The present invention is directed to a solid pharmaceutical dosage form comprising at least one HIV protease inhibitor, and a process for preparing same.
The virus causing acquired immunodeficiency syndrome (AIDS) is known by different names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up until now, two distinct families have been identified, i.e., HIV-1 and HIV-2.
One of the critical pathways in a retroviral life cycle is the processing of polyprotein precursors by aspartic protease. For instance with the HIV virus the gag-pol protein is processed by HIV protease. The correct processing of the precursor polyproteins by the aspartic protease is required for the assembly of infectious virions, thus making the aspartic protease an attractive target for antiviral therapy. In particular for HIV treatment, the HIV protease is an attractive target.
A measure of the potential usefulness of an oral dosage form of a pharmaceutical agent is the bioavailability observed after oral administration of the dosage form. Various factors can affect the bioavailability of a drug when administered orally. These factors include aqueous solubility, drug absorption throughout the gastrointestinal tract, dosage strength and first pass effect. Aqueous solubility is one of the most important of these factors. Unfortunately, HIV protease inhibiting compounds typically are characterized by having poor aqueous solubility.
For a variety of reasons, such as patient compliance and taste masking, a solid dosage form is usually preferred over a liquid dosage form. In most instances however, oral solid dosage forms of a drug provide a lower bioavailability than oral solutions of the drug.
There have been attempts to improve the bioavailability provided by solid dosage forms by forming solid solutions of the drug. The term “solid solution” defines a system in a solid state wherein the drug is molecularly dispersed throughout a matrix such that the system is chemically and physically uniform or homogenous throughout. Solid solutions are preferred physical systems because the components therein readily form liquid solutions when contacted with a liquid medium such as gastric juice. The ease of dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of the components from a crystalline or microcrystalline solid phase. If, however, the drug absorption in the gastrointestinal tract is slow the drug released from the solid solution may result in a high supersaturation and precipitate in the aqueous fluids of the gastrointestinal tract.
There is a continuing need for the development of improved oral solid dosage forms for HIV protease inhibitors which have suitable oral bioavailability and stability and which do not necessitate high vehicle volumes.
The present invention provides a solid pharmaceutical dosage form comprising a solid dispersion of at least one HIV protease inhibitor in at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant. In one embodiment, the pharmaceutically acceptable water-soluble polymer has a glass transition temperature (Tg) of at least about 50° C.
The term “solid dispersion” defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed evenly throughout the other component or components. For example, the active ingredient or combination of active ingredients is dispersed in a matrix comprised of the pharmaceutically acceptable water-soluble polymer(s) and pharmaceutically acceptable surfactant(s). The term “solid dispersion” encompasses systems having small particles, typically of less than 1 μm in diameter, of one phase dispersed in another phase. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase (as defined in thermodynamics), such a solid dispersion will be called a “solid solution” or a “glassy solution”. A glassy solution is a homogeneous, glassy system in which a solute is dissolved in a glassy solvent. Glassy solutions and solid solutions of HIV protease inhibitors are preferred physical systems. These systems do not contain any significant amounts of active ingredients in their crystalline or microcrystalline state, as evidenced by thermal analysis (DSC) or X-ray diffraction analysis (WAXS).
In one embodiment of the present invention, the pharmaceutical dosage form is comprising from about 5 to about 30% by weight of the total dosage form (preferably from about 10 to about 25% by weight of the total dosage form) of an HIV protease inhibitor or a combination of HIV protease inhibitors, from about 50 to about 85% by weight of the total dosage form (preferably from about 60 to about 80% by weight of the total dosage form) of a water-soluble polymer (or any combination of such polymers), from about 2 to about 20% by weight of the total dosage form (preferably from about 3 to about 15% by weight of the total dosage form) of the surfactant (or combination of surfactants), and from about 0 to about 15% by weight of the total dosage form of additives.
HIV protease inhibiting compounds suitable for use in the present invention include for example, but are not limited thereto:
amprenavir (VX-478); DMP-323; DMP-450; AG1343 (nelfinavir); atazanavir (BMS 232,632);
tipranavir;
palinavir;
TMC-114;
RO033-4649;
fosamprenavir (GW433908);
P-1946;
BMS 186,318; SC-55389a; BILA 1096 BS; and U-140690, or combinations thereof.
In one embodiment, ritonavir (Abbott Laboratories, Abbott Park, Ill., USA) is an HIV protease inhibitor which may be formulated into the dosage form of the invention. This and other compounds as well as methods for preparing same are disclosed in U.S. Pat. Nos. 5,542,206 and 5,648,497, the disclosures of which are herein incorporated by reference. In a further embodiment, the present invention provides a dosage form wherein said HIV protease inhibitor is ritonavir or a combination of ritonavir and at least one other HIV protease inhibitor, the dosage form showing a dose-adjusted AUC of ritonavir plasma concentration in dogs of at least about 9 μg·h/ml/100 mg.
In another embodiment, lopinavir (Abbott Laboratories, Abbott Park, Ill., USA) is an HIV protease inhibitor which may be formulated into the dosage form of the invention. This and other compounds, as well as methods for preparing same, are identified in U.S. Pat. No. 5,914,332, the disclosure of which is herein incorporated by reference. In a further embodiment, the present invention provides a dosage form wherein said HIV protease inhibitor is lopinavir or a combination of lopinavir and at least one other HIV protease inhibitor, the dosage form showing a dose-adjusted AUC of lopinavir plasma concentration in dogs of at least about 20 μg·h/ml/100 mg (preferably at least about 22.5 μg·h/ml/100 mg, most preferred at least about 35 μg·h/ml/100 mg).
In yet another embodiment, nelfinavir mesylate (marketed under the tradename Viracept by Agouron Pharmaceuticals, Inc. in La Jolla, Calif.) is an HIV protease inhibitor which may be formulated into the dosage form of the invention.
The dosage forms of the present invention exhibit a release and absorption behaviour that is characterized by high attainable AUC, high attainable Cmax (maximum plasma concentration), and low Tmax (time to reach maximum plasma concentration).
In still another embodiment, the present invention provides a dosage form wherein said HIV protease inhibitor is a combination of ritonavir and lopinavir, the dosage form showing a dose-adjusted AUC of ritonavir plasma concentration in dogs of at least about 9 μg·h/ml/100 mg and a dose-adjusted AUC of lopinavir plasma concentration of at least about 20 μg·h/ml/100 mg (preferably at least about 22.5 μg·h/ml/100 mg, most preferred at least about 35 μg·h/ml/100 mg).
The term “AUC” means “Area Under the Curve” and is used in its normal meaning, i.e. as the area under the plasma concentration-time curve from 0 to 24 hours, where the dosage form has been administered orally to dogs (beagle) under non-fasting conditions. “Non-fasting condition” means that the dogs receive a nutritionally balanced daily ration during the pre-test period and the whole test period. The AUC has units of concentration times time. Once the experimental concentration-time points have been determined, the AUC may conveniently be calculated, e.g. by a computer program or by the trapezoidal method. All AUC data herein were dose adjusted to the 100 mg dose level. For the purposes herein, the AUC is determined within a dose range where the AUC increases proportionally with dose. Administration of 50 mg ritonavir or 200 mg lopinavir, respectively, to dogs is considered suitable for determining the AUC values as used herein.
The dosage forms according to the invention are characterized by an excellent stability and, in particular, exhibit high resistance against recrystallization or decomposition of the active ingredient(s). Thus, upon storage for 6 weeks at 40° C. and 75% humidity (e.g., when kept in high density polyethylene (HDPE) bottles without desiccant), the dosage forms according to the present invention usually do not exhibit any sign of crystallinity (as evidenced by DSC or WAXS analysis) and contain at least about 98% of the initial active ingredient content (as evidenced by HPLC analysis).
The term “pharmaceutically acceptable surfactant” as used herein refers to a pharmaceutically acceptable non-ionic surfactant. In one embodiment, the dosage form is comprising at least one surfactant having an hydrophilic lipophilic balance (HLB) value of from about 4 to about 10, preferably from about 7 to about 9. The HLB system (Fiedler, H. B., Encylopedia of Excipients, 5th ed., Aulendorf: ECV-Editio-Cantor-Verlag (2002)) attributes numeric values to surfactants, with lipophilic substances receiving lower HLB values and hydrophilic substances receiving higher HLB values. Surfactants having an HLB value of from about 4 to about 10 suitable for use in the present invention include for example, but are not limited thereto:
polyoxyethylene alkyl ethers, e.g. polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ethers, e.g. polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether, polyoxyethylene (3) octylphenyl ether;
polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate;
alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®);
sucrose fatty acid esters, e.g. sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate; or
sorbitan fatty acid mono esters such as sorbitan mono laurate (Span® 20), sorbitan monooleate, sorbitan monopalmitate (Span® 40), or sorbitan stearate, or mixtures of one or more thereof.
The sorbitan mono fatty acid esters are preferred, with sorbitan mono laurate and sorbitan monopalmitate being particularly preferred.
Besides the surfactant having an HLB value of from about 4 to about 10, the dosage form may comprise additional pharmaceutically acceptable surfactants such as polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor® RH 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60); or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, Poloxamer® 407 (BASF Wyandotte Corp.); or a mono fatty acid ester of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20).
Where such additional surfactants are used, the surfactant having an HLB value of from about 4 to about 10 generally accounts for at least about 50% by weight, preferably at least about 60% by weight, of the total amount of surfactant used.
The water-soluble polymer employed in the present invention has a Tg of at least about 50° C., preferably at least about 60° C., most preferred from about 80° C. to about 180° C. Methods for determining Tg values of the organic polymers are described in “Introduction to Physical Polymer Science”, 2nd Edition by L. H. Sperling, published by John Wiley & Sons, Inc., 1992. The Tg value can be calculated as the weighted sum of the Tg values for homopolymers derived from each of the individual monomers, i.e., that make up the polymer: Tg=ΣWi Xi where W is the weight percent of monomer i in the organic polymer, and X is the Tg value for the homopolymer derived from monomer i. Tg values for the homopolymers may be taken from “Polymer Handbook”, 2nd Edition by J. Brandrup and E. H. Immergut, Editors, published by John Wiley & Sons, Inc., 1975.
Water-soluble polymers having a Tg as defined above allow for the preparation of solid dispersions that are mechanically stable and, within ordinary temperature ranges, sufficiently temperature stable so that the solid dispersions may be used as dosage forms without further processing or be compacted to tablets with only a small amount of tabletting aids.
The water-soluble polymer comprised in the dosage form is a polymer that preferably has an apparent viscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v), of about 1 to about 5000 mPa·s. more preferably of about 1 to about 700 mPa·s, and most preferred of about 5 to about 100 mPa·s. Water-soluble polymers suitable for use in the present invention include for example, but are not limited thereto:
homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP), copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate,
cellulose esters and cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate;
high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide,
polyacrylates and polymethacrylates such as methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),
polyacrylamides,
vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified “polyvinyl alcohol”), polyvinyl alcohol,
oligo- and polysaccharides such as carrageenans, galactomannans and xanthan gum, or mixtures of one or more thereof.
Of these, homopolymers or copolymers of N-vinyl pyrrolidone, in particular a copolymer of N-vinyl pyrrolidone and vinyl acetate, are preferred. A particularly preferred polymer is a copolymer of about 60% by weight of the copolymer, N-vinyl pyrrolidone and about 40% by weight of the copolymer, vinyl acetate.
The dosage forms of the invention may contain at least one conventional additive, such as flow regulators, lubricants, bulking agents (fillers) and disintegrants. In general, the additive is contained in an amount of about 0.01 to about 15% by weight relative to the weight of the dosage form.
Various methods can be used for manufacturing the solid dosage forms according to the invention. These methods comprise the preparation of a solid solution of the HIV protease inhibitor or the combination of HIV protease inhibitors in a matrix of the water-soluble polymer and the surfactant, and shaping into the required tablet form. Alternatively, the solid solution product may be subdivided to granules, e.g. by grinding or milling, and the granules may subsequently be compacted to tablets.
Various techniques exist for preparing solid solutions including melt-extrusion, spray-drying and solution-evaporation with melt-extrusion being preferred.
The melt-extrusion process comprises the steps of preparing a homogeneous melt of the HIV protease inhibitor or the combination of HIV protease inhibitors, the water-soluble polymer and the surfactant, and cooling the melt until it solidifies. “Melting” means a transition into a liquid or rubbery state in which it is possible for one component to get embedded homogeneously in the other. Typically, one component will melt and the other components will dissolve in the melt thus forming a solution. Melting usually involves heating above the softening point of the water-soluble polymer. The preparation of the melt can take place in a variety of ways. The mixing of the components can take place before, during or after the formation of the melt. For example, the components can be mixed first and then melted or be simultaneously mixed and melted. Usually, the melt is homogenized in order to disperse the active ingredients efficiently. Also, it may be convenient first to melt the water-soluble polymer and then to mix in and homogenize the active ingredients.
Usually, the melt temperature is in the range of about 70 to about 250° C., preferably from about 80 to about 180° C., most preferred from about 100 to about 140° C.
The active ingredients can be employed as such or as a solution or dispersion in a suitable solvent such as alcohols, aliphatic hydrocarbons or esters. Another solvent which can be used is liquid carbon dioxide. The solvent is removed, e.g. evaporated, upon preparation of the melt.
Various additives may be included in the melt, for example flow regulators such as colloidal silica; lubricants, fillers, disintegrants, plasticizers, stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack.
The melting and/or mixing takes place in an apparatus customary for this purpose. Particularly suitable ones are extruders or kneaders. Suitable extruders include single screw extruders, intermeshing screw extruders or else multiscrew extruders, preferably twin screw extruders, which can be corotating or counterrotating and, optionally, be equipped with kneading disks. It will be appreciated that the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used. Part of the energy needed to melt, mix and dissolve the components in the extruder can be provided by heating elements. However, the friction and shearing of the material in the extruder may also provide a substantial amount of energy to the mixture and aid in the formation of a homogeneous melt of the components.
The melt ranges from pasty to viscous. Shaping of the extrudate conveniently is carried out by a calender with two counter-rotating rollers with mutually matching depressions on their surface. A broad range of tablet forms can be attained by using rollers with different forms of depressions. Alternatively, the extrudate is cut into pieces, either before (hot-cut) or after solidification (cold-cut).
Optionally, the resulting solid solution product is milled or ground to granules. The granules may then be compacted. Compacting means a process whereby a powder mass comprising the granules is densified under high pressure in order to obtain a compact with low porosity, e.g. a tablet. Compression of the powder mass is usually done in a tablet press, more specifically in a steel die between two moving punches. Where a solid dosage form of the invention comprises a combination of more than one HIV protease inhibitor (or a combination of an HIV protease inhibitor with one or more other active ingredients) it is of course possible to separately prepare solid solution products of the individual active ingredients and to blend the milled or ground products before compacting.
At least one additive selected from flow regulators, disintegrants, bulking agents (fillers) and lubricants is preferably used in compacting the granules. Disintegrants promote a rapid disintegration of the compact in the stomach and keeps the granules which are liberated separate from one another. Suitable disintegrants are crosslinked polymers such as crosslinked polyvinyl pyrrolidone and crosslinked sodium carboxymethylcellulose. Suitable bulking agents (also referred to as “fillers”) are selected from lactose, calcium hydrogenphosphate, microcrystalline cellulose (Avicell®), silicates, in particular silicium dioxide, magnesium oxide, talc, potato or corn starch, isomalt, polyvinyl alcohol.
Suitable flow regulators are selected from highly dispersed silica (Aerosil®), and animal or vegetable fats or waxes.
A lubricant is preferably used in compacting the granules. Suitable lubricants are selected from polyethylene glycol (e.g., having a Mw of from 1000 to 6000), magnesium and calcium stearates, sodium stearyl fumarate, and the like.
Various other additives may be used, for example dyes such as azo dyes, organic or inorganic pigments such as aluminium oxide or titanium dioxide, or dyes of natural origin; stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack.
Dosage forms according to the invention may be provided as dosage forms consisting of several layers, for example laminated or multilayer tablets. They can be in open or closed form. “Closed dosage forms” are those in which one layer is completely surrounded by at least one other layer. Multilayer forms have the advantage that two active ingredients which are incompatible with one another can be processed, or that the release characteristics of the active ingredient(s) can be controlled. For example, it is possible to provide an initial dose by including an active ingredient in one of the outer layers, and a maintenance dose by including the active ingredient in the inner layer(s). Multilayer tablets types may be produced by compressing two or more layers of granules. Alternatively, multilayer dosage forms may be produced by a process known as “coextrusion”. In essence, the process comprises preperation of at least two different melt compositions as explained above, and passing these molten compositions into a joint coextrusion die. The shape of the coextrusion die depends on the required drug form. For example, dies with a plain die gap, called slot dies, and dies with an annular slit are suitable.
In order to facilitate the intake of such a dosage form by a mammal, it is advantageous to give the dosage form an appropriate shape. Large tablets that can be swallowed comfortably are therefore preferably elongated rather than round in shape.
A film coat on the tablet further contributes to the ease with which it can be swallowed. A film coat also improves taste and provides an elegant appearance. If desired, the film-coat may be an enteric coat. The film-coat usually includes a polymeric film-forming material such as hydroxypropyl methylcellulose, hydroxypropylcellulose, and acrylate or methacrylate copolymers. Besides a film-forming polymer, the film-coat may further comprise a plasticizer, e.g. polyethylene glycol, a surfactant, e.g. a Tween® type, and optionally a pigment, e.g. titanium dioxide or iron oxides. The film-coating may also comprise talc as anti-adhesive. The film coat usually accounts for less than about 5% by weight of the dosage form.
The exact dose and frequency of administration depends on the particular condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art.
Exemplary compositions of the present invention for combined administration of ritonavir/lopinavir are shown below in Table 1, and the values are % by weight.
Exemplary compositions of the invention for administration of ritonavir only are shown below in Table 2. The values are % by weight.
18-22.5
The above compositions are processed by melt extrusion. The resulting extrudates may be used as such or milled and compressed into tablets, preferably by the use of suitable tabletting aids such as sodium stearyl fumarate, colloidal silica, lactose, isomalt, calcium silicate, and magnesium stearate, cellulose or calcium hydrogenphosphate.
The following examples will serve to further illustrate the invention without limiting it.
Protocol for the Oral Bioavailability Studies
Dogs (beagle dogs, mixed sexes, weighing approximately 10 kg) received a balanced diet with 27% fat and were permitted water ad libitum. Each dog received a 100 μg/kg subcutaneous dose of histamine approximately 30 minutes prior to dosing. A single dose corresponding to about 200 mg lopinavir, about 50 mg ritonavir, or about 200 mg lopinavir and about 50 mg ritonavir, respectively, was administered to each dog. The dose was followed by approximately 10 milliliters of water. Blood samples were obtained from each animal prior to dosing and 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after drug administration. The plasma was separated from the red cells by centrifugation and frozen (−30° C.) until analysis. Concentrations of HIV protease inhibitors were determined by reverse phase HPLC with low wavelength UV detection following liquid-liquid extraction of the plasma samples. The area under the curve (AUC) was calculated by the trapezoidal method over the time course of the study. Each dosage form was evaluated in a group containing 8 dogs; the values reported are averages for each group of dogs.
Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 78.17 parts by weight) was mixed with ritonavir (4.16 parts by weight), lopinavir (16.67 parts by weight) and colloidal silica (1.0 part by weight). The powdery mixture was then fed into a twin-screw extruder (screw diameter 18 mm) at a rate of 2.0 kg/h and a melt temperature of 133° C. The clear, fully transparent melt was fed to a calendar with two counter-rotating rollers having mutually matching cavities on their surfaces. Tablets of 1080 mg were thus obtained. DSC and WAXS analysis did not reveal any evidence of crystalline drug material in the formulation.
The dose-adjusted AUC in dogs was 0.52 μg·h/ml/100 mg for ritonavir and 4.54 μg·h/ml/100 mg for lopinavir. This example shows that solid solutions of HIV protease inhibitors without added surfactant yield a very poor bioavailabilty.
Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 68.17 parts by weight) was blended with Cremophor RH40 (polyoxyethyleneglycerol oxystearate; 10.00 parts by weight) in a Diosna high-shear mixer. The resulting granules were mixed with ritonavir (4.17 parts by weight), lopinavir (16.67 parts by weight) and colloidal silica (1.00 parts by weight). The powdery mixture was then fed into a Leistritz Micro 18 twin-screw extruder at a rate of 2.3 kg/h and a melt temperature of 126° C. The extrudate was cut into pieces and allowed to solidify. The extruded pieces were milled using a high impact universal mill. The milled material (86.49 parts by weight) was blended in a bin blender with lactose monohydrate (6.00 parts by weight), crosslinked PVP (6.00 parts by weight), colloidal silica (1.00 part by weight) and magnesium stearate (0.51 parts by weight). The powdery blend was compressed to tablets of 1378.0 mg on a Fette E 1 single punch tablet press. The tablets were then film-coated in a coating pan by spraying an aqueous dispersion for film coating (Opadry, available from Colorcon) at a temperature of 60° C.
The dose-adjusted AUC in dogs was 0.60 μg·h/ml/100 mg for ritonavir and 7.43 μg·h/ml/100 mg for lopinavir. This example shows that inclusion of a surfactant into solid solutions of HIV protease inhibitors improves the bioavailabilty attained.
Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 853.8 parts by weight) was blended with Span 20 (Sorbitan monolaurate; 83.9 parts by weight) in a Diosna high-shear mixer. The resulting granules were mixed with ritonavir (50 parts by weight), lopinavir (200 parts by weight) and colloidal silica (12 parts by weight). The powdery mixture was then fed into a twin-screw extruder (screw diameter 18 mm) at a rate of 2.1 kg/h and a melt temperature of 119° C. The extrudate was fed to a calender with two counter-rotating rollers having mutually matching cavities on their surfaces. Tablets of 1120 mg were thus obtained.
The dose-adjusted AUC in dogs was 10.88 μg·h/ml/100 mg for ritonavir and 51.2 μg·h/ml/100 mg for lopinavir. This example shows that inclusion of a surfactant having an HLB of 4 to 10 into solid solutions of HIV protease inhibitors markedly improves the bioavailability attained.
Example 2 was repeated, however, the extrudate was cut into pieces and allowed to solidify. The extruded pieces were milled to a particle size of about 250 μm, using a high impact universal mill. The milled material was blended in a bin blender with sodium stearyl fumarate (12.3 parts by weight) and colloidal silica (8.0 parts by weight) for 20 min. The powdery blend was compressed on a rotary tablet machine with 3 punches (6500 tablets/h). The tablets were then film-coated in a coating pan by spraying an aqueous dispersion for film coating (Opadry) at a temperature of 60° C.
The dose-adjusted AUC in dogs was 14.24 μg·h/ml/100 mg for ritonavir and 52.2 μg·h/ml/100 mg for lopinavir.
Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 841.3 parts by weight) was blended with Cremophor RH40 (polyoxyethyleneglycerol oxystearate; 36.2 parts by weight), Span 20 (Sorbitan monolaurate; 60.2 parts by weight) in a Diosna high-shear mixer. The resulting granules were mixed with ritonavir (50 parts by weight), lopinavir (200 parts by weight) and colloidal silica (12 parts by weight). The powdery mixture was then fed into a twin-screw extruder (screw diameter 18 mm) at a rate of 2.1 kg/h and a melt temperature of 114° C. The extrudate was fed to a calender with two counter-rotating rollers having mutually matching cavities on their surfaces. Tablets of 1120 mg were thus obtained.
The dose-adjusted AUC in dogs was 10.96 μg·h/ml/100 mg for ritonavir and 46.5 μg·h/ml/100 mg for lopinavir. This example shows that a combination of a surfactant having an HLB of 4 to 10 and a further surfactant can successfully be used.
Example 4 was repeated, however, the extrudate was cut into pieces and allowed to solidify. The extruded pieces were milled to a particle size of about 250 μm, using a high impact universal mill. The milled material was blended in a bin blender with sodium stearylfumarate (13.9 parts by weight), colloidal silica (7.0 parts by weight), isomalt DC100 (159.4 parts by weight) and calcium silicate (7.0 parts by weight) for 20 min. The blend was compressed and film-coated as described in example 1.
The dose-adjusted AUC in dogs was 10.38 μg·h/ml/100 mg for ritonavir and 42.7 μg·h/ml/100 mg for lopinavir.
Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 683.3 parts by weight) was blended with Span 40 (sorbitan monopalmitate; 67.2 parts by weight) in a Diosna high-shear mixer. The resulting granules were mixed with lopinavir (200 parts by weight) and colloidal silica (9.6 parts by weight). The powdery mixture was then fed into a twin-screw extruder (screw diameter 18 mm) at a rate of 2.1 kg/h and a melt temperature of 119° C. The extrudate was cut into pieces and allowed to solidify. The extruded pieces were milled using a high impact universal mill. The milled material was blended in a bin blender with sodium stearylfumarate (7.9 parts by weight), colloidal silica (11.3 parts by weight), isomalt DC100 (129.1 parts by weight) and sodium dodecyl sulfate (15.6 parts by weight). The blend was compressed and film-coated as described in example 1.
Tablets corresponding to 200 mg lopinavir were coadministered to dogs together with 50 mg ritonavir. The dose-adjusted AUC of lopinavir was 38.8 μg·h/ml/100 mg.
Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 151.5 parts by weight) was blended with Cremophor RH40 (24 parts by weight) and PEG 6000 (12 parts by weight) in a Diosna high-shear mixer. The resulting granules were mixed with ritonavir (50 parts by weight) and colloidal silica (2.4 parts by weight). The powdery mixture was then fed into a twin-screw extruder and was melt-extruded. The ex trudate was cut into pieces and allowed to solidify. The extruded pieces were milled using a high impact universal mill. The milled material was blended in a bin blender with colloidal silica (1.4 parts by weight), isomalt DC100 (31.9 parts by weight) and calcium silicate (4.2 parts by weight). The blend was compressed and film-coated as described in example 1.
The dose-adjusted AUC in dogs was 9.98 μg·h/ml/100 mg.
This application is a continuation of U.S. patent application Ser. No. 13/240,119, filed on Sep. 22, 2011, which is a continuation of U.S. patent application Ser. No. 10/925,442, filed on Aug. 25, 2004 and now U.S. Pat. No. 8,025,899, which claims priority from U.S. Provisional Application Ser. No. 60/498,412, filed on Aug. 28, 2003.
Number | Name | Date | Kind |
---|---|---|---|
4540602 | Motoyama et al. | Sep 1985 | A |
4590065 | Piechota, Jr. et al. | May 1986 | A |
4758427 | Leeson | Jul 1988 | A |
4769235 | Schlesinger et al. | Sep 1988 | A |
4769236 | Panoz et al. | Sep 1988 | A |
4801460 | Goertz et al. | Jan 1989 | A |
4804699 | Nelson et al. | Feb 1989 | A |
4806337 | Snipes et al. | Feb 1989 | A |
4851438 | Flashinski | Jul 1989 | A |
4880585 | Klimesch et al. | Nov 1989 | A |
4904699 | Bauer | Feb 1990 | A |
4957681 | Klimesch et al. | Sep 1990 | A |
4996058 | Sinnreich | Feb 1991 | A |
5073379 | Klimesch et al. | Dec 1991 | A |
5145683 | Rhodes | Sep 1992 | A |
5368864 | Lahr et al. | Nov 1994 | A |
5403923 | Kashimura et al. | Apr 1995 | A |
5405616 | Wunderlich et al. | Apr 1995 | A |
5456923 | Nakamichi et al. | Oct 1995 | A |
5476667 | Kristensen et al. | Dec 1995 | A |
5484926 | Dressman et al. | Jan 1996 | A |
5490990 | Grabowski et al. | Feb 1996 | A |
5501858 | Fuisz | Mar 1996 | A |
5525628 | Nicola et al. | Jun 1996 | A |
5541206 | Kempf et al. | Jul 1996 | A |
5545628 | Deboeck et al. | Aug 1996 | A |
5552159 | Mueller et al. | Sep 1996 | A |
5559158 | Al-Razzak et al. | Sep 1996 | A |
5567823 | Tien et al. | Oct 1996 | A |
5585397 | Tung et al. | Dec 1996 | A |
5610193 | Al-Razzak et al. | Mar 1997 | A |
5635523 | Kempf et al. | Jun 1997 | A |
5641516 | Grabowski et al. | Jun 1997 | A |
5648497 | Kempf et al. | Jul 1997 | A |
5654003 | Fuisz et al. | Aug 1997 | A |
5674882 | Kempf et al. | Oct 1997 | A |
5695784 | Pollinger et al. | Dec 1997 | A |
5707648 | Yiv | Jan 1998 | A |
5725878 | Al-Razzak et al. | Mar 1998 | A |
5727878 | Sullivan, Jr. | Mar 1998 | A |
5741519 | Rosenberg et al. | Apr 1998 | A |
5762961 | Roser et al. | Jun 1998 | A |
5773025 | Baichwal | Jun 1998 | A |
5776495 | Duclos et al. | Jul 1998 | A |
5834472 | Sangekar et al. | Nov 1998 | A |
5852195 | Romines et al. | Dec 1998 | A |
5858401 | Bhalani et al. | Jan 1999 | A |
5889051 | Chen et al. | Mar 1999 | A |
5897910 | Rosenberg et al. | Apr 1999 | A |
5914332 | Sham et al. | Jun 1999 | A |
5935936 | Fasbender et al. | Aug 1999 | A |
5939099 | Grabowski et al. | Aug 1999 | A |
5945123 | Hermelin | Aug 1999 | A |
5945127 | Breitenbach et al. | Aug 1999 | A |
5948426 | Jefferies | Sep 1999 | A |
5948436 | Al-Razzak et al. | Sep 1999 | A |
5955475 | Krape et al. | Sep 1999 | A |
5958452 | Oshlack et al. | Sep 1999 | A |
5958455 | Roser et al. | Sep 1999 | A |
5965161 | Oshlack et al. | Oct 1999 | A |
5965163 | Miller et al. | Oct 1999 | A |
5969181 | Breitenbach et al. | Oct 1999 | A |
6001391 | Zeidler et al. | Dec 1999 | A |
6009690 | Rosenberg et al. | Jan 2000 | A |
6027747 | Terracol et al. | Feb 2000 | A |
6037157 | Norbeck et al. | Mar 2000 | A |
6042847 | Kerc et al. | Mar 2000 | A |
6045829 | Liversidge et al. | Apr 2000 | A |
6051253 | Zettler et al. | Apr 2000 | A |
6063821 | Breitenbach et al. | May 2000 | A |
6066334 | Kolter et al. | May 2000 | A |
6071539 | Robinson et al. | Jun 2000 | A |
6083518 | Lindahl | Jul 2000 | A |
6113941 | Takada et al. | Sep 2000 | A |
6120802 | Breitenbach et al. | Sep 2000 | A |
6132659 | Rosenberg et al. | Oct 2000 | A |
6136346 | Eljamal et al. | Oct 2000 | A |
6150424 | Breitenbach et al. | Nov 2000 | A |
6162467 | Miller et al. | Dec 2000 | A |
6187342 | Zeidler et al. | Feb 2001 | B1 |
6197781 | Guitard et al. | Mar 2001 | B1 |
6197787 | Franson et al. | Mar 2001 | B1 |
6207197 | Illum et al. | Mar 2001 | B1 |
6221368 | Breitenbach et al. | Apr 2001 | B1 |
6221399 | Rolfes et al. | Apr 2001 | B1 |
6232333 | Lipari et al. | May 2001 | B1 |
6248363 | Patel et al. | Jun 2001 | B1 |
6248775 | Vazquez et al. | Jun 2001 | B1 |
6251434 | Breitenbach et al. | Jun 2001 | B1 |
6261599 | Oshlack et al. | Jul 2001 | B1 |
6264981 | Zhang et al. | Jul 2001 | B1 |
6268207 | Bailey | Jul 2001 | B1 |
6271307 | Huff et al. | Aug 2001 | B1 |
6274727 | Maul et al. | Aug 2001 | B1 |
6281282 | Breitenbach et al. | Aug 2001 | B1 |
6284270 | Lagoviyer et al. | Sep 2001 | B1 |
6284803 | Kothrade et al. | Sep 2001 | B1 |
6290990 | Grabowski et al. | Sep 2001 | B1 |
6294192 | Patel et al. | Sep 2001 | B1 |
6312726 | Nakamichi et al. | Nov 2001 | B1 |
6318650 | Breitenbach et al. | Nov 2001 | B1 |
6319520 | Wuthrich et al. | Nov 2001 | B1 |
6322816 | Zeidler et al. | Nov 2001 | B1 |
6333048 | Asmussen et al. | Dec 2001 | B1 |
6350398 | Breitenbach et al. | Feb 2002 | B1 |
6372259 | Kumar | Apr 2002 | B1 |
6372905 | Chemburkar et al. | Apr 2002 | B1 |
6379707 | Vladyka, Jr. et al. | Apr 2002 | B2 |
6383471 | Chen et al. | May 2002 | B1 |
6387401 | Rosenberg et al. | May 2002 | B2 |
6391338 | Frisbee et al. | May 2002 | B1 |
6423256 | Kothrade et al. | Jul 2002 | B1 |
6436440 | Meffert et al. | Aug 2002 | B1 |
6440946 | Kiso et al. | Aug 2002 | B1 |
6451339 | Patel et al. | Sep 2002 | B2 |
6462093 | Miyamoto et al. | Oct 2002 | B1 |
6465010 | Lagoviyer et al. | Oct 2002 | B1 |
6465011 | Law et al. | Oct 2002 | B2 |
6488939 | Zeidler et al. | Dec 2002 | B1 |
6488961 | Robinson et al. | Dec 2002 | B1 |
6488963 | McGinity et al. | Dec 2002 | B1 |
6497905 | Vladyka, Jr. et al. | Dec 2002 | B1 |
6511681 | Vladyka, Jr. et al. | Jan 2003 | B2 |
6528089 | Kothrade et al. | Mar 2003 | B1 |
6541030 | Vaghefi | Apr 2003 | B2 |
6541034 | Gergely et al. | Apr 2003 | B1 |
6547997 | Breitenbach et al. | Apr 2003 | B1 |
6569455 | Kanikanti et al. | May 2003 | B1 |
6576255 | Petereit et al. | Jun 2003 | B1 |
6579521 | Sahner | Jun 2003 | B2 |
6599528 | Rosenberg et al. | Jul 2003 | B1 |
6599931 | Breitenbach et al. | Jul 2003 | B1 |
6608198 | Dickman et al. | Aug 2003 | B2 |
6610764 | Martin et al. | Aug 2003 | B1 |
6632389 | Ernst et al. | Oct 2003 | B1 |
6632455 | Sangekar et al. | Oct 2003 | B2 |
6649186 | Robinson et al. | Nov 2003 | B1 |
6669879 | Spengler et al. | Dec 2003 | B1 |
6669883 | Rosenberg et al. | Dec 2003 | B1 |
6677362 | Ghebre-Sellassie et al. | Jan 2004 | B1 |
6692767 | Burnside et al. | Feb 2004 | B2 |
6703403 | Norbeck et al. | Mar 2004 | B2 |
6706281 | Oshlack et al. | Mar 2004 | B2 |
6706283 | Appel et al. | Mar 2004 | B1 |
6713081 | Robinson et al. | Mar 2004 | B2 |
6730319 | Maeder et al. | May 2004 | B2 |
6733781 | Abu-Izza et al. | May 2004 | B2 |
6737005 | Rosenberg et al. | May 2004 | B1 |
6743442 | Oshlack et al. | Jun 2004 | B2 |
6763607 | Beyerinck et al. | Jul 2004 | B2 |
6787157 | Rosenberg et al. | Sep 2004 | B1 |
6805881 | Kanikanti et al. | Oct 2004 | B1 |
6834310 | Munger et al. | Dec 2004 | B2 |
6872336 | Tanno et al. | Mar 2005 | B2 |
6894171 | Bauer et al. | May 2005 | B1 |
6899899 | Takagi et al. | May 2005 | B2 |
6923988 | Patel et al. | Aug 2005 | B2 |
6973741 | Beyerinck et al. | Dec 2005 | B2 |
6982094 | Sowden | Jan 2006 | B2 |
7014810 | Krull et al. | Mar 2006 | B2 |
7022344 | Kothrade et al. | Apr 2006 | B1 |
7122143 | Sowden et al. | Oct 2006 | B2 |
7148359 | Chemburkar et al. | Dec 2006 | B2 |
7229641 | Cherukuri | Jun 2007 | B2 |
7235260 | Crew et al. | Jun 2007 | B2 |
7282218 | Kulkarni et al. | Oct 2007 | B2 |
7297345 | Sowden | Nov 2007 | B2 |
7364752 | Fort et al. | Apr 2008 | B1 |
7407670 | Six et al. | Aug 2008 | B2 |
7413690 | Cheboyina et al. | Aug 2008 | B1 |
7419685 | Kothrade et al. | Sep 2008 | B2 |
7491407 | Pourdeyhimi et al. | Feb 2009 | B2 |
7550158 | Appel et al. | Jun 2009 | B2 |
7645474 | Pathak et al. | Jan 2010 | B1 |
7687071 | Heger et al. | Mar 2010 | B1 |
7727551 | Massironi | Jun 2010 | B2 |
7771632 | Ghebre-Sellassie et al. | Aug 2010 | B2 |
7780988 | Beyerinck et al. | Aug 2010 | B2 |
7785512 | Pathak | Aug 2010 | B1 |
7846477 | Rosenberg et al. | Dec 2010 | B2 |
7867517 | Massironi | Jan 2011 | B2 |
7887840 | Curatolo et al. | Feb 2011 | B2 |
7923026 | Moschwitzer | Apr 2011 | B2 |
7951401 | Colombo et al. | May 2011 | B2 |
7968120 | Li et al. | Jun 2011 | B2 |
7972624 | Li et al. | Jul 2011 | B2 |
20010006650 | Burnside et al. | Jul 2001 | A1 |
20010006677 | McGinity et al. | Jul 2001 | A1 |
20010038852 | Kolter et al. | Nov 2001 | A1 |
20010039551 | Saito et al. | Nov 2001 | A1 |
20010044409 | Ghebre-Sellassie et al. | Nov 2001 | A1 |
20010048946 | Ghebre-Sellassie | Dec 2001 | A1 |
20010051721 | Dickman et al. | Dec 2001 | A1 |
20020001617 | Lee et al. | Jan 2002 | A1 |
20020006443 | Curatolo et al. | Jan 2002 | A1 |
20020009494 | Curatolo et al. | Jan 2002 | A1 |
20020015731 | Appel et al. | Feb 2002 | A1 |
20020031547 | Takagi et al. | Mar 2002 | A1 |
20020044968 | Van Lengerich | Apr 2002 | A1 |
20020102300 | Miller et al. | Aug 2002 | A1 |
20020114833 | Abu-Izza et al. | Aug 2002 | A1 |
20020122825 | Hinrichs et al. | Sep 2002 | A1 |
20020142043 | Kato et al. | Oct 2002 | A1 |
20020160042 | Petereit et al. | Oct 2002 | A1 |
20020161884 | Munger et al. | Oct 2002 | A1 |
20020187188 | Cherukuri | Dec 2002 | A1 |
20020198160 | Everitt et al. | Dec 2002 | A1 |
20030015814 | Krull et al. | Jan 2003 | A1 |
20030021840 | Infeld et al. | Jan 2003 | A1 |
20030021842 | Lagoviyer et al. | Jan 2003 | A1 |
20030039686 | Maeder et al. | Feb 2003 | A1 |
20030054038 | Crew et al. | Mar 2003 | A1 |
20030059468 | Mattern et al. | Mar 2003 | A1 |
20030064108 | Lukas et al. | Apr 2003 | A1 |
20030072801 | Curatolo et al. | Apr 2003 | A1 |
20030086976 | Hayes et al. | May 2003 | A1 |
20030091626 | Katsuta | May 2003 | A1 |
20030091630 | Louie-Helm et al. | May 2003 | A1 |
20030091643 | Friesen et al. | May 2003 | A1 |
20030096791 | Gupte et al. | May 2003 | A1 |
20030099690 | Awamura et al. | May 2003 | A1 |
20030099703 | Aoki | May 2003 | A1 |
20030099708 | Rowe et al. | May 2003 | A1 |
20030104063 | Babcock et al. | Jun 2003 | A1 |
20030104065 | Brodin et al. | Jun 2003 | A1 |
20030104068 | Mathiowitz et al. | Jun 2003 | A1 |
20030109639 | Lippold et al. | Jun 2003 | A1 |
20030129250 | Batycky et al. | Jul 2003 | A1 |
20030133984 | Ambühl et al. | Jul 2003 | A1 |
20030141378 | Raehse et al. | Jul 2003 | A1 |
20030147965 | Bassett et al. | Aug 2003 | A1 |
20030152619 | Stevens et al. | Aug 2003 | A1 |
20030153608 | Maegerlein et al. | Aug 2003 | A1 |
20030161884 | Rosenberg et al. | Aug 2003 | A1 |
20030170309 | Babcock et al. | Sep 2003 | A1 |
20030203027 | Verreck et al. | Oct 2003 | A1 |
20030206947 | Kanikanti et al. | Nov 2003 | A1 |
20030206978 | Sherwood et al. | Nov 2003 | A1 |
20030211168 | Lynenskjold et al. | Nov 2003 | A1 |
20030211197 | Burkle et al. | Nov 2003 | A1 |
20030212102 | Koretke et al. | Nov 2003 | A1 |
20030219489 | Curatolo et al. | Nov 2003 | A1 |
20030224043 | Appel et al. | Dec 2003 | A1 |
20030228358 | Perlman et al. | Dec 2003 | A1 |
20040001888 | Jin | Jan 2004 | A1 |
20040009222 | Chou et al. | Jan 2004 | A1 |
20040013697 | Berndl et al. | Jan 2004 | A1 |
20040013734 | Babcock et al. | Jan 2004 | A1 |
20040013735 | Martin-Letellier et al. | Jan 2004 | A1 |
20040013736 | Nakano et al. | Jan 2004 | A1 |
20040014817 | Rosenberg et al. | Jan 2004 | A1 |
20040024031 | Morissette et al. | Feb 2004 | A1 |
20040029892 | Rosenberg et al. | Feb 2004 | A1 |
20040044196 | Davidson et al. | Mar 2004 | A1 |
20040062778 | Shefer et al. | Apr 2004 | A1 |
20040062802 | Hermelin | Apr 2004 | A1 |
20040067256 | Juppo | Apr 2004 | A1 |
20040076673 | Bateman et al. | Apr 2004 | A1 |
20040081694 | Oshlack et al. | Apr 2004 | A1 |
20040081701 | Erkoboni et al. | Apr 2004 | A1 |
20040086569 | Sparer et al. | May 2004 | A1 |
20040091529 | Edgren et al. | May 2004 | A1 |
20040096499 | Vaya et al. | May 2004 | A1 |
20040104501 | Petereit et al. | Jun 2004 | A1 |
20040110694 | Ghebre-Sellassie et al. | Jun 2004 | A1 |
20040115256 | MacAllister et al. | Jun 2004 | A1 |
20040115273 | Sparer et al. | Jun 2004 | A1 |
20040120927 | Nathan | Jun 2004 | A1 |
20040138231 | Bateman et al. | Jul 2004 | A1 |
20040146550 | Ng et al. | Jul 2004 | A1 |
20040151056 | Omtveit et al. | Aug 2004 | A1 |
20040154317 | Shekunov et al. | Aug 2004 | A1 |
20040156894 | Grother et al. | Aug 2004 | A1 |
20040156905 | Babcock et al. | Aug 2004 | A1 |
20040166153 | McAllister et al. | Aug 2004 | A1 |
20040185112 | Beyerinck et al. | Sep 2004 | A1 |
20040185170 | Chungi et al. | Sep 2004 | A1 |
20040194338 | Beyerinck et al. | Oct 2004 | A1 |
20040197411 | Gao et al. | Oct 2004 | A1 |
20040197414 | Ahola et al. | Oct 2004 | A1 |
20040198645 | Ambuhl et al. | Oct 2004 | A1 |
20040198901 | Graham et al. | Oct 2004 | A1 |
20040219222 | Sjoblom | Nov 2004 | A1 |
20040220081 | Kreitz et al. | Nov 2004 | A1 |
20040228916 | Tanno et al. | Nov 2004 | A1 |
20040234597 | Shefer et al. | Nov 2004 | A1 |
20040234673 | Letavernier et al. | Nov 2004 | A1 |
20040247624 | Unger et al. | Dec 2004 | A1 |
20040247666 | Massironi | Dec 2004 | A1 |
20040247687 | Petereit et al. | Dec 2004 | A1 |
20040253314 | Petereit et al. | Dec 2004 | A1 |
20040258752 | Paruthi et al. | Dec 2004 | A1 |
20040265378 | Peng et al. | Dec 2004 | A1 |
20050003004 | Vehring et al. | Jan 2005 | A1 |
20050008697 | Gorissen | Jan 2005 | A1 |
20050008706 | Holm et al. | Jan 2005 | A1 |
20050013856 | Trivedi et al. | Jan 2005 | A1 |
20050014304 | Moon et al. | Jan 2005 | A1 |
20050025791 | Remenar et al. | Feb 2005 | A1 |
20050031691 | McGurk et al. | Feb 2005 | A1 |
20050031692 | Beyerinck et al. | Feb 2005 | A1 |
20050031693 | Babcock et al. | Feb 2005 | A1 |
20050031696 | Kolhe et al. | Feb 2005 | A1 |
20050042293 | Jackson et al. | Feb 2005 | A1 |
20050048112 | Breitenbach et al. | Mar 2005 | A1 |
20050048116 | Straub et al. | Mar 2005 | A1 |
20050058705 | Remon et al. | Mar 2005 | A1 |
20050058710 | Straub et al. | Mar 2005 | A1 |
20050079138 | Chickering, III et al. | Apr 2005 | A1 |
20050084529 | Rosenberg et al. | Apr 2005 | A1 |
20050089568 | Oshlack et al. | Apr 2005 | A1 |
20050100586 | Sournac et al. | May 2005 | A1 |
20050100598 | Mizumoto et al. | May 2005 | A1 |
20050106257 | Albayrak | May 2005 | A1 |
20050143404 | Rosenberg et al. | Jun 2005 | A1 |
20050158385 | Verreck et al. | Jul 2005 | A1 |
20050158386 | Tanno et al. | Jul 2005 | A1 |
20050163852 | Bresciani et al. | Jul 2005 | A1 |
20050163853 | Szente et al. | Jul 2005 | A1 |
20050169988 | Tao et al. | Aug 2005 | A1 |
20050175687 | McAllister et al. | Aug 2005 | A1 |
20050202090 | Clarke | Sep 2005 | A1 |
20050245483 | Brogmann et al. | Nov 2005 | A1 |
20050281876 | Li et al. | Dec 2005 | A1 |
20060003011 | Crew et al. | Jan 2006 | A1 |
20060003942 | Tung et al. | Jan 2006 | A1 |
20060013869 | Ignatious et al. | Jan 2006 | A1 |
20060029678 | Deghenghi | Feb 2006 | A1 |
20060034887 | Pelissier | Feb 2006 | A1 |
20060051412 | Petereit et al. | Mar 2006 | A1 |
20060073203 | Ljusberg-Wahren et al. | Apr 2006 | A1 |
20060078609 | Vandecruys et al. | Apr 2006 | A1 |
20060115539 | Prasch | Jun 2006 | A1 |
20060134203 | Ambuhl et al. | Jun 2006 | A1 |
20060147538 | Craig et al. | Jul 2006 | A1 |
20060177496 | McAllister et al. | Aug 2006 | A1 |
20060204577 | Crew et al. | Sep 2006 | A1 |
20060216351 | Friesen et al. | Sep 2006 | A1 |
20060251724 | Farrell et al. | Nov 2006 | A1 |
20060257470 | Rosenberg et al. | Nov 2006 | A1 |
20060269608 | Abu Shmeis-Ziadeh et al. | Nov 2006 | A1 |
20060286169 | Leigh et al. | Dec 2006 | A1 |
20070009592 | Remon et al. | Jan 2007 | A1 |
20070014856 | Takagi et al. | Jan 2007 | A1 |
20070031501 | Van Es et al. | Feb 2007 | A1 |
20070042044 | Fischer et al. | Feb 2007 | A1 |
20070053978 | Sherwood et al. | Mar 2007 | A1 |
20070077305 | Le et al. | Apr 2007 | A1 |
20070098795 | Miller et al. | May 2007 | A1 |
20070122482 | Holm et al. | May 2007 | A1 |
20070134336 | Worle et al. | Jun 2007 | A1 |
20070249643 | Rosenberg et al. | Oct 2007 | A1 |
20070249692 | Fort et al. | Oct 2007 | A1 |
20070275058 | Tanaka et al. | Nov 2007 | A1 |
20070287664 | Ralston, II et al. | Dec 2007 | A1 |
20070298116 | Bechtold-Peters et al. | Dec 2007 | A1 |
20080038340 | Kusaki et al. | Feb 2008 | A1 |
20080063708 | Perlman et al. | Mar 2008 | A1 |
20080138419 | Liao et al. | Jun 2008 | A1 |
20080153925 | Pierobon et al. | Jun 2008 | A1 |
20080181948 | Berndl et al. | Jul 2008 | A1 |
20080187612 | Kannar et al. | Aug 2008 | A1 |
20080199516 | McAllister | Aug 2008 | A1 |
20080206349 | Barnwell et al. | Aug 2008 | A1 |
20080206350 | Gryczke | Aug 2008 | A1 |
20080213371 | Jain et al. | Sep 2008 | A1 |
20080234352 | Fischer et al. | Sep 2008 | A1 |
20080241261 | Kolter et al. | Oct 2008 | A1 |
20080248107 | Pilgaonkar et al. | Oct 2008 | A1 |
20080254124 | Bar-Shalom | Oct 2008 | A1 |
20080260814 | Petereit et al. | Oct 2008 | A1 |
20080260835 | Hayes et al. | Oct 2008 | A1 |
20080292707 | Babcock et al. | Nov 2008 | A1 |
20080305168 | Moon et al. | Dec 2008 | A1 |
20080317851 | Appel et al. | Dec 2008 | A1 |
20090011024 | Babcock et al. | Jan 2009 | A1 |
20090017125 | Lynenskjold et al. | Jan 2009 | A1 |
20090036551 | Venkatesh et al. | Feb 2009 | A1 |
20090053317 | Vigo et al. | Feb 2009 | A1 |
20090104269 | Graham et al. | Apr 2009 | A1 |
20090148517 | Oshlack et al. | Jun 2009 | A1 |
20090218731 | Rogasch et al. | Sep 2009 | A1 |
20090258953 | Dobrawa et al. | Oct 2009 | A1 |
20090263479 | Moschwitzer et al. | Oct 2009 | A1 |
20090304795 | Bernigal et al. | Dec 2009 | A1 |
20090324694 | Mohammad | Dec 2009 | A1 |
20100010101 | Cherukuri | Jan 2010 | A1 |
20100062073 | Beyerinck et al. | Mar 2010 | A1 |
20100068268 | Rahmouni et al. | Mar 2010 | A1 |
20100112050 | Ryoo et al. | May 2010 | A1 |
20100137455 | Bouillo et al. | Jun 2010 | A1 |
20100166857 | Yan et al. | Jul 2010 | A1 |
20100172974 | Oshlack et al. | Jul 2010 | A1 |
20100179182 | Shmeis et al. | Jul 2010 | A1 |
20100204259 | Tygesen et al. | Aug 2010 | A1 |
20100204425 | Mertoglu et al. | Aug 2010 | A1 |
20100215753 | Sherwood et al. | Aug 2010 | A1 |
20100222220 | Hanna et al. | Sep 2010 | A1 |
20100247612 | Fuisz | Sep 2010 | A1 |
20100256110 | Babcock et al. | Oct 2010 | A1 |
20110008430 | Rosenberg et al. | Jan 2011 | A1 |
20110015216 | Berndl et al. | Jan 2011 | A1 |
20110020455 | Yoshida et al. | Jan 2011 | A1 |
20110091546 | Tanaka et al. | Apr 2011 | A1 |
20110123652 | Berndl et al. | May 2011 | A1 |
20110217381 | Angus et al. | Sep 2011 | A1 |
20110236443 | Hall et al. | Sep 2011 | A1 |
20110244002 | Shen et al. | Oct 2011 | A1 |
20110250269 | Xu et al. | Oct 2011 | A1 |
20110277339 | Beyerinck et al. | Nov 2011 | A1 |
20110288181 | Koltzenburg et al. | Nov 2011 | A1 |
20110311595 | Berndl et al. | Dec 2011 | A1 |
Number | Date | Country |
---|---|---|
3113893 | Jul 1993 | AU |
1270201 | Jun 1990 | CA |
2227272 | Mar 1997 | CA |
2343234 | Mar 2000 | CA |
2352874 | Jun 2000 | CA |
2367020 | Sep 2000 | CA |
2368625 | Oct 2000 | CA |
2374931 | Jan 2001 | CA |
2408915 | Nov 2002 | CA |
2479749 | Oct 2003 | CA |
2501245 | Apr 2004 | CA |
2568378 | Dec 2005 | CA |
2229650 | Aug 2006 | CA |
973095 | Dec 1959 | DE |
19536387 | Apr 1997 | DE |
19629753 | Jan 1998 | DE |
19637479 | Mar 1998 | DE |
0240904 | Oct 1987 | EP |
0240906 | Oct 1987 | EP |
252886 | Jan 1988 | EP |
0414422 | Feb 1991 | EP |
421581 | Apr 1991 | EP |
421582 | Apr 1991 | EP |
240906 | May 1991 | EP |
0435450 | Jul 1991 | EP |
0272336 | Oct 1991 | EP |
240904 | Jul 1992 | EP |
0570327 | Nov 1993 | EP |
358105 | Mar 1994 | EP |
414422 | Apr 1994 | EP |
732923 | Sep 1996 | EP |
0852140 | Jul 1998 | EP |
864324 | Sep 1998 | EP |
864326 | Sep 1998 | EP |
0942721 | Sep 1999 | EP |
0551820 | Nov 1999 | EP |
988106 | Mar 2000 | EP |
1003485 | May 2000 | EP |
1027886 | Aug 2000 | EP |
1027887 | Aug 2000 | EP |
1070496 | Jan 2001 | EP |
988106 | Aug 2001 | EP |
732923 | Dec 2001 | EP |
1175205 | Jan 2002 | EP |
1227797 | Aug 2002 | EP |
942721 | Jan 2003 | EP |
864324 | Oct 2003 | EP |
852140 | Dec 2003 | EP |
864326 | Jun 2004 | EP |
1227797 | Jan 2005 | EP |
1175205 | Jun 2006 | EP |
2311435 | Apr 2011 | EP |
2011382 | Jul 1979 | GB |
2053681 | Feb 1981 | GB |
2011382 | Aug 1982 | GB |
2173703 | Oct 1986 | GB |
61205208 | Sep 1986 | JP |
61243012 | Oct 1986 | JP |
6048920 | Feb 1994 | JP |
WO8905138 | Jun 1989 | WO |
WO9006115 | Jun 1990 | WO |
WO9118613 | Dec 1991 | WO |
WO9209614 | Jun 1992 | WO |
WO9307859 | Apr 1993 | WO |
WO9311749 | Jun 1993 | WO |
WO9315736 | Aug 1993 | WO |
WO9320138 | Oct 1993 | WO |
WO9507696 | Mar 1995 | WO |
WO9509614 | Apr 1995 | WO |
WO9522319 | Aug 1995 | WO |
WO9600179 | Jan 1996 | WO |
WO9619962 | Jul 1996 | WO |
WO9619963 | Jul 1996 | WO |
WO9623499 | Aug 1996 | WO |
WO9636318 | Nov 1996 | WO |
WO9701349 | Jan 1997 | WO |
WO9706781 | Feb 1997 | WO |
WO9713503 | Apr 1997 | WO |
WO9721685 | Jun 1997 | WO |
WO9734645 | Sep 1997 | WO |
WO9744014 | Nov 1997 | WO |
WO9746222 | Dec 1997 | WO |
WO9807429 | Feb 1998 | WO |
WO9822094 | May 1998 | WO |
WO9822106 | May 1998 | WO |
WO9824430 | Jun 1998 | WO |
WO9938496 | Aug 1999 | WO |
WO9955774 | Nov 1999 | WO |
WO9963841 | Dec 1999 | WO |
WO0000179 | Jan 2000 | WO |
WO0040220 | Jul 2000 | WO |
WO0057854 | Oct 2000 | WO |
WO0074677 | Dec 2000 | WO |
WO0100175 | Jan 2001 | WO |
WO0122938 | Apr 2001 | WO |
WO0123362 | Apr 2001 | WO |
WO0134118 | May 2001 | WO |
WO0134119 | May 2001 | WO |
WO0152821 | Jul 2001 | WO |
WO0191727 | Dec 2001 | WO |
WO0203955 | Jan 2002 | WO |
WO0205788 | Jan 2002 | WO |
WO0220057 | Mar 2002 | WO |
WO0235991 | May 2002 | WO |
WO0238126 | May 2002 | WO |
WO0245696 | Jun 2002 | WO |
WO02089835 | Nov 2002 | WO |
WO02092595 | Nov 2002 | WO |
WO02096395 | Dec 2002 | WO |
WO03006382 | Jan 2003 | WO |
WO03006383 | Jan 2003 | WO |
WO03047551 | Jun 2003 | WO |
WO03063833 | Aug 2003 | WO |
WO03080120 | Oct 2003 | WO |
WO2004032903 | Apr 2004 | WO |
WO2004039349 | May 2004 | WO |
WO2004050068 | Jun 2004 | WO |
WO2004054568 | Jul 2004 | WO |
WO2004062643 | Jul 2004 | WO |
WO2004100930 | Nov 2004 | WO |
WO2004112755 | Dec 2004 | WO |
WO2005004836 | Jan 2005 | WO |
WO2005007070 | Jan 2005 | WO |
WO2005007139 | Jan 2005 | WO |
WO2005035514 | Apr 2005 | WO |
WO2005039551 | May 2005 | WO |
WO2006091529 | Aug 2006 | WO |
WO2007002041 | Jan 2007 | WO |
WO2007050631 | May 2007 | WO |
WO2010017053 | Feb 2010 | WO |
WO2011090724 | Jul 2011 | WO |
WO2011159626 | Dec 2011 | WO |
9608134 | Mar 1998 | ZA |
9608134 | Mar 1998 | ZA |
9708219 | Dec 1999 | ZA |
Number | Date | Country | |
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20120202858 A1 | Aug 2012 | US |
Number | Date | Country | |
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60498412 | Aug 2003 | US |
Number | Date | Country | |
---|---|---|---|
Parent | 13240119 | Sep 2011 | US |
Child | 13449958 | US | |
Parent | 10925442 | Aug 2004 | US |
Child | 13240119 | US |