US20070026073A1 - Amorphous efavirenz and the production thereof - Google Patents

Amorphous efavirenz and the production thereof Download PDF

Info

Publication number
US20070026073A1
US20070026073A1 US11/496,030 US49603006A US2007026073A1 US 20070026073 A1 US20070026073 A1 US 20070026073A1 US 49603006 A US49603006 A US 49603006A US 2007026073 A1 US2007026073 A1 US 2007026073A1
Authority
US
United States
Prior art keywords
efavirenz
composition
solvent
polymer
amorphous
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.)
Abandoned
Application number
US11/496,030
Other languages
English (en)
Inventor
John Doney
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.)
ISP Investments LLC
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to US11/496,030 priority Critical patent/US20070026073A1/en
Assigned to ISP INVESTMENTS INC. reassignment ISP INVESTMENTS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DONEY, JOHN ALFRED
Publication of US20070026073A1 publication Critical patent/US20070026073A1/en
Assigned to THE BANK OF NOVA SCOTIA, AS ADMINISTRATIVE AGENT reassignment THE BANK OF NOVA SCOTIA, AS ADMINISTRATIVE AGENT SECURITY AGREEMENT Assignors: AQUALON COMPANY, ASHLAND LICENSING AND INTELLECTUAL PROPERTY LLC, HERCULES INCORPORATED, ISP INVESTMENT INC.
Assigned to ISP CAPITAL, INC., ISP CHEMICAL PRODUCTS, INC., VERONA, INC. reassignment ISP CAPITAL, INC. PATENT RELEASE Assignors: JPMORGAN CHASE BANK, N.A. (F/K/A THE CHASE MANHATTAN BANK)
Assigned to ASHLAND LICENSING AND INTELLECTUAL PROPERTY LLC, AQUALON COMPANY, HERCULES INCORPORATED, ISP INVESTMENTS INC. reassignment ASHLAND LICENSING AND INTELLECTUAL PROPERTY LLC RELEASE OF PATENT SECURITY AGREEMENT Assignors: THE BANK OF NOVA SCOTIA
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention is directed to compositions containing amorphous efavirenz and methods for producing amorphous efavirenz. More particularly, the present invention relates to compositions and methods for preparing amorphous efavirenz utilizing at least one solubility-enhancing polymer.
  • the efavirenz is dissolved in a solvent containing the polymer.
  • a blend of solvent/non-solvent for the polymer is employed.
  • the amorphous efavirenz product can be produced by any method suitable to the composition. When necessary, solvent can be removed from compositions to yield the amorphous efavirenz product.
  • efavirenz-polymer-solvent (or a solvent/non-solvent blend) is spray dried to produce efavirenz in a form that exhibits improved bioavailability.
  • the bioenhanced efavirenz composition can be prepared by methods other than spray drying as recognized by those skilled in the art. Those methods include, without limitation: melt extrusion, spray congealing, granulation and freeze drying.
  • a significant portion of the efavirenz is provided in the amorphous state.
  • the efavirenz is converted almost entirely to the amorphous state.
  • the efavirenz is converted to the completely amorphous state.
  • Efavirenz is (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. It is a benzoxazinone useful as a non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI) and may be used in combination with other anti-retroviral agents for the treatment of HIV-1 infection in children and adults.
  • NRTI non-nucleoside inhibitor of HIV-1 reverse transcriptase
  • Efavirenz is currently available in dosage forms containing 50 mg, 100 mg, 200 mg, and 600 mg of active. These dosage forms contain efavirenz in microcrystalline form and one or more disintegrants such as croscarmellose sodium to aid in tablet disintegration and dissolution. As described in WO99/64405, crystalline efavirenz exists in several physical forms that can be characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC).
  • PXRD powder X-ray diffraction
  • DSC differential scanning calorimetry
  • efavirenz exhibiting enhanced bioavailability compared to the crystalline form of the compound.
  • aqueous solubility and bioavailability are increased.
  • efavirenz presented as an amorphous solid may facilitate manufacturing of both the active ingredient and the finished product and enable the use of reduced size dosage forms.
  • the selective customization of the properties of particles comprising efavirenz can offer intriguing opportunities for pharmaceutical production and drug delivery.
  • the morphology of individual particles plays a central role in this pursuit, since morphology directly influences bulk powder properties, such as density, residual solvent content, and flowability.
  • techniques that modify particle shape and interior structure may profoundly affect pharmacokinetic properties, such as drug release rate, solubility, and bioavailability.
  • the ability to design particle morphology has significant implications for the production process and product attributes.
  • the present invention provides compositions and methods for producing amorphous efavirenz.
  • a composition comprising a solid dispersion of efavirenz and at least one solubility-enhancing polymer wherein the efavirenz in the dispersion is substantially amorphous is provided in certain embodiments of the present invention.
  • the disclosed invention describes the conversion of crystalline efavirenz to the amorphous state.
  • One method for producing this conversion is through solvent spray drying.
  • Other techniques that accomplish this conversion include, without limitation: flash solvent evaporation, melt-congeal spraying, freeze drying, and melt-extrusion. These methods can use a single solubility-enhancing polymer or blends of polymers.
  • the degree of efavirenz amorphous conversion depends on various factors, including, but not limited to, polymer type and amount and processing conditions.
  • a single organic solvent, blends of solvents, or solvent/non-solvent blends can be used.
  • the invention relates to spray-dried powders or granulated products comprising amorphous efavirenz.
  • the resulting powders produced in accordance with certain embodiments typically possess lower residual solvent content and higher tap density than their counterparts produced by conventional methods, due to a change in the particle morphology and size.
  • a system of polymers can be used to modify not only particle morphology, but also the pharmacokinetic properties of the active.
  • amorphous efavirenz prepared from compositions containing efavirenz and a solubility-enhancing polymer in a solvent or solvent blend.
  • This solvent or solvent blend includes one or more solvents in which the polymer is soluble.
  • soluble means that the attractive force between polymer and solvent molecules is greater than the competing inter- and intramolecular attractive forces between polymer molecules. For simplicity, this solvent is simply called “solvent.”
  • Compositions also are described in which the solvent blend contains a solvent for which the opposite is true: The attractive force between polymer and solvent molecules is less than the inter- and intramolecular attractive force between polymer molecules. This second solvent is termed the “non-solvent.” The polymer may swell but does not dissolve in the non-solvent.
  • a solubility-enhancing polymer and a suitable solvent/non-solvent blend are provided.
  • the solvent possesses a lower boiling point than the non-solvent.
  • the solvent and non-solvent are miscible. The ratio of solvent to non-solvent is such that the polymer can be considered “dissolved” in the solvent system.
  • Unique particle properties can be created by evaporating the solvent/non-solvent blend. For example, this evaporation can occur during the spray drying of the feed solution or granulation processes.
  • Atomized droplets containing a blend of solvents will experience a change in the total solvent composition due to evaporation. The method appears to be independent of how the droplets are generated or atomized. Initially, the polymer exists in a dissolved state, due to a sufficient amount of the solvent. As it evaporates (the solvent boils at a lower temperature than the non-solvent), the concentration of non-solvent in the droplet increases. Eventually, the solvent composition is insufficient to maintain the polymer in solution. In doing so, the polymer collapses from solution. This change in polymer conformation can alter the evaporation dynamics of the droplet to create particle morphologies that influence final powder properties.
  • the primary polymer may be paired with the solvent/non-solvent system in order to affect not only the morphology of the particle, but also that of the efavirenz, and thereby affect the efavirenz loading, crystallinity, solubility, stability and release.
  • additional polymers may contribute to the final particle morphology by their interaction with the first polymer and the solvent system. These additional polymers may also be advantageous to create special release properties of the active.
  • the primary polymer may be paired with the solvent/non-solvent system in order to affect particle morphology, and thereby residual solvent content and bulk powder density.
  • Additional polymeric adjuvants may be added to serve additional purposes: further inhibit active recrystallization, further maximize active concentration, and further enhance/delay/retard dissolution rate. To accomplish these functionalities, it is necessary to suitably match the adjuvant solubilities with the solvent blend selected for the primary polymer.
  • FIG. 1 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #1.
  • FIG. 2 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #1 after storage for 196 days at 20° C. and 40° C.
  • FIG. 3 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #3.
  • FIG. 4 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #3 after storage for 216 days at 20° C. and 40° C.
  • FIG. 5 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #5.
  • FIG. 6 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #5 after storage for 92 days at 20° C. and 40° C.
  • FIGS. 7 A-B are photomicrograph images of particles from Examples #5 and #7.
  • FIG. 8 is a plot of heat flow versus temperature for spray dried samples produced in accordance with Example #8.
  • FIG. 9 is a plot of percent efavirenz released in water as a function of time for spray dried product using solvent and solvent/non-solvent methods in accordance with Example #8.
  • FIG. 10 is a plot of mean plasma concentration-time profiles for efavirenz in male Sprague Dawley rats after an oral dose of 40 mg/kg in accordance with Example #9.
  • solid dispersion refers to a system in a solid state comprising at least two components, wherein one component is dispersed evenly throughout the other component or components.
  • solid dispersion includes systems having small particles either completely crystalline, completely amorphous or any state in between, typically less than about 1 ⁇ m in diameter, of one phase dispersed in another phase.
  • solid solution refers to a type of solid dispersion wherein one component is molecularly dispersed throughout another component such that the system is chemically and physically uniform and homogeneous throughout. These systems do not contain any significant amounts of active ingredients in their crystalline or microcrystalline state as evidenced by thermal analysis or x-ray diffraction.
  • solubility-enhancing polymer refers to a polymer that provides at least one of the following properties as a result of its presence in the composition compared to a control composition without the solubility-enhancing polymer:
  • the present invention is not limited to efavirenz spray-dried compositions.
  • the scope of the invention includes other methods described herein that are also useful in converting efavirenz to the amorphous state and corresponding enhanced bioavailability. Those methods include, without limitation: melt extrusion, spray congealing, granulation and freeze drying.
  • solubility-enhancing polymer(s) includes, but is not limited to: blended, co-mingled, dissolved, extruded, granulated, melted, milled, mixed, sieved, slurried, sprayed, stirred, and the combination of these and other methods. Other techniques may be identified by those skilled in the art.
  • the present invention is related to a method for preparing a spray-dried composition by providing a mixture containing efavirenz and a polymer in a single solvent, a solvent blend or a blend of a solvent and a non-solvent for the polymer and spray drying the mixture to form the spray-dried composition.
  • a polymer system comprising a polymer—called the primary polymer—and a suitable solvent or solvent blend.
  • This approach comprises a solvent in which the polymer is soluble.
  • Equation ⁇ 1 can be written for branched polymers in an analogous manner, using square-average radius of gyration about the center of gravity, s 2 , and the corresponding unperturbed dimension, s o 2 .
  • Polymer solubility is provided when ⁇ is unity or greater, and solvents that satisfy this condition are called “good solvents,” or simply “solvents.” Solvents uncoil (or expand) the polymer molecule, since the polymer-solvent attractive force is greater than that of polymer-polymer.
  • Light scattering methods such light scattering detectors (e.g., Triple Detector Array, Viscotek Corp.), can be used to determine the variables expressed in equation ⁇ 1. These concepts are defined in the text Polymer Chemistry, An Introduction , by Malcolm P. Stevens, which is incorporated by reference.
  • solvents When ⁇ equals unity, a special condition exists in that polymer-solvent and polymer-polymer forces are balanced. Solvents that enable this condition are called ⁇ solvents. Within the context of this invention, solvents are considered “good solvents” when ⁇ is about equal to 1 or more. It is appreciated that temperature influences ⁇ , such that a good solvent may be transformed into a non-solvent merely by changing the temperature.
  • the solvent blend also contains a solvent for which the opposite is true: Polymer-polymer forces dominate polymer-solvent forces. In this case, ⁇ is less than one and the solvent is termed a “non-solvent,” because the polymer exists in a collapsed state.
  • one polymer is provided with a suitable solvent/non-solvent blend.
  • the blend of solvent/non-solvent maintains a solvated state of the polymer, such that the polymer can be considered “dissolved” in the solvent system.
  • the solvent possesses a lower boiling point than the non-solvent. (Solvent/non-solvent pairs that form an azeotrope do not satisfy this criterion.)
  • the solvent and non-solvent are miscible.
  • Unique particle properties can be created by evaporating the solvent/non-solvent blend. For example, this evaporation can occur during the spray drying of the feed solution or granulation processes.
  • Atomized droplets containing a blend of solvents will experience a change in the total solvent composition due to evaporation. The method appears to be independent of how the droplets are generated or atomized. Initially, the polymer exists in a dissolved state, due to a sufficient amount of the solvent. As it evaporates (the solvent boils at a lower temperature than the non-solvent), the concentration of non-solvent in the droplet increases. Eventually, the solvent composition is insufficient to maintain the polymer in solution. In doing so, the polymer collapses and precipitates from solution.
  • polymer/solvent/non-solvent combinations include, without limitation, polyvinylpyrrolidone/dichloromethane/acetone, polyvinylpyrrolidone-co-vinyl acetate/acetone/hexane, and ethylcellulose/acetone/water.
  • the ratio R c for a given system can be determined experimentally by identifying the mass fractions of each component that produce a significant increase in solution turbidity. If an R c value can be identified for a system, then the system comprises a solvent/non-solvent blend.
  • One example is a solution consisting of about 10% (w/w) polyvinylpyrrolidone, 18% (w/w) dichloromethane, and 72% (w/w) acetone, for which R c equals 0.80.
  • Polymer systems will typically be used at solvent/non-solvent blends that are below the R c value for the system. It may be advantageous to formulate more complex polymer/solvent systems in order to control particle morphology/size as well as the crystallinity, solubility, bioavailability and/or release characteristics of the efavrienz.
  • the present invention in accordance with other embodiments provides a method to increase the density of spray-dried powders.
  • spray drying produces sphere-like particles with some degree of interior void. This void increases particle bulk without mass and creates low-density material.
  • Adding a non-solvent to the working solution/dispersion changes the particle size and morphology, leading to an increase in density. Particles may be smaller, wrinkled, dimpled, and/or collapsed compared to those prepared using only solvent.
  • the solvent/non-solvent approach also reduces the mean particle size, allowing the powder to pack better.
  • powder flow and powder-powder mixing properties are enhanced.
  • the present invention in accordance with certain aspects provides a method to reduce or eliminate the need for secondary drying of spray-dried powders and granulated materials. These products often contain residual solvent, and it is desirable or necessary to produce a drier product.
  • a high residual solvent content can result from formulation or processing limitations.
  • the general practice has been to use a solvent that dissolves the solids being spray dried. In doing so, solvent can be trapped inside the spray dried powder or granulated bead due to case hardening.
  • the intentional pairing of a lower-boiling solvent with a higher-boiling non-solvent for the materials being processed can yield products of lower residual solvent due to the effect(s) of the non-solvent on the process polymers.
  • the present invention may further provide a method to enhance the aqueous solubility and modify the release of active ingredients through selection of a polymer system with the solvent or solvent/non-solvent blend.
  • the polymer system is chosen so that one (or more) polymer(s) work with the solvent/non-solvents to create novel particle morphologies. Additional polymer(s) may be added as needed to affect the solubility and release properties of the efavirenz, as well as particle morphology.
  • Enhanced solubility can be achieved by a number of factors, including (but not limited to): improved wettability, creation of amorphous drug forms, stabilization against recrystallization, and/or co-solvation effects.
  • Modified release refers to changing the time frame in which the active is released, i.e., immediate, delay, extended. These modified releases are created by matching functional polymer(s) with the appropriate solvent/non-solvent blend.
  • Solvents and non-solvents suitable for use in the process of the present invention can be any organic compound (including water) in which the primary polymer is soluble in the case of solvents, or insoluble, in the case of non-solvents.
  • the choice and ratio of solvent/non-solvent depends on the choice of the primary polymer. Accordingly, the identification of an organic compound as a solvent or non-solvent depends on the primary polymer. Therefore, a solvent in one system may be a non-solvent in another.
  • solvents and non-solvents include, but are not limited to: acetic acid, acetone, acetonitrile, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, chlorobenzene, chloroform, cumene, cyclohexane, 1-2-dichloroethane, dichloromethane, 1-2-dimethoxyethane, N-N-dimethylacetamide, N-N-dimethylformamide, 1-4-dioxane, ethanol, 2-ethoxyethanol, ethyl acetate, ethylene glycol, ethyl ether, ethyl formate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, methyl acetate, 2-methoxyethanol, 3-methyl-1-butanol, methylbutyl
  • solvent blends at the azeotropic composition can comprise either the solvent or non-solvent, but not the solvent/non-solvent blend.
  • Solubility-enhancing polymers that are suitable for use in the mixtures of the present invention should result in conversion of at least some of the crystalline efavirenz to the amorphous state.
  • at least one polymer should be soluble in the solvent and not soluble in the non-solvent.
  • useful polymers include, but are not limited to: aliphatic polyesters (e.g., poly D-lactide), carbohydrates (e.g., sucrose), carboxyalkylcelluloses (e.g., carboxymethylcellulose), alkylcelluloses (e.g., ethylcellulose), gelatins, hydroxyalkylcelluloses (e.g., hydroxymethylcellulose), hydroxyalkylalkylcelluloses (e.g., hydroxyethylmethyl cellulose), hydroxyalkylalkylcellulose derivatives (e.g.
  • polyamines e.g., chitosan
  • polyethylene glycols e.g., PEG 8000, PEG 20000
  • methacrylic acid polymers and copolymers e.g., Eudragit series of polymers
  • homo- and copolymers of N-vinyl pyrrolidone e.g., polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate
  • homo- and copolymers of vinyllactam starches, polysaccharides (e.g., alginic acid), poly glycols (e.g., propylene glycol, polyethylene glycol), polyvinyl esters (e.g., polyvinyl acetate), and refined/modified shellac.
  • the amount of the polymer present in the mixture may range from about 1% to about 95%, more particularly from about 5% to 90%,
  • the spray-dried mixture includes efavirenz as an active ingredient.
  • the mixture may contain from about 1% to about 95% active, more particularly from about 20% to about 80% active, depending on the desired dose of the active.
  • the weight ratio of efavirenz to polymer typically will be from about 95% efavirenz:5% total polymer to about 5% efavirenz:95% total polymer, more particularly from about 70% efavirenz:30% total polymer to about 30% efavirenz:70% total polymer and in accordance with certain aspects from about 60% efavirenz:40% total polymer to about 40% efavirenz:60% total polymer.
  • compositions of the present invention produces composition wherein at least a portion of efavirenz is in the amorphous state.
  • amorphous refers to a compound in a non-crystalline state. In other words, an amorphous compound lacks long-ranged, defined crystalline structure.
  • at least some, more particularly at least about 10%, at least about 25%, or at least about 40% of the efavirenz in the composition is in an amorphous form.
  • at least a major portion of the compound in the composition is amorphous.
  • the term “a major portion” of the compound means that at least about 50% of the compound in the composition is in the amorphous form, rather than the crystalline form.
  • the compound in the composition may be substantially amorphous.
  • substantially amorphous means that the amount of the compound in the crystalline form does not exceed about 25% (i.e., more than about 75% of the compound is in the amorphous form).
  • the compound in the composition is “almost completely amorphous” meaning that the amount of drug in the crystalline form does not exceed about 10% (i.e., more than about 90% of the compound is in the amorphous form).
  • Compositions are also provided wherein the compound in the composition is considered to be “completely amorphous” meaning that the crystalline form of the drug is not detectable using conventional techniques, such as x-ray diffraction or thermal analysis. Reference to a composition as completely amorphous does not exclude compositions containing trace amounts (less than about 1%) of the crystalline form of the drug.
  • Amorphous materials lack some measurable properties, such as melting endotherms as measured by differential scanning calorimetry that characterize crystalline forms. Amounts of crystalline drug may be measured by powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), or any other standard quantitative analysis. The amounts of crystalline efavirenz present in the composition may be detected by other standard measurement known to those of ordinary skill in the art. It is appreciated that the measurement of such properties may be dependent on instrument type and sensitivity.
  • the spray dried product produced in accordance with the present invention provides enhanced bioavailability of efavirenz compared to products containing the principle crystalline form.
  • the increased bioavailability of the active can also lead to reduced dosage sizes and dose amounts for the active.
  • Applicants have also determined that the rate of drug release can be controlled through proper selection of the polymers added into the solvent solution for processing.
  • the process is spray drying.
  • the spray dried mixture may also contain additional polymeric materials that can modify properties of the composition.
  • additional polymeric materials that can modify properties of the composition.
  • certain polymers can be included to control particle morphology/size as well as the bioavailability and release characteristics of the active ingredient.
  • Additional polymers may also be included in the mixture to further inhibit active recrystallization, further maximize active concentration and further enhance/delay/retard dissolution rate. Additional polymers that can be incorporated into this system are not particularly limited.
  • the mixture to be spray dried typically contains from about 40% to 99.9% by weight total solvent or solvent/non-solvent, more particularly from about 80% to 95% by weight total solvent or solvent/non-solvent based on the total weight of the mixture.
  • the critical ratio R c can vary from about 0.01-0.99, more particularly from about 0.1-0.9, still more particularly from about 0.3-0.8.
  • the mixture to be spray dried may also include other ingredients to improve performance, handling or processing of the mixture.
  • these ingredients also may be admixed into the already-prepared efavirenz-polymer by methods including, but not limited to tumble blending and granulation technologies.
  • Typical ingredients include, but are not limited to, surfactants, pH modifiers, fillers, complexing agents, solubilizer, pigments, lubricants, glidants, flavor agents, plasticizers, taste masking agents, etc., which may be used for customary purposes and in typical amounts.
  • the spray drying apparatus used in the process of the present invention can be any of the various commercially available apparatus.
  • specific spray drying devices include spray dryers manufactured by Niro Inc. (e.g., SD-Micro®, PSD®-1, PSD®-2, etc.), the Mini Spray Dryer (Buchi Labortechnik AG), spray dryers manufactured by Spray Drying Systems, Inc. (e.g., models 30, 48, 72), and SSP Pvt. Ltd.
  • Spray drying processes and spray drying equipment are described generally in Perry's Chemical Engineers' Handbook , Sixth Edition (R. H. Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984, pages 20-54 to 20-57. More details on spray drying processes and equipment are reviewed by Marshall “Atomization and Spray Drying,” 50 Chem. Eng. Prog. Monogr. Series 2 (1954). The contents of these references are hereby incorporated by reference.
  • spray drying is used conventionally and, in general, refers to processes involving breaking up liquid mixtures into small droplets and rapidly removing solvent from the mixture in a container (spray drying apparatus) where there is a strong driving force for evaporation of solvent from the droplets.
  • Atomization techniques include two-fluid and pressure nozzles, and rotary atomizers.
  • the strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of solvent in the spray drying apparatus well below the vapor pressure of the solvent at the temperatures of the drying droplets. This may be accomplished by either (1) maintaining the pressure in the spray drying apparatus at a partial vacuum; (2) mixing the liquid droplets with a warm drying gas; or (3) both.
  • the temperature and flow rate of the drying gas and spray dryer design are chosen so that the polymer/active solution droplets are dry enough by the time they reach the wall of the apparatus that they are essentially solid and so that they form a fine powder and do not stick to the apparatus wall. It is also possible to operate a spray dryer so that product collects on the apparatus wall, and then is collected by removing the material manually, pneumatically, mechanically or other means. The actual length of time to achieve the preferred level of dryness depends on the size of the droplets, the formulation, and spray dryer operation. Following the solidification, the solid powder may stay in the spray drying chamber for 5-60 seconds, further evaporating solvent from the solid powder.
  • the final solvent content of the solid dispersion as it exits the dryer should be low, since this improves the stability of the product.
  • the residual solvent content of the spray-dried composition should be less than about 10% by weight and preferably less than about 2% by weight.
  • the residual solvent content is within the limits set forth in the International Conference on Harmonization (ICH) Guidelines.
  • ICH International Conference on Harmonization
  • Methods to further lower solvent levels include, but are not limited to fluid bed drying, infra-red drying, tumble drying, vacuum drying, and combinations of these and other processes. Additional detail with respect to a particular spray drying process is described in more detail in the examples. However, the operating conditions to spray dry a powder are well known in the art and can be easily adjusted by the skilled artisan. Furthermore, the examples describe results obtained with a laboratory scale spray dryer. One of ordinary skill in the art would readily appreciate the variables that must be modified to obtain similar results with a production scale unit.
  • compositions of the present invention may be prepared by other processes including, but not limited to, extrusion, spheronization and spray congealing.
  • Extrusion is a well-known method of applying pressure to a damp or melted composition until it flows through an orifice or a defined opening.
  • the extrudable length varies with the physical characteristics of the material to be extruded, the method of extrusion, and the process of manipulation of the particles after extrusion.
  • Various types of extrusion devices can be employed, such as screw, sieve and basket, roll, and ram extruders.
  • melt extrusion components can be melted and extruded with a continuous process with or without solvent and with or without inclusion of additives. Such a process is well-established and well-known to skilled practitioners in the art.
  • Spheronization is the process of converting material into spheres, the shape with the lowest surface area to volume ratio. Spheronization typically begins with damp extruded particles. The extruded particles are broken into uniform lengths instantaneously and gradually transformed into spherical shapes. In addition, powdered raw materials, which require addition of either liquid or material from a mixer, can be processed in an air-assisted spheronizer.
  • Spray congealing is a method that is generally used in changing the structure of the materials, to obtain free flowing powders from liquids and to provide pellets ranging in size from about 0.25 to 2.0 mm.
  • Spray congealing involves allowing a substance of interest to melt, disperse, or dissolve in a hot melt of other additives. The molten mixture is then sprayed into an air chamber wherein the temperature is below the melting point of the formulation components, to provide spherical congealed pellets. The temperature of the cooled air used depends on the freezing point of the product. The particles are held together by solid bonds formed from the congealed melts.
  • the particles Due to the absence of solvent evaporation in most spray congealing processes, the particles are generally non porous and strong, and remain intact upon agitation.
  • the characteristics of the final congealed product depend in part on the properties of the additives used.
  • the rate of feeding and inlet/outlet temperatures are adjusted to ensure congealing of the atomized liquid droplet.
  • the feed should have adequate viscosity to ensure homogeneity.
  • the conversion of molten feed into powder is a single, continuous step. Proper atomization and a controlled cooling rate are critical to obtain high surface area, uniform and homogeneous congealed pellets. Adjustment of these parameters is readily achieved by one skilled in the art.
  • the spray congealing method is similar to spray drying, except that solvent is not used. Instead, the active ingredient(s) is dispersed and/or melted into a matrix comprising melt-processable polymer(s). Spray congealing is a uniform and rapid process, and is completed before the product comes in contact with any equipment surface. Most actives and additives that are solid at room temperature and melt without decomposition are suitable for this method.
  • spray dryers operating with cool inlet air have been used for spray congealing.
  • atomization of molten mass can be employed, such as pressure, or pneumatic or centrifugal atomization.
  • pressure or pneumatic or centrifugal atomization.
  • formulation aspects such as matrix materials, viscosity, and processing factors, such as temperature, atomization and cooling rate affect the quality (morphology, particle size distribution, polymorphism and dissolution characteristics) of spray congealed pellets.
  • the spray congealed particles may be used in tablet granulation form, encapsulation form, or can be incorporated into a liquid suspension form.
  • Efavirenz produced in accordance with some embodiments of the invention exhibit enhanced bioavailability when present in solid state forms such as solid solutions or solid dispersions.
  • the efavirenz may be present in such compositions at levels exceeding about 5% by weight, more particularly exceeding about 10%, and in some cases exceeding about 25%, 40%, 50% or even 75% by weight of the composition and still exhibit enhanced bioavailability compared to crystalline forms of the compound.
  • solubility-enhancing polymers function as solubility-enhancing polymers in that the presence of the polymer in the composition improves solubility of the efavirenz under various conditions.
  • the solubility-enhancing polymer provides at least one of the following properties as a result of its presence in the composition compared to a control composition without the solubility-enhancing polymer or to a composition containing the crystalline form of the drug:
  • Initial release refers to the percent of drug released after 15 minutes in accordance with a standard dissolution test method.
  • Extent of release refers to the percent of drug released after 240 minutes in accordance with the same standard dissolution test method.
  • a composition prepared from a system comprising a polymer and amorphous efavirenz spray dried from a solvent/non-solvent system as described herein exhibits a dissolution profile wherein the percent active released at some point in time is at least about 25%, more particularly at least about 50% and in certain cases at least about 100% greater than a control composition prepared from a system comprising the same polymer and efavirenz spray dried under similar conditions from the same solvent without the non-solvent.
  • these limits are obtained within about 120 minutes, more particularly within about 60 minutes and still more particularly within about 30 minutes.
  • Dissolution profiles can be determined using USP apparatus II (paddles) (VK 7010®, Varian Inc.), with a bath temperature of 37° C. and a paddle speed of 100 rpm for 240 minutes.
  • a composition prepared from a system comprising a polymer and an efavirenz spray dried from a solvent/non-solvent system as described herein exhibits an increase in bulk density or tap density wherein the density is at least about 25%, more particularly at least about 50% and in certain cases at least about 100% greater than a control composition prepared from a system comprising the same polymer and efavirenz spray dried under similar conditions from the same solvent without the non-solvent.
  • Efavirenz compositions prepared from a solvent/non-solvent system typically result in reduced particle size.
  • a composition prepared from a system comprising a polymer and an efavirenz spray dried from a solvent/non-solvent system as described herein results in a reduction of particle size on the order of at least about 50%, more particularly at least about 100% and in certain cases at least about 300% compared to a control composition prepared from a system comprising the same polymer and efavirenz spray dried under similar conditions from the same solvent without the non-solvent.
  • compositions of the present invention may be delivered by a wide variety of routes, including, but not limited to: buccal, dermal, intravenous, nasal, oral, pulmonary, rectal, subcutaneous, sublingual, and vaginal. Generally, the oral route is preferred.
  • compositions of the invention may be presented in a numerous forms.
  • Exemplary presentation forms are powders, granules, and multiparticulates. These forms may be added directly to capsules; compressed to produce tablets, capsules, or pills; or reconstituted by addition of water or other liquids to form a paste, slurry, ointment, suspension or solution.
  • Various additives may be mixed, ground, or granulated with the compositions of this invention to form a material suitable for the above dosage forms.
  • compositions of the invention may be formulated in various forms so that they are delivered as a suspension of particles in a liquid vehicle.
  • Such suspensions may be formulated as a liquid or as a paste at the time of manufacture, or they may be formulated as a dry powder with a liquid, typically water, added at a later time but prior to oral administration.
  • Such powders that are constituted into a suspension are often referred to as sachets or oral powders for constitution (OPC).
  • Such dosage forms can be formulated and reconstituted via any known procedure.
  • solid-dose pharmaceutical spray dried powders typically have a mean particle size of about 0.5 ⁇ m-500 ⁇ m and are generally prepared from solutions at concentrations of 1% or more total solids, more particularly from about 2%-50%, and still more particularly from about 3%-30% solids.
  • solid dose pharmaceutical granules typically have a mean particle size of about 50 ⁇ m-5000 ⁇ m.
  • Techniques to produce granules include, but are not limited to, wet granulation and various fluid bed granulating methods.
  • compositions comprising the efavirenz of enhanced bioavailability described herein may be prepared in accordance with conventional techniques.
  • a pharmaceutical dosage form comprising efavirenz and a disintegrant.
  • the disintegrant used in the composition is preferably of the so-called superdisintegrant type, disintegrants of this type being well-known to the person skilled in the art.
  • these disintegrants the following can be mentioned: cross-linked polyvinylpyrrolidones, particularly crospovidone, modified starches, particularly sodium starch glycolate, modified celluloses, particularly croscarmellose sodium (cross-linked sodium carboxymethylcellulose) and LHPC (low-substituted hydroxypropylcellulose).
  • the disintegrant or superdisintegrant may be present in an amount of from about 2% to about 90%, preferably from about 3% to 60% of the composition.
  • the efavirenz product of these compositions and produced by the methods described herein may be administered to man or animal.
  • the compositions described herein may be administered as pharmaceutical compositions.
  • the efavirenz composition may be administered in a therapeutically effective amount to a human or animal in need of such treatment.
  • therapeutically effective amount refers to an amount of a pharmaceutical ingredient that is effective to treat, prevent or alleviate the symptoms of a disease.
  • the pharmaceutical compositions of the present invention may be used alone or in combination with other anti-retroviral agents to treat a variety of diseases such as, but not limited to, the treatment of HIV-1 infection in children and adults.
  • compositions of the current invention may include additional active ingredients to the efavirenz.
  • Additional active pharmaceutical ingredients include, but are not limited to: analgesics, anti-arrhythmics, anti-bacterials, anti-convulsants, anti-Alzheimer's agents, anti-diabetics, anti-emetics, anti-fungals, anti-histiminics, anti-hyperlipidemics, anti-hyperlipoproteinemics, anti-hypertensives, anti-inflamatory agents, anti-Parkinsonian agents, anti-pulmonary hypertensives, anti-rheumatics, anti-ulceratives, anti-virals, cardiovascular agents, chemotherapy agents, central nervous system sedatives and stimulants, diuretics, gastrointestinal agents, hormones, respiratory agents, skin agents, as well as actives for the treatment of acne, benign prostatic hypertrophy, irritable bowel syndrome.
  • Efavirenz was spray dried with PVP (Plasdone® K-29/32, ISP) in the ratio 1 efavirenz:3 PVP with 2% sodium lauryl sulfate (dry weight basis) from two solutions.
  • PVP Plasdone® K-29/32, ISP
  • formula solvent composition 8a 100% solvent 8b 20% non-solvent, 80% solvent

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Cardiology (AREA)
  • AIDS & HIV (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Glanulating (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Vaporization, Distillation, Condensation, Sublimation, And Cold Traps (AREA)
US11/496,030 2005-07-28 2006-07-28 Amorphous efavirenz and the production thereof Abandoned US20070026073A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/496,030 US20070026073A1 (en) 2005-07-28 2006-07-28 Amorphous efavirenz and the production thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70337405P 2005-07-28 2005-07-28
US11/496,030 US20070026073A1 (en) 2005-07-28 2006-07-28 Amorphous efavirenz and the production thereof

Publications (1)

Publication Number Publication Date
US20070026073A1 true US20070026073A1 (en) 2007-02-01

Family

ID=37450928

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/496,030 Abandoned US20070026073A1 (en) 2005-07-28 2006-07-28 Amorphous efavirenz and the production thereof
US11/495,993 Active 2033-01-05 US10532028B2 (en) 2005-07-28 2006-07-28 Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/495,993 Active 2033-01-05 US10532028B2 (en) 2005-07-28 2006-07-28 Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced

Country Status (6)

Country Link
US (2) US20070026073A1 (ja)
EP (2) EP1909762A2 (ja)
JP (2) JP2009502969A (ja)
CN (3) CN101272769B (ja)
BR (1) BRPI0614455A2 (ja)
WO (2) WO2007016435A2 (ja)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080085315A1 (en) * 2006-10-10 2008-04-10 John Alfred Doney Amorphous ezetimibe and the production thereof
US20100081628A1 (en) * 2008-06-11 2010-04-01 Pharmasset, Inc. Nucleoside cyclicphosphates
WO2010075517A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
WO2010075554A1 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Synthesis of purine nucleosides
WO2010075549A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside phosphoramidates
WO2010135569A1 (en) 2009-05-20 2010-11-25 Pharmasset, Inc. N- [ (2 ' r) -2 ' -deoxy-2 ' -fluoro-2 ' -methyl-p-phenyl-5 ' -uridylyl] -l-alanine 1-methylethyl ester and process for its production
WO2011123645A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Nucleoside phosphoramidates
WO2011123672A1 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Purine nucleoside phosphoramidate
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
WO2014081581A2 (en) * 2012-11-08 2014-05-30 Isp Investments Inc. Highly loaded amorphous efavirenz composition and process for preparing the same
US20180297945A1 (en) * 2013-08-29 2018-10-18 Cadila Healthcare Limited Polymorphic form of pyrrole derivative and intermediate thereof
CN114404377A (zh) * 2022-01-10 2022-04-29 安徽贝克生物制药有限公司 一种阿巴卡韦、拉米夫定、依非韦伦复方片及其制备方法

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY169670A (en) 2003-09-03 2019-05-08 Tibotec Pharm Ltd Combinations of a pyrimidine containing nnrti with rt inhibitors
US8293819B2 (en) * 2006-11-24 2012-10-23 Canon Kabushiki Kaisha Method for producing particles and particles
US20080152717A1 (en) * 2006-12-14 2008-06-26 Isp Investments, Inc. Amorphous valsartan and the production thereof
AR065720A1 (es) * 2007-03-14 2009-06-24 Tibotec Pharm Ltd Polvos para reconstitucion que comprenden rilpivirina dispersos en ciertos polimeros. uso. proceso.
ITMI20071502A1 (it) * 2007-07-25 2009-01-26 Archimica Srl Procedimento per la preparazione di formulazioni solide a rilascio controllato contenenti oxcarbazepina e formulazioni ottenibili con tale procedimento
ITMI20080807A1 (it) 2008-05-05 2009-11-06 Antibioticos Spa Procedimento per la preparazione di tigeciclina in forma amorfa
CN102164576B (zh) * 2008-09-25 2013-08-28 Isp投资公司 光滑的高固体含量片剂包衣组合物
US11458105B2 (en) * 2008-12-04 2022-10-04 International Flavors & Fragrances Inc. Hybrid fragrance encapsulate formulation and method for using the same
KR101906177B1 (ko) * 2008-12-10 2018-10-10 시플라 리미티드 리팍시민 복합체
EP2343056A1 (en) * 2009-12-30 2011-07-13 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Producing stable adefovir dipivoxil solid dispersions
JP2011153119A (ja) * 2010-01-27 2011-08-11 Mylan Seiyaku Ltd バンコマイシンまたはその塩を含有する錠剤
WO2012063498A2 (ja) * 2010-11-12 2012-05-18 富士化学工業株式会社 新規なエキセメスタン固体分散体
EA027791B1 (ru) 2010-11-24 2017-09-29 Мелинта Терапьютикс, Инк. Фармацевтические композиции
CN103429228B (zh) 2011-01-05 2016-10-26 赫士睿股份有限公司 万古霉素的喷雾干燥
GB201115633D0 (en) * 2011-09-09 2011-10-26 Univ Liverpool Compositions of efavirenz
WO2014043208A1 (en) 2012-09-11 2014-03-20 Medivation Prostate Therapeutics, Inc. Formulations of enzalutamide
CN104043104B (zh) 2013-03-15 2018-07-10 浙江创新生物有限公司 含盐酸万古霉素的喷雾干粉及其工业化制备方法
CN104119209B (zh) * 2013-04-25 2018-03-02 浙江医药股份有限公司新昌制药厂 一种还原型辅酶q10干粉及其组合物以及制备方法
CA2929499C (en) * 2013-11-22 2019-01-08 Merck Sharp & Dohme Corp. Composition of a non-nucleoside reverse transcriptase inhibitor
TR201809617T4 (tr) * 2013-12-04 2018-07-23 Hovione Scientia Ltd Tat maskeleme formülasyonları içeren kontrast ortamlar.
PT107568B (pt) * 2014-03-31 2018-11-05 Hovione Farm S A Processo de secagem por atomização para a produção de pós com propriedades melhoradas.
CN105853482A (zh) * 2015-01-21 2016-08-17 熊慧 人参总次苷在制备治疗和/或预防心肌缺血后脂质代谢异常的药物中的应用
EP3103440A1 (en) 2015-06-12 2016-12-14 INDENA S.p.A. Solid dispersions of coenzyme q10
WO2018148230A1 (en) * 2017-02-09 2018-08-16 Med-El Elektromedizinische Geraete Gmbh Implantable electrode with dexamethasone coating
CN110267706B (zh) * 2017-02-09 2023-06-20 Med-El电气医疗器械有限公司 与电极载体一起使用的地塞米松涂层
WO2020002595A1 (en) * 2018-06-29 2020-01-02 Dsm Ip Assets B.V. Fast release benzoic acid in feed
WO2024092404A1 (zh) * 2022-10-31 2024-05-10 南京百正生物医药有限公司 哌拉西林他唑巴坦喷雾干燥粉末的工业化生产方法

Citations (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3981676A (en) * 1970-03-03 1976-09-21 L'oreal Lyophilized dyes and the use thereof to color keratinic fibers
US4572915A (en) * 1984-05-01 1986-02-25 Bioglan Laboratories Clear micellized solutions of fat soluble essential nutrients
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US4956386A (en) * 1980-04-25 1990-09-11 Gist-Brocades N.V. Pharmaceutical compositions and process for their preparation
US5340591A (en) * 1992-01-24 1994-08-23 Fujisawa Pharmaceutical Co., Ltd. Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine
US5443842A (en) * 1993-03-30 1995-08-22 Inverni Della Beffa Farmaceutici S.R.L. Oral formulations of ubidecarenone in form of capsules
US5519021A (en) * 1992-08-07 1996-05-21 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5871775A (en) * 1996-09-27 1999-02-16 Valpharma S.A. Controlled release pharmaceutical compositions for the oral administration containing nifedipine as active substance
US5989583A (en) * 1996-04-02 1999-11-23 Pharmos Ltd. Solid lipid compositions of lipophilic compounds for enhanced oral bioavailability
US6056971A (en) * 1996-07-24 2000-05-02 Biosytes Usa, Inc. Method for enhancing dissolution properties of relatively insoluble dietary supplements and product incorporating same
US6143211A (en) * 1995-07-21 2000-11-07 Brown University Foundation Process for preparing microparticles through phase inversion phenomena
US6184255B1 (en) * 1996-08-16 2001-02-06 Kaneka Corporation Pharmaceutical composition comprising coenzyme Q10
US6197349B1 (en) * 1993-08-12 2001-03-06 Knoll Aktiengesellschaft Particles with modified physicochemical properties, their preparation and uses
US6221398B1 (en) * 1995-04-13 2001-04-24 Astra Aktiebolag Process for the preparation of respirable particles
US6300377B1 (en) * 2001-02-22 2001-10-09 Raj K. Chopra Coenzyme Q products exhibiting high dissolution qualities
US20020006443A1 (en) * 1999-12-23 2002-01-17 Curatolo William J. Pharmaceutical compositions providing enhanced drug concentrations
US20020009494A1 (en) * 1997-08-11 2002-01-24 Curatolo William J. Solid pharmaceutical dispersions with enhanced bioavailability
US6403116B1 (en) * 2000-11-03 2002-06-11 Triarco Inductries, Inc. Coenzyme Q10 formulation
US20020142050A1 (en) * 1999-05-27 2002-10-03 Acusphere Inc. Porous drug matrices and methods of manufacture thereof
US6462093B1 (en) * 1995-08-11 2002-10-08 Nissan Chemical Industries, Ltd. Method for converting sparingly water-soluble medical substance to amorphous state
US20030049321A1 (en) * 1999-08-19 2003-03-13 Dominique Begon Process for producing fine medicinal substances
US6548555B1 (en) * 1999-02-09 2003-04-15 Pfizer Inc Basic drug compositions with enhanced bioavailability
US6555133B2 (en) * 1998-04-07 2003-04-29 Bristol-Myers Squibb Company Formulation of fast-dissolving efavirenz capsules or tablets using super-disintegrants
US20030091643A1 (en) * 2001-06-22 2003-05-15 Friesen Dwayne T. Pharmaceutical compositions of dispersions of drugs and neutral polymers
US20030104063A1 (en) * 2001-06-22 2003-06-05 Babcock Walter C. Pharmaceutical compositions of dispersions of amorphous drugs mixed with polymers
US6579521B2 (en) * 2000-10-20 2003-06-17 Chiron Corporation Methods of therapy for HIV infection
US6582729B1 (en) * 1995-04-14 2003-06-24 Naktar Therapeutics Powered pharmaceutical formulations having improved dispersibility
US20030147965A1 (en) * 2001-12-10 2003-08-07 Spherics, Inc. Methods and products useful in the formation and isolation of microparticles
US20030157182A1 (en) * 2000-04-05 2003-08-21 Staniforth John Nicholas Pharmaceutical preparations and their manufacture
US20030170309A1 (en) * 2001-06-22 2003-09-11 Babcock Walter C. Pharmaceutical compositions containing polymer and drug assemblies
US20030224043A1 (en) * 2002-02-01 2003-12-04 Pfizer Inc. Immediate release dosage forms containing solid drug dispersions
US20040013734A1 (en) * 1999-02-10 2004-01-22 Pfizer Inc. Pharmaceutical solid dispersions
US6689755B1 (en) * 1997-11-03 2004-02-10 Boehringer Mannheim Gmbh Method of stabilizing biologically active substances
US6723359B2 (en) * 2001-10-18 2004-04-20 Firmenich Sa Spray-dried compositions and method for their preparation
US6740338B1 (en) * 2000-01-20 2004-05-25 Raj K. Chopra Reduced form of Cenzyme Q in high bioavailability stable oral dosage form
US6746635B2 (en) * 2001-08-08 2004-06-08 Brown University Research Foundation Methods for micronization of hydrophobic drugs
US6763607B2 (en) * 2002-02-01 2004-07-20 Pfizer Inc. Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus
US20040175428A1 (en) * 1999-02-10 2004-09-09 Pfizer Inc. Controlled release by extrusion of solid amorphous dispersions of drugs
US20050002870A1 (en) * 1998-09-03 2005-01-06 Quadrant Healthcare (Uk) Limited Microparticles
US20050031692A1 (en) * 2003-08-04 2005-02-10 Pfizer Inc Spray drying processes for forming solid amorphous dispersions of drugs and polymers
US20050079138A1 (en) * 2002-12-19 2005-04-14 Chickering Donald E. Methods for making pharmaceutical formulations comprising microparticles with improved dispersibility, suspendability or wettability
US20050133949A1 (en) * 2003-12-19 2005-06-23 Pragtech, Inc. Polymer solidification and coating process
US20050139144A1 (en) * 2002-03-27 2005-06-30 Muller Bernd W. Method for the production and the use of microparticles and nanoparticles by constructive micronisation
US20050143404A1 (en) * 2003-08-28 2005-06-30 Joerg Rosenberg Solid pharmaceutical dosage formulation
US6923988B2 (en) * 1999-11-23 2005-08-02 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20050169988A1 (en) * 2001-08-03 2005-08-04 Shaklee Corporation High molecular weight, lipophilic, orally ingestible bioactive agents in formulations having improved bioavailability
US20050170002A1 (en) * 2000-12-22 2005-08-04 Kipp James E. Method for preparing submicron particle suspensions
US20050170000A1 (en) * 2003-05-08 2005-08-04 Walker Stephen E. Particulate materials

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT251459B (de) * 1962-08-13 1967-01-10 Du Pont Verfahren zur Herstellung von brisanten, organischen Sprengstoffen in feinkristalliner Form
GB1201171A (en) * 1967-03-28 1970-08-05 Atomic Energy Authority Uk Improvements in or relating to the production of fine powders
DE2223896A1 (de) * 1972-05-17 1973-11-29 Sanol Arznei Schwarz Gmbh Verfahren zum ueberziehen von feinteiligen arzneimitteln
JPS5313346B2 (ja) * 1974-03-20 1978-05-09
JPS5836628A (ja) * 1981-08-26 1983-03-03 Ngk Spark Plug Co Ltd 無機質粉体の造粒方法
WO1995024929A2 (en) * 1994-03-15 1995-09-21 Brown University Research Foundation Polymeric gene delivery system
US5958458A (en) * 1994-06-15 1999-09-28 Dumex-Alpharma A/S Pharmaceutical multiple unit particulate formulation in the form of coated cores
WO1997013503A1 (en) 1995-10-13 1997-04-17 The Penn State Research Foundation Synthesis of drug nanoparticles by spray drying
EP1058539A1 (en) 1999-01-06 2000-12-13 Korea Research Institute Of Chemical Technology Method of preparing pharmaceutical active ingredient comprising water-insoluble drug and pharmaceutical composition for oral administration comprising the same
US20020045668A1 (en) * 2000-07-17 2002-04-18 Wenbin Dang Compositions for sustained release of analgesic agents, and methods of making and using the same
IL157955A0 (en) * 2001-04-02 2004-03-28 Astrazeneca Ab Solid pharmaceutical composition comprising 4-cyano-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m toluidide and pvp
KR100463167B1 (ko) 2001-04-13 2004-12-23 주식회사 태평양 고분자 나노입자를 이용한 경피흡수제 및 이를 함유한외용제 조성물
SE0103838D0 (sv) * 2001-11-16 2001-11-16 Astrazeneca Ab Pharmaceutical formulation & product
WO2003045327A2 (en) * 2001-11-27 2003-06-05 Bristol-Myers Squibb Company Efavirenz tablet formulation having unique biopharmaceutical characteristics
BR0307515A (pt) 2002-02-01 2004-12-07 Pfizer Prod Inc Método para fabricar dispersões de drogas amorfas sólidas secas por aspersão homogêneas usando bicos de pressão
US20050142123A1 (en) * 2002-02-14 2005-06-30 Chyi-Cheng Chen Water-dispersible coenzyme q10 dry powders
WO2004098570A1 (en) * 2002-10-30 2004-11-18 Spherics, Inc. Nanoparticulate bioactive agents
MXPA05012821A (es) 2003-05-28 2006-02-13 Nektar Therapeutics Formulacion farmaceutica que comprende un agente activo insoluble en agua.
US20050096365A1 (en) 2003-11-03 2005-05-05 David Fikstad Pharmaceutical compositions with synchronized solubilizer release
US20080145427A1 (en) 2005-02-03 2008-06-19 Alfred Berchielli Dosage Forms Providing Controlled and Immediate Release of Cholesteryl Ester Transfer Protein Inhibitors and Immediate Release of Hmg-Coa Reductase Inhibitors
DE102005026755A1 (de) * 2005-06-09 2006-12-14 Basf Ag Herstellung von festen Lösungen schwerlöslicher Wirkstoffe durch Kurzzeitüberhitzung und schnelle Trocknung
WO2006134610A1 (en) 2005-06-16 2006-12-21 Hetero Drugs Limited Efavirenz pharmaceutical composition having enhanced dissolution profile
CN101217981A (zh) * 2005-07-05 2008-07-09 阿伯特有限及两合公司 包含固体或半固体基质的组合物和剂型
DK1912626T3 (en) * 2005-08-08 2016-08-01 Abbvie Deutschland Dosage forms with improved bioavailability
PL1978936T3 (pl) * 2006-02-03 2013-11-29 Evonik Roehm Gmbh Kompozycje farmaceutyczne zawierające mieszaniny polimerów i trudno rozpuszczalnych w wodzie substancji czynnych
EP2010162A4 (en) * 2006-04-03 2013-01-09 Isa Odidi COMPOSITION FOR DISPOSING A MEDICINAL PRODUCT

Patent Citations (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3981676A (en) * 1970-03-03 1976-09-21 L'oreal Lyophilized dyes and the use thereof to color keratinic fibers
US4956386A (en) * 1980-04-25 1990-09-11 Gist-Brocades N.V. Pharmaceutical compositions and process for their preparation
US4572915A (en) * 1984-05-01 1986-02-25 Bioglan Laboratories Clear micellized solutions of fat soluble essential nutrients
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US5340591A (en) * 1992-01-24 1994-08-23 Fujisawa Pharmaceutical Co., Ltd. Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine
US5665720A (en) * 1992-08-07 1997-09-09 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5519021A (en) * 1992-08-07 1996-05-21 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5663169A (en) * 1992-08-07 1997-09-02 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5811423A (en) * 1992-08-07 1998-09-22 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5443842A (en) * 1993-03-30 1995-08-22 Inverni Della Beffa Farmaceutici S.R.L. Oral formulations of ubidecarenone in form of capsules
US6197349B1 (en) * 1993-08-12 2001-03-06 Knoll Aktiengesellschaft Particles with modified physicochemical properties, their preparation and uses
US6221398B1 (en) * 1995-04-13 2001-04-24 Astra Aktiebolag Process for the preparation of respirable particles
US6582729B1 (en) * 1995-04-14 2003-06-24 Naktar Therapeutics Powered pharmaceutical formulations having improved dispersibility
US6143211A (en) * 1995-07-21 2000-11-07 Brown University Foundation Process for preparing microparticles through phase inversion phenomena
US6462093B1 (en) * 1995-08-11 2002-10-08 Nissan Chemical Industries, Ltd. Method for converting sparingly water-soluble medical substance to amorphous state
US5989583A (en) * 1996-04-02 1999-11-23 Pharmos Ltd. Solid lipid compositions of lipophilic compounds for enhanced oral bioavailability
US6056971A (en) * 1996-07-24 2000-05-02 Biosytes Usa, Inc. Method for enhancing dissolution properties of relatively insoluble dietary supplements and product incorporating same
US6184255B1 (en) * 1996-08-16 2001-02-06 Kaneka Corporation Pharmaceutical composition comprising coenzyme Q10
US5871775A (en) * 1996-09-27 1999-02-16 Valpharma S.A. Controlled release pharmaceutical compositions for the oral administration containing nifedipine as active substance
US20020009494A1 (en) * 1997-08-11 2002-01-24 Curatolo William J. Solid pharmaceutical dispersions with enhanced bioavailability
US6689755B1 (en) * 1997-11-03 2004-02-10 Boehringer Mannheim Gmbh Method of stabilizing biologically active substances
US6555133B2 (en) * 1998-04-07 2003-04-29 Bristol-Myers Squibb Company Formulation of fast-dissolving efavirenz capsules or tablets using super-disintegrants
US20050002870A1 (en) * 1998-09-03 2005-01-06 Quadrant Healthcare (Uk) Limited Microparticles
US6548555B1 (en) * 1999-02-09 2003-04-15 Pfizer Inc Basic drug compositions with enhanced bioavailability
US20050049223A1 (en) * 1999-02-09 2005-03-03 Curatolo William J. Basic drug compositions with enhanced bioavailability
US20040013734A1 (en) * 1999-02-10 2004-01-22 Pfizer Inc. Pharmaceutical solid dispersions
US20040175428A1 (en) * 1999-02-10 2004-09-09 Pfizer Inc. Controlled release by extrusion of solid amorphous dispersions of drugs
US20020142050A1 (en) * 1999-05-27 2002-10-03 Acusphere Inc. Porous drug matrices and methods of manufacture thereof
US20030049321A1 (en) * 1999-08-19 2003-03-13 Dominique Begon Process for producing fine medicinal substances
US6923988B2 (en) * 1999-11-23 2005-08-02 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20020006443A1 (en) * 1999-12-23 2002-01-17 Curatolo William J. Pharmaceutical compositions providing enhanced drug concentrations
US6740338B1 (en) * 2000-01-20 2004-05-25 Raj K. Chopra Reduced form of Cenzyme Q in high bioavailability stable oral dosage form
US20030157182A1 (en) * 2000-04-05 2003-08-21 Staniforth John Nicholas Pharmaceutical preparations and their manufacture
US6579521B2 (en) * 2000-10-20 2003-06-17 Chiron Corporation Methods of therapy for HIV infection
US6403116B1 (en) * 2000-11-03 2002-06-11 Triarco Inductries, Inc. Coenzyme Q10 formulation
US20050170002A1 (en) * 2000-12-22 2005-08-04 Kipp James E. Method for preparing submicron particle suspensions
US6300377B1 (en) * 2001-02-22 2001-10-09 Raj K. Chopra Coenzyme Q products exhibiting high dissolution qualities
US20030091643A1 (en) * 2001-06-22 2003-05-15 Friesen Dwayne T. Pharmaceutical compositions of dispersions of drugs and neutral polymers
US20030170309A1 (en) * 2001-06-22 2003-09-11 Babcock Walter C. Pharmaceutical compositions containing polymer and drug assemblies
US20030104063A1 (en) * 2001-06-22 2003-06-05 Babcock Walter C. Pharmaceutical compositions of dispersions of amorphous drugs mixed with polymers
US20050169988A1 (en) * 2001-08-03 2005-08-04 Shaklee Corporation High molecular weight, lipophilic, orally ingestible bioactive agents in formulations having improved bioavailability
US6746635B2 (en) * 2001-08-08 2004-06-08 Brown University Research Foundation Methods for micronization of hydrophobic drugs
US6723359B2 (en) * 2001-10-18 2004-04-20 Firmenich Sa Spray-dried compositions and method for their preparation
US20030147965A1 (en) * 2001-12-10 2003-08-07 Spherics, Inc. Methods and products useful in the formation and isolation of microparticles
US20030224043A1 (en) * 2002-02-01 2003-12-04 Pfizer Inc. Immediate release dosage forms containing solid drug dispersions
US20040194338A1 (en) * 2002-02-01 2004-10-07 Pfizer Inc Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus
US6763607B2 (en) * 2002-02-01 2004-07-20 Pfizer Inc. Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus
US6973741B2 (en) * 2002-02-01 2005-12-13 Pfizer, Inc. Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus
US20050139144A1 (en) * 2002-03-27 2005-06-30 Muller Bernd W. Method for the production and the use of microparticles and nanoparticles by constructive micronisation
US20050079138A1 (en) * 2002-12-19 2005-04-14 Chickering Donald E. Methods for making pharmaceutical formulations comprising microparticles with improved dispersibility, suspendability or wettability
US20050170000A1 (en) * 2003-05-08 2005-08-04 Walker Stephen E. Particulate materials
US20050031692A1 (en) * 2003-08-04 2005-02-10 Pfizer Inc Spray drying processes for forming solid amorphous dispersions of drugs and polymers
US20050143404A1 (en) * 2003-08-28 2005-06-30 Joerg Rosenberg Solid pharmaceutical dosage formulation
US20050133949A1 (en) * 2003-12-19 2005-06-23 Pragtech, Inc. Polymer solidification and coating process

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080085315A1 (en) * 2006-10-10 2008-04-10 John Alfred Doney Amorphous ezetimibe and the production thereof
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
US20100081628A1 (en) * 2008-06-11 2010-04-01 Pharmasset, Inc. Nucleoside cyclicphosphates
US8759510B2 (en) 2008-06-11 2014-06-24 Gilead Pharmasset Llc Nucleoside cyclicphosphates
WO2010075517A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
WO2010075554A1 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Synthesis of purine nucleosides
WO2010075549A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside phosphoramidates
EP3222628A1 (en) 2008-12-23 2017-09-27 Gilead Pharmasset LLC Nucleoside phosphoramidates
US9045520B2 (en) 2008-12-23 2015-06-02 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8957045B2 (en) 2008-12-23 2015-02-17 Gilead Pharmasset Llc Nucleoside phosphoramidates
EP2671888A1 (en) 2008-12-23 2013-12-11 Gilead Pharmasset LLC 3',5'-cyclic nucleoside phosphate analogues
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8716262B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
EP2910562A1 (en) 2009-05-20 2015-08-26 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2 '-fluoro-2'-methyl-p-phenyl-5 '-uridylyl]-l-alanine 1-methylethyl ester in crystalline form
EP2913337A1 (en) 2009-05-20 2015-09-02 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl]-l-alanine 1-methylethyl ester and process for its production
EP2610264A2 (en) 2009-05-20 2013-07-03 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl]-l-alanine 1-methylethyl ester and process for its production
EP3321275A1 (en) 2009-05-20 2018-05-16 Gilead Pharmasset LLC Crystalline form of sofosbuvir
WO2010135569A1 (en) 2009-05-20 2010-11-25 Pharmasset, Inc. N- [ (2 ' r) -2 ' -deoxy-2 ' -fluoro-2 ' -methyl-p-phenyl-5 ' -uridylyl] -l-alanine 1-methylethyl ester and process for its production
WO2011123672A1 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Purine nucleoside phosphoramidate
EP3290428A1 (en) 2010-03-31 2018-03-07 Gilead Pharmasset LLC Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
EP2609923A2 (en) 2010-03-31 2013-07-03 Gilead Pharmasset LLC Nucleoside Phosphoramidates
EP2752422A1 (en) 2010-03-31 2014-07-09 Gilead Pharmasset LLC Stereoselective synthesis of phosphorus containing actives
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
WO2011123668A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Stereoselective synthesis of phosphorus containing actives
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
WO2011123645A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Nucleoside phosphoramidates
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
EP3042910A2 (en) 2010-11-30 2016-07-13 Gilead Pharmasset LLC 2'-spiro-nucleosides for use in the therapy of hepatitis c
US9394331B2 (en) 2010-11-30 2016-07-19 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
US8841275B2 (en) 2010-11-30 2014-09-23 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
US9114170B2 (en) 2012-11-08 2015-08-25 Isp Investments Inc. Highly loaded amorphous efavirenz composition and process for preparing the same
WO2014081581A2 (en) * 2012-11-08 2014-05-30 Isp Investments Inc. Highly loaded amorphous efavirenz composition and process for preparing the same
WO2014081581A3 (en) * 2012-11-08 2014-07-17 Isp Investments Inc. Highly loaded amorphous efavirenz composition and process for preparing the same
US20180297945A1 (en) * 2013-08-29 2018-10-18 Cadila Healthcare Limited Polymorphic form of pyrrole derivative and intermediate thereof
CN114404377A (zh) * 2022-01-10 2022-04-29 安徽贝克生物制药有限公司 一种阿巴卡韦、拉米夫定、依非韦伦复方片及其制备方法

Also Published As

Publication number Publication date
WO2007014393A3 (en) 2007-05-31
CN101272769A (zh) 2008-09-24
US20070026083A1 (en) 2007-02-01
WO2007014393A2 (en) 2007-02-01
JP2009502487A (ja) 2009-01-29
JP2009502969A (ja) 2009-01-29
WO2007016435A2 (en) 2007-02-08
CN101277682B (zh) 2015-07-29
US10532028B2 (en) 2020-01-14
EP1909762A2 (en) 2008-04-16
BRPI0614455A2 (pt) 2011-03-29
CN101272769B (zh) 2013-04-24
CN101277682A (zh) 2008-10-01
JP5243247B2 (ja) 2013-07-24
WO2007016435A3 (en) 2008-02-14
EP1912730A2 (en) 2008-04-23
CN101272848B (zh) 2013-03-13
CN101272848A (zh) 2008-09-24

Similar Documents

Publication Publication Date Title
US20070026073A1 (en) Amorphous efavirenz and the production thereof
US20080085315A1 (en) Amorphous ezetimibe and the production thereof
JP5426165B2 (ja) 優れた生物学的利用能のベンゾキノン類
US20080152717A1 (en) Amorphous valsartan and the production thereof
JP5508859B2 (ja) 噴霧乾燥製品を製造するための調剤処理方法
JP5147703B2 (ja) 経口投与でき、かつ活性成分の迅速な放出を有する固形医薬投与形態
US8613946B2 (en) Carotenoids of enhanced bioavailability
US11413295B2 (en) Oral preparation of obeticholic acid
US20180280302A1 (en) Solid dispersions of compounds using polyvinyl alcohol as a carrier polymer
JP5103173B2 (ja) ジヒドロピリジン系化合物の分解を防止する方法
RU2713428C1 (ru) Частицы, содержащие аморфный эмпаглифлозин, способ их получения и содержащий их лекарственный препарат
WO2008086400A2 (en) Sirtuin-activating compounds of enhanced bioavailability
JP2023539729A (ja) Ｍａｌｔ１阻害剤の非晶質形態及びその製剤
US20080181961A1 (en) Amorphous oxcarbazepine and the production thereof
EP3572069A1 (en) Increasing solubility and bioavailability of enzalutamide
EP3811932A1 (en) Dosage form of apalutamide
BR112018071673B1 (pt) Uso de sorbitol seco por pulverização, composição em pó, e seu processo de produção

Legal Events

Date Code Title Description
AS Assignment

Owner name: ISP INVESTMENTS INC., DELAWARE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:DONEY, JOHN ALFRED;REEL/FRAME:018217/0818

Effective date: 20060810

AS Assignment

Owner name: THE BANK OF NOVA SCOTIA, AS ADMINISTRATIVE AGENT,

Free format text: SECURITY AGREEMENT;ASSIGNORS:ASHLAND LICENSING AND INTELLECTUAL PROPERTY LLC;HERCULES INCORPORATED;AQUALON COMPANY;AND OTHERS;REEL/FRAME:026918/0052

Effective date: 20110823

AS Assignment

Owner name: VERONA, INC., NEW JERSEY

Free format text: PATENT RELEASE;ASSIGNOR:JPMORGAN CHASE BANK, N.A. (F/K/A THE CHASE MANHATTAN BANK);REEL/FRAME:026930/0774

Effective date: 20110823

Owner name: ISP CAPITAL, INC., NEW JERSEY

Free format text: PATENT RELEASE;ASSIGNOR:JPMORGAN CHASE BANK, N.A. (F/K/A THE CHASE MANHATTAN BANK);REEL/FRAME:026930/0774

Effective date: 20110823

Owner name: ISP CHEMICAL PRODUCTS, INC., NEW JERSEY

Free format text: PATENT RELEASE;ASSIGNOR:JPMORGAN CHASE BANK, N.A. (F/K/A THE CHASE MANHATTAN BANK);REEL/FRAME:026930/0774

Effective date: 20110823

AS Assignment

Owner name: ASHLAND LICENSING AND INTELLECTUAL PROPERTY LLC, OHIO

Free format text: RELEASE OF PATENT SECURITY AGREEMENT;ASSIGNOR:THE BANK OF NOVA SCOTIA;REEL/FRAME:030025/0320

Effective date: 20130314

Owner name: ASHLAND LICENSING AND INTELLECTUAL PROPERTY LLC, O

Free format text: RELEASE OF PATENT SECURITY AGREEMENT;ASSIGNOR:THE BANK OF NOVA SCOTIA;REEL/FRAME:030025/0320

Effective date: 20130314

Owner name: HERCULES INCORPORATED, DELAWARE

Free format text: RELEASE OF PATENT SECURITY AGREEMENT;ASSIGNOR:THE BANK OF NOVA SCOTIA;REEL/FRAME:030025/0320

Effective date: 20130314

Owner name: ISP INVESTMENTS INC., DELAWARE

Free format text: RELEASE OF PATENT SECURITY AGREEMENT;ASSIGNOR:THE BANK OF NOVA SCOTIA;REEL/FRAME:030025/0320

Effective date: 20130314

Owner name: AQUALON COMPANY, DELAWARE

Free format text: RELEASE OF PATENT SECURITY AGREEMENT;ASSIGNOR:THE BANK OF NOVA SCOTIA;REEL/FRAME:030025/0320

Effective date: 20130314

STCB Information on status: application discontinuation

Free format text: ABANDONED -- AFTER EXAMINER'S ANSWER OR BOARD OF APPEALS DECISION