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Abstract

L'invention concerne une nouvelle méthode de criblage rapide de préparations d'administration de médicaments, ladite méthode faisant appel à un jeu ordonné d'échantillons à rendement élevé pour cribler plusieurs échantillons. Cette méthode surveille la déplétion d'une substance d'essai à partir d'une cupule donatrice, la migration de la substance dans une membrane d'essai, et/ou la migration de la substance à travers une membrane dans une cupule réceptrice. On peut l'utiliser pour découvrir de nouvelles préparations, ainsi que pour optimiser les préparations existantes d'administration de médicaments par voies transdermiques, orales ou injectables.
PCT/US2001/026473 2000-08-23 2001-08-23 Methode combinatoire de criblage rapide de preparations d'administration de medicaments WO2002016941A2 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6758099B2 (en) 2000-07-14 2004-07-06 Transform Pharmaceuticals, Inc. System and method for optimizing tissue barrier transfer of compounds
WO2005009510A2 (fr) * 2003-07-23 2005-02-03 The Regents Of The University Of California Combinaisons d'amplificateurs de penetration pour administration transdermique
US6852526B2 (en) 2000-07-14 2005-02-08 Transform Pharmaceuticals, Inc. Transdermal assay with magnetic clamp
WO2005036138A1 (fr) * 2003-09-24 2005-04-21 3M Innovative Properties Company Systeme, kit et procede de mesure de la diffusion membranaire
WO2005036165A1 (fr) * 2003-09-24 2005-04-21 3M Innovative Properties Company Procede de criblage permettant de formuler une composition pharmaceutique en utilisant des composes modeles
EP1556501A1 (fr) * 2002-10-28 2005-07-27 Transform Pharmaceuticals, Inc. Dosage transdermique a l'aide d'un dispositif de blocage magnetique
US7172859B2 (en) 2000-07-14 2007-02-06 Transform Pharmaceuticals, Inc. System and method for optimizing tissue barrier transfer of compounds
US7449307B2 (en) 2002-10-28 2008-11-11 Transform Pharmaceuticals, Inc. Raised surface assay plate
CN103308564A (zh) * 2013-06-03 2013-09-18 拉芳家化股份有限公司 一种化妆品活性成分经皮吸收效率的检测方法
CN103323496A (zh) * 2013-05-24 2013-09-25 阮仕荣 高通量经皮腐蚀与吸收检测板
CN113514370A (zh) * 2021-04-14 2021-10-19 广州健康元呼吸药物工程技术有限公司 一种用于测定载药非血管支架药物的单向渗透性装置及测定方法

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US7172859B2 (en) 2000-07-14 2007-02-06 Transform Pharmaceuticals, Inc. System and method for optimizing tissue barrier transfer of compounds
US6758099B2 (en) 2000-07-14 2004-07-06 Transform Pharmaceuticals, Inc. System and method for optimizing tissue barrier transfer of compounds
US6852526B2 (en) 2000-07-14 2005-02-08 Transform Pharmaceuticals, Inc. Transdermal assay with magnetic clamp
EP1556501A4 (fr) * 2002-10-28 2009-04-08 Transform Pharmaceuticals Inc Dosage transdermique a l'aide d'un dispositif de blocage magnetique
EP1556501A1 (fr) * 2002-10-28 2005-07-27 Transform Pharmaceuticals, Inc. Dosage transdermique a l'aide d'un dispositif de blocage magnetique
US7449307B2 (en) 2002-10-28 2008-11-11 Transform Pharmaceuticals, Inc. Raised surface assay plate
US7763455B2 (en) 2003-05-16 2010-07-27 Transform Pharmaceuticals, Inc. Raised surface assay plate
WO2005009510A3 (fr) * 2003-07-23 2005-04-07 Univ California Combinaisons d'amplificateurs de penetration pour administration transdermique
WO2005009510A2 (fr) * 2003-07-23 2005-02-03 The Regents Of The University Of California Combinaisons d'amplificateurs de penetration pour administration transdermique
WO2005036138A1 (fr) * 2003-09-24 2005-04-21 3M Innovative Properties Company Systeme, kit et procede de mesure de la diffusion membranaire
WO2005036165A1 (fr) * 2003-09-24 2005-04-21 3M Innovative Properties Company Procede de criblage permettant de formuler une composition pharmaceutique en utilisant des composes modeles
US7635452B2 (en) 2003-09-24 2009-12-22 3M Innovative Properties Company System, kit, and method for measuring membrane diffusion
CN103323496A (zh) * 2013-05-24 2013-09-25 阮仕荣 高通量经皮腐蚀与吸收检测板
CN103308564A (zh) * 2013-06-03 2013-09-18 拉芳家化股份有限公司 一种化妆品活性成分经皮吸收效率的检测方法
CN113514370A (zh) * 2021-04-14 2021-10-19 广州健康元呼吸药物工程技术有限公司 一种用于测定载药非血管支架药物的单向渗透性装置及测定方法

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