WO2007115381A2 - Solid dispersion of poorly soluble drugs in graft copolymers - Google Patents
Solid dispersion of poorly soluble drugs in graft copolymers Download PDFInfo
- Publication number
- WO2007115381A2 WO2007115381A2 PCT/BE2007/000033 BE2007000033W WO2007115381A2 WO 2007115381 A2 WO2007115381 A2 WO 2007115381A2 BE 2007000033 W BE2007000033 W BE 2007000033W WO 2007115381 A2 WO2007115381 A2 WO 2007115381A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dosage form
- drug
- graft copolymer
- medical dosage
- medical
- Prior art date
Links
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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61P31/10—Antimycotics
Definitions
- the present invention relates generally to use of a polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG graft co-polymer), such as Kollicoat IR, in the formulation of solid dispersions of low aqueous solubility and dissolution rate bioactive compound and, more particularly to a system and method for improving the solubility and dissolution rate of such low aqueous solubility and dissolution rate bioactive compound, in particular the drug of low aqueous solubility, such as a BCS Class II or Class IV drug compounds.
- PVA-PEG graft co-polymer such as Kollicoat IR
- the pK a4 is determined to be 4.0
- pK a3 is calculated to be 1.5-2.0
- its other ionisable nitrogens pK al and PK 32
- the calculated log P is 6.2 (Peeters et al., 2002).
- Itraconazole is a class II drug, according to the biopharmaceutical classification system (Amidon et al., 1995).
- a severe limitation in the oral bioavailability of class II compounds is that dissolution takes longer than the transit time through their absorptive sites, resulting in incomplete bioavailability (Dressman and Reppas, 2000).
- the Biopharmaceutical Classification System (BCS), originally developed by G. Amidon, separates pharmaceuticals for oral administration into four classes depending on their solubility and their absorbability: Class I ⁇ High Permeability, High Solubility Class II— High Permeability, Low Solubility Class III— Low Permeability, High Solubility Class IV-- Low Permeability, Low Solubility
- the solubility class boundary is based on the highest dose strength of an immediate release ("IR") formulation and a pH- solubility profile of the test drug in aqueous media with a pH range of 1 to 7. 5. Solubility can be measured by the shake-flask or titration method or analysis by a validated stability-indicating assay.
- a drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1-7.5.
- the volume estimate of 250 ml is derived from typical bioequivalence (BE) study protocols that prescribe administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water.
- a drug is considered highly soluble when 90% or more of an administered dose, based on a mass determination or in comparison to an intravenous reference dose, is dissolved.
- Class II drugs are particularly insoluble, or slow to dissolve, but readily are absorbed from solution by the lining of the stomach and/or the intestine. Prolonged exposure to the lining of the GI tract is required to achieve absorption. Such drugs are found in many therapeutic classes.
- a class of particular interest is antifungal agents, such as itraconazole.
- low-solubility compounds are compounds whose highest dose is not soluble in 250 mL or less of aqueous media from pH 1. 2 to 7.5 at 37° C. See Cynthia K. Brown, et al., " Acceptable Analytical Practices for Dissolution Testing of Poorly Soluble Compounds", Pharmaceutical Technology (Dec. 2004).
- the permeability class boundary is based, directly, on measurements of the rate of mass transfer across human intestinal membrane, and, indirectly, on the extent of absorption (fraction of dose absorbed, not systemic bioavailability) of a drug substance in humans.
- the extent of absorption in humans is measured using mass-balance pharmacokinetic studies; absolute bioavailability studies; intestinal permeability methods; in vivo intestinal perfusion studies in humans; and in vivo or in situ intestinal perfusion studies in animals, hi vitro permeation experiments can be conducted using excised human or animal intestinal tissue and in vitro permeation experiments can be conducted with epithelial cell monolayers.
- nonhuman systems capable of predicting the extent of drug absorption in humans can be used (e.g., in vitro epithelial cell culture methods).
- a drug substance is considered highly permeable when the extent of absorption in humans is determined to be greater than 90% of an administered dose, based on mass- balance or in comparison to an intravenous reference dose.
- a drug substance is considered to have low permeability when the extent of absorption in humans is determined to be less than 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.
- An IR drug product is considered rapidly dissolving when no less than 85% of the labelled amount of the drug substance dissolves within 30 minutes, using U.S.
- USP Pharmacopoeia Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1 N HCI or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.
- the known class II drugs are hydrophobic, and have historically been difficult to administer. Moreover, because of the hydrophobicity, there tends to be a significant variation in absorption depending on whether the patient is fed or fasted at the time of taking the drug. This in turn can affect the peak level of serum concentration, making calculation of dosage and dosing regimens more complex. Many of these drugs are also relatively inexpensive, so that simple formulation methods are required and some inefficiency in yield is acceptable.
- the drug is intraconazole or a related drug, such as fluoconazole, terconazole, ketoconazole, and saperconazole.
- Itraconazole is a class II medicine used to treat fungal infections and is effective against a broad spectrum of fungi including dermatophytes (tinea infections), Candida, malassezia, and chromoblastomycosis. Itraconazole works by destroying the cell wall and critical enzymes of yeast and other fungal infectious agents. Itraconazole can also decrease testosterone levels, which makes it useful in treating prostate cancer and can reduce the production of excessive adrenal corticosteroid hormones, which makes it useful for Cushing's syndrome. Itraconazole is available in capsule and oral solution form. For fungal infections the recommended dosage of oral capsules is 200-400 mg once a day.
- Itraconazole has been available in capsule form since 1992, in oral solution form since 1997, and in an intravenous formulation since 1999. Since Itraconazole is a highly lipophilic compound, it achieves high concentrations in fatty tissues and purulent exudates. However, its penetration into aqueous fluids is very limited. Gastric acidity and food heavily influence the absorption of the oral formulation (Bailey, et el., Pharmacotherapy, 10: 146-153 (1990)). The absorption of itraconazole oral capsule is variable and unpredictable, despite having a bioavailability of 55%.
- Suitable drugs include class II anti-infective drugs, such as griseofulvin and related compounds such as griseoverdin; some anti malaria drugs (e.g. Atovaquone); immune system modulators (e.g cyclosporine); and cardiovascular drugs (e.g. digoxin and spironolactone); and ibuprofen.
- class II anti-infective drugs such as griseofulvin and related compounds such as griseoverdin
- some anti malaria drugs e.g. Atovaquone
- immune system modulators e.g cyclosporine
- cardiovascular drugs e.g. digoxin and spironolactone
- ibuprofen e.g. digoxin and spironolactone
- sterols or steroids may be used.
- Drugs such as Danazol, carbamazepine, and acyclovir may also be used in the compositions.
- Danazol is derived from ethisterone and is a synthetic steroid. Danazol is designated as 17a- Pregna-2,4-dien-20-yno[2,3-d]-isoxazol-17-ol, has the formula of C 22 H 27 NO 2 , and a molecular weight of 337.46. Danazol is a synthetic steroid hormone resembling a group of natural hormones (androgens) that are found in the body. Danazol is used in the treatment of endometriosis. It is also useful in the treatment of fibrocystic breast disease and hereditary angioedema.
- Danazol works to reduce oestrogen levels by inhibiting the production of hormones called gonadotrophins by the pituitary gland. Gonadotrophins normally stimulate the production of sex hormones such as oestrogen and progestogen, which are responsible for body processes such as menstruation and ovulation.
- Danazol is administered orally, has a bioavailability that is not directly dose-related, and a half-life of 4-5 hours. Dosage increases in danazol are not proportional to increases in plasma concentrations. It has been shown that doubling the dose may yield only a 30-40% increase in plasma concentration. Danazol peak concentrations occur within 2 hours, but the therapeutic effect usually does not occur for approximately 6-8 weeks after taking daily doses.
- Acyclovir is a synthetic nucleoside analogue that acts as an antiviral agent.
- Acyclovir is available for oral administration in capsule, tablet, and suspension forms. It is a white, crystalline powder designated as 2- amino-l,9-dihydro-9-[(2-hydroxyethoxy) methyl]-6H- purin-6- one, has an empirical formula of C 8 H ⁇ N 5 O 3 and a molecular weight of 225.
- Acyclovir has an absolute bioavailability of 20% at a 200 mg dose given every 4 hours, with a half-life of 2.5 to 3.3 hours. In addition, the bioavailability decreases with increasing doses. Despite its low bioavailability, acyclovir is highly specific in its inhibitory activity of viruses due to its high affinity for thymidine kinase (TK) (encoded by the virus). TK converts acyclovir into a nucleotide analogue which prevents replication of viral DNA by inhibition and/or inactivation of the viral DNA polymerase, and through termination of the growing viral DNA chain.
- TK thymidine kinase
- Carbamazepine is used in the treatment of psychomotor epilepsy, and as an adjunct in the treatment of partial epilepsies. It can also relieve or diminish pain that is associated with trigeminal neuralgia. Carbamazepine given as a monotherapy or in combination with lithium or neuroleptics has also been found useful in the treatment of acute mania and the prophylactic treatment of bipolar disorders.
- Carbamazepine is a white to off-white powder, is designated as 5H-dibenz[b,fJazepine-5- carboxamide, and has a molecular weight of 236.77. It is practically insoluble in water and soluble in alcohol and acetone. The absorption of carbamazepine is relatively slow, despite a bioavailability of 89% for the tablet form. When taken in a single oral dose, the carbamazepine tablets and chewable tablets yield peak plasma concentrations of unchanged carbamazepine within 4 to 24 hours. The therapeutic range for the steady-state plasma concentration of carbamazepine generally lies between 4 and 10 mcg/rnL.
- Class II drugs of the BCS system dissolve poorly hi the gastrointestinal (GI) tract, but are readily absorbed from solution. Such drugs tend to show a significant difference in their eventual absorption, depending on whether the patient is recently fed versus fasting when taking an oral dose. These drugs may also pass through the GI tract with variable proportions of absorption. These effects make oral formulations of Class II drugs both important and difficult.
- a variety of methods are available for providing drugs in a form which has a large surface, especially as small particles of a few microns hi diameter or smaller. Besides fine grinding of crystals, the formation of microparticles from solution by precipitation, spray drying, freeze-drying, and similar methods is known. In addition, the drug solution can be coated onto small particles to achieve its dispersion, as described, for example, in U.S. Pat. No. 5,633, 015 to Gilis et al.
- Micronized drug on its own tends to re-agglomerate when administered, and this decreases the advantage of improved release kinetics obtained by micronization. Hence, it is also necessary to prevent fine particles of drug from aggregating hi formulation.
- Polymers and other excipients may form a matrix that separates the micronized particles as they are released.
- hydrophilic materials whether polymers or small molecules, are mixed with the fine particles either during or after manufacture.
- the dried composite materials are typically tableted or put in a capsule. Then, when the capsule or tablet enters the stomach or intestine, the finely dispersed drug is dispersed into the gastrointestinal fluid without aggregating. Such compositions are sometimes referred to as "immediate release".
- Immediate release solid oral dosage forms are typically prepared by blending drug particles with fillers, such as lactose and microcrystalline cellulose; glidants, such as talc and silicon dioxide; disintegrants, such as starch, crosprovidone; and/or lubricants, such as magnesium stearate; and compressing the mixture into the form of a tablet.
- fillers such as lactose and microcrystalline cellulose
- glidants such as talc and silicon dioxide
- disintegrants such as starch, crosprovidone
- lubricants such as magnesium stearate
- Hydrophilic polymers may also be used to form a matrix with hydrophobic drugs to separate drug particles, improve wetting and improve dissolution.
- Polymers such as hydroxylpropylcellulose (HPC), hydroxpropyhnethylcellulose (HPMC), and carboxymethylcellulose (CMC) are commonly used for this purpose.
- the matrix may be formed by blending and direct compression, hot melt extrusion, spray-drying, spray- congealing, wet granulation and extrusion-spheronization.
- the rate of absorption is dependant on whether or not the patient ate when taking the drug.
- the absorption of the drug is significantly higher when the drug is taken with a meal than when it is not. This may be due to competition between dissolution of drug, and aggregation of drug particles as the water-soluble material dissolves. The latter effect may be minimized in the presence of food.
- Present invention proposes the formulation solid dispersions of class II drugs in a graft copolymer such as PVA-PEG graft copolymer, exipient as Kollicoat IR on the other hand or a like, which resulted in rapid dissolution, with the class II drug, Itraconazole, and supersaturation was maintained for a period of 4 hours for dispersions containing 15, 20 and 25% of Itraconazole.
- the miscibility of Itraconazole and Kollicoat IR was sufficiently high for drug loads up to 30%.
- Kollicoat IR reduces the surface tension of water (surface tension of a 0% solution is 61.6 mN/m and 41.4 mN/m for a 20% solution) (Kolter et al., 2002, BASF, 2001).
- surface tension of a 0% solution is 61.6 mN/m and 41.4 mN/m for a 20% solution
- Kollicoat IR a polymeric carrier in the formulation of solid dispersions of Itraconazole prepared by hot stage extrusion and found that Kollicoat IR is a valuable excipient in the formulation of dispersed class II compounds and can effectively been used in solid dispersion formulation to increase the solubility and dissolution rate of class II drugs.
- Kollicoat IR a polyvinyl alcohol - polyethylene glycol graft copolymer
- the polyvinyl alcohol moiety has good film-forming properties and the polyethylene glycol part acts as an internal plasticizer.
- the molecule is hydrophilic and thus readily soluble in water. As its structure (fig. 1) is non-ionic, its solubility does not change when the pH increases or decreases along the gastro-intestinal tract.
- the present invention solves the problems of the related art of poor dissolution rate of some of the oral delivered drugs, in particular the class II and the class IV (Biopharmaceutical Classification System) drugs.
- Kollicoat IR 5 a new pharmaceutical excipient developed as a coating polymer for instant release tablets, as a carrier in solid dispersions of Itraconazole.
- the solid dispersions were prepared by hot stage extrusion. Hot extrusion can be carried out a temperature of 100 - 250°C, preferably at 120 - 220 0 C, more preferably at 150 - 200°C and most preferably at about 180°C. Modulated temperature differential scanning calorimetry and X-ray powder diffraction were used to evaluate the miscibility of the drug and the carrier.
- the pharmaceutical performance was evaluated by dissolution experiments, performed in simulated gastric fluid without pepsin (SGF sp ). In the X-ray diffractograms no Itraconazole peaks were visible; the polymer on the other hand appeared to be semi-crystalline. Moreover its crystallinity increased during the extrusion process due to exposure to heat and shear forces.
- Modulated temperature differential scanning calorimetry analysis showed that the drug and the polymer formed a two phase system. Separate clusters of glassy Itraconazole were present for drug loads of 40% or higher, indicating further phase separation.
- Dissolution measurements demonstrated a significantly increased dissolution rate for the solid dispersions compared to physical mixtures.
- the physical mixture made up of glassy Itraconazole and Kollicoat IR (20/80 w/w) showed a dissolution rate and maximum that was much higher than that of the physical mixture made up of crystalline Itraconazole and that of pure glassy Itraconazole.
- a graft copolymer in particular a polyvinyl alcohol- polyethylene glycol graft copolymer (PVA-PEG graft co-polymer), such as Kollicoat IR is a promising excipient for the formulation of solid dispersions of Itraconazole prepared by hot stage extrusion.
- PVA-PEG graft co-polymer polyvinyl alcohol- polyethylene glycol graft copolymer
- Kollicoat IR Kollicoat IR
- a medical dosage form of enhanced solubility and dissolution rate in an aqueous environment of low aqueous solubility drugs characterised in that it comprises a solid dispersion of at least one drug of low aqueous solubility in graft copolymer of 1) water- soluble chains of the vinyl polymer on 2) a polymer chain of water-soluble waxy of alcohols with general formula C2 n H 4n +2O n +l or a polymer chain of polyethylene glycols, polyalkylene glycols, polypropylene glycols, polyisobutylene glycols or polymethylpentene glycols.
- the graft copolymer has 1) poly(vinyl acetate) and/or poly(vinyl alcohol) and/or poly(vinyl chloride) and poly(vinyl ester) on 2) a polymer chain of polyethylene glycols, polyalkylene glycols, polypropylene glycols, polyisobutylene glycols or polymethylpentene glycols.
- the graft copolymer has a 1) polymer chains of a general structure
- graft copolymer is non-ionic and reduces the surface tension of water.
- the solid dispersion is preferably a homogenous dispersion and comprises a supersaturated drug.
- the graft copolymer is Kollicoat IR.
- Such delivery form of solid dispersions of drug in the graft copolymer can be obtainable after exposure to heat and shear forces during the extrusion process, for instance it can be prepared by hot stage extrusion. But it also can be obtainable by other processes, for instance involving spray-drying.
- the graft copolymer is a graft copolymers of vinyl acetate, crotonic acid and polyalkylene glycol
- the graft copolymer is a polyvinyl alcohol - polyethylene glycol graft copolymer, in particular such graft polymer may be composed of 75% polyvinyl alcohol units and about 25% polyethylene glycol units with PEG providing the backbone of the branched co-polymer, with the PVA forming the branches
- the polyethylene glycol graft copolymer has a viscosity lower than 200 mPas in a 20% w/w aqueous solution, preferably the polyethylene glycol graft copolymer has a viscosity lower than 150 mPas in a 20% w/w aqueous solution, more preferably the polyethylene glycol graft copolymer has a viscosity is between 70 mPas and 130 mPas in a 20% w/w aqueous solution, and most preferably polyethylene glycol graft copolymer has a viscosity is about 115 mPas or lower in a 20% w/w aqueous solution.
- drug hi the dosage form of present invention is from the BCS Class II compounds hi the Biopharmaceutical Classification System.
- drug in the dosage form of present invention is from the BCS Class IV compounds in the Biopharmaceutical Classification System.
- the medical dosage form comprises a solid dispersion containing up to 40% of drug load, preferably up to 40% of drug load, yet more preferably a drug load in the solid dispersion between 15 to 25%.
- the dosage form of present invention is characterised in that it enhances the bioavailability hi an aqueous environment of a medically administered bioactive compound, for instance in an aqueous environment such as a gastro- intestinal fluid or a gastric fluid.
- the dosage form of present invention can be used to enhance the enhanced solubility and dissolution rate in an aqueous environment of several drugs such as the drugs selected from the group consisting of anti-fungal drugs, antibiotics, steroids, hormones, and immunosuppressants, or the drugs selected from the group consisting of itraconazole, fluoconazole, terconazole, ketoconazole, saperconazole, griseofulvin, griseoverdin, danazole, atovaquone, cyclosporine, digoxin, spironolactone, mefenamic acid, nisoldipine, nifedipine, nicardipine, felodipine, glibenclamide and carbamazepine.
- drugs selected from the group consisting of anti-fungal drugs, antibiotics, steroids, hormones, and immunosuppressants
- itraconazole fluoconazole, terconazole, ketoconazole, saperconazole, griseofulvin, gris
- the dosage form of present invention can also be used to enhance the enhanced solubility and dissolution rate hi an aqueous environment of several drugs such as the drugs selected from the group consisting of arovaquone, carbamazepine, danazol, glibenclamide, griseofulvin, ketoconazole, troglitazone; or the drug selected from the group consisting of chlorothiazide, furosemide, cyclosporine A, itraconazole; or the drug selected from the group consisting of carbamazepin, dapsone, grisefulvin, buprofen, nifedipine, nitrofurantion, phentytoin, sulfamethoxazole, valproic acid and trimethoprin.
- drugs selected from the group consisting of arovaquone, carbamazepine, danazol, glibenclamide, griseofulvin, ketoconazole, troglitazone
- the dosage form of present invention is used to enhance the enhanced solubility and dissolution rate in an aqueous environment of several drugs such as the drugs selected from the group consisting of furosemide, indinavir, ritonavir, saquinavir, acetazolamide and azathioprine; or from the group of compounds consisting of, iopanoic acid, nalidixic acid, nevirapine, praziquantel, rifampicin; or from the group of compounds consisting of albendazole, amitrptyline, artemether, lumefantrine, chloropromazine, ciprofloxacin, clofazimine, efavirenz, lopinavir, folic acid, glibenclamide, haloperidol, ivermectin, mebendazole, niclosamide, pyrantel, pyrimethamine, retinol vitamin, sul
- drugs selected from the
- the medical dosage form of present invention may be in the form of a composition elected from the group consisting of tablets, capsules, minitabs, filled tablets, osmotic devices, slurries, dispersions, and suspensions. Moreover the medical dosage form may be particulate. Furthermore the medical dosage form of present invention may comprise a permeation or absorption enhancer or a porous matrix, preferably a molecular sieve.
- the drug releasing performance of the medical dosage form of present invention is preferably that 60 % of the drug is released in 50 minutes in vitro in an aqueous solution, more preferably that 70 % of the drug is released in 50 minutes in vitro in an aqueous solution and most preferably 80 % or more of the drug is released in 50 minutes in vitro in an aqueous solution.
- Yet another embodiment of present invention is a pharmaceutical composition comprising, the medical dosage form of present invention.
- Oral pharmaceutical compositions are preferred for those therapeutic agents that are orally active, and include tablets, capsules, caplets, solutions, suspensions and/or syrups, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated.
- Such pharmaceutical compositions are prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts, e.g., in Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, A.R., Ed. (Lippincott, Williams and Wilkins, 2000). Tablets and capsules represent the most convenient oral pharmaceutical compositions, in which case solid pharmaceutical carriers are employed. Tablets may be manufactured using standard tablet processing procedures and equipment.
- One method for forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives, or the like.
- tablets can be prepared using wet granulation or dry-granulation processes. Tablets may also be moulded rather than compressed, starting with a moist or otherwise tractable material; however, compression and granulation techniques are preferred.
- tablets prepared for oral administration using the method s of the invention will generally contain other materials such as binders, diluents, lubricants, - disintegrants, fillers, stabilizers, surfactants, colouring agents, and the like. Binders are used to impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact after compression.
- Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinised starch), gelatins, sugars (including sucrose, glucose, dextrose and 1 ⁇ lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum. Diluents are typically necessary to increase bulk so that a practical size tablet is ultimately provided.
- Suitable diluents include lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar.
- Lubricants are used to facilitate tablet manufacture; examples of suitable lubricants include, for example, magnesium stearate and stearic acid. Stearates, if present, preferably present at no more than approximately 2 % w/w with respect to the drug- containing core.
- Disintegrants are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums or crosslinked polymers.
- Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol.
- Stabilisers are used to inhibit or retard drug decomposition reactions that include, by way of example; oxidative reactions.
- Surfactants may be anionic, cationic, amphoteric or non- ionic surface active agents.
- the pharmaceutical composition may also be a capsule, in which case the active agent- containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets) .
- Suitable capsules may be either hard or soft, and are generally made of gelatine, starch, or a cellulosic material, with gelatin capsules preferred.
- Two-piece hard gelatine capsules are preferably sealed, such as with gelatine bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, which describes materials and methods for preparing encapsulated pharmaceuticals.
- a liquid carrier is necessary to dissolve the active agent(s).
- the carrier must be compatible with the capsule material and all components of the pharmaceutical composition, and must be suitable for ingestion.
- Solid pharmaceutical compositions may, if desired, be coated so as to provide for delayed release.
- Pharmaceutical compositions with delayed release coatings may be manufactured using standard coating procedures and equipment. Such procedures are known to those skilled in the art and described in the pertinent texts, e.g., in Remington, supra.
- a delayed release coating composition is applied using a coating pan, an airless spray technique, fluidised bed coating equipment, or the like.
- Delayed release coating compositions comprise a polymeric material, e.g., cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed from acrylic acid, methacrylic acid, and/or esters thereof.
- a polymeric material e.g., cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl
- a pharmaceutical preparation, in perorally administrable form containing hydrophobized granules of buflomedil-HCl coated with an acrylic acid polymer and/or a cellulose ether or cellulose ether deriv. to mask the bitter taste of the drug without delaying its release in the digestive tract has for instance been described by Durr Manfred and Gajdos Benedikt in W09427596.
- transepidermal effective amounts of drugs may be administered topically on the respective nerve entrapment areas.
- the pharmaceutical product can be used as liquid, semi-solid or solid medicine.
- Liquid medicines are solutions, suspensions, emulsions or dispersions of the above-cited active ingredients or combinations of active ingredients as drops, tinctures and sprays.
- semi-solid medicines for example, gels, ointments, creams and foams are used while, for example, powders, toilet powders, granulates, pellets and microcapsules are used as solid medicines.
- a suitable kind of pharmaceutical form may be a topical delivery form of the above- described active ingredient, which is made by the application of the solid, liquid or semisolid pharmaceutical product onto a gauze strip, a compress or a plaster so that such a gauze strip, such a compress or such a plaster then is only locally applied onto the spot which is to be treated.
- the pharmaceutical product can be filled into the known receptacles, as for example bottles, tubes, toilet powder boxes and baby powder boxes as well as seal edge bags, which are possibly provided with metering means, as for example droplet forming means, metering valves or metering chambers.
- a graft co-polymer more particularly polyvinyl alcohol-polyethylene glycol graft copolymer (for instance Kollicoat IR) is a valuable excipient in the formulation of solid dispersions of a poorly soluble drug such as Itraconazole.
- a rapid dissolution was obtained and supersaturation was maintained for a period of 4 hours for dispersions containing 15, 20 and 25% of Itraconazole.
- the miscibility of Itraconazole and Kollicoat IR was sufficiently high for drug loads up to 30%.
- an increase in crystallinity of Kollicoat IR when exposed to heat and shear forces during the extrusion process might be a possible drawback for the of use melting methods to prepare solid dispersions.
- Good properties are obtainable by controlling shear and heating to achieve temperatures below the re-crystallization temperature or by additives.
- graft co-polymer refers to a copolymer in which chains of a first polymer made of monomer B are grafted onto a second polymer chain of monomer A in other words a graft copolymer has polymer chains of one kind growing out of the sides of polymer chains with a different chemical composition.
- a preferred graft co-polymer for use in the present invention is a co-polymer consisting of chains of polyvinyl alcohol grafted onto a polyethylene glycol backbone.
- supersaturation is the cause to have a chemical solution to be more highly concentrated than is normally possible under given conditions of temperature and pressure for instance a solution that contains more of the dissolved material than could be dissolved by the solvent under normal circumstances.
- a preferred graft co-polymer for improving the solubility and dissolution rate of compound class II compounds by the dosage form of the present invention is a co-polymer being one of polyvinyl alcohol (PVA) and polyethylene glycol (PEG).
- PVA-PEG graft copolymer is available as Kollicoat IR (BASF 5 Mount Olive, NJ.) or as polyvinyl alcohol/polyethylene glycol graft copolymer (Mowiol GE 597 from Hoechst).
- the PVA- PEG graft co-polymer consists of 75% polyvinyl alcohol units and 25% polyethylene glycol units with PEG providing the backbone of the branched co-polymer, with the PVA forming the branches.
- PVA-PEG is very readily soluble in water and has been used mainly for the production of instant-release coatings for tablets.
- hi present invention involves a dosage form of solid dispersions of low aqueous solubility and dissolution rate bioactive compound in said the graft co-polymer, preferably in a polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG graft co-polymer), such as Kollicoat IR, which has been demonstrated to enhance the solubility and dissolution rate of such low aqueous solubility and dissolution rate bioactive compound.
- PVA-PEG graft co-polymer polyvinyl alcohol-polyethylene glycol graft copolymer
- Kollicoat IR Kollicoat IR
- solid dispersions are defined as 'a dispersion of one or more active ingredients in an inert carrier or matrix, prepared by the melting, solvent, or melting solvent method (Chiou and Riegelman, 1971).
- the physical state of the drug in solid dispersions is often transformed from crystalline to amorphous and the dissolution surface increases because of particle size reduction.
- the presence of the carrier improves the contact between the drug and the dissolution medium and impedes aggregation and agglomeration.
- the ultimate in particle size reduction are solid solutions in which the drug is molecularly dispersed in the carrier
- the extrusion process with this polymer can be optimized by technologies of the state of the art and variation of extend crystallinity will influences the stability and pharmaceutical performance of the extrudates.
- the graft co-polymer for use in present invention has preferably the following physical parameters: Molecular weight approx. 45,000 Daltons, pH value of a 20% solution in water of 5.0-8.0, viscosity of a 20% solution in water max. 250 mPa ⁇ s (as determined according to EN ISO 2555 at 23 °C using a shear rate of 100 rpm), ester value 10-75.
- the polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG graft co-polymer) for use of present invention preferably consists of 75% polyvinyl alcohol units and 25% polyethylene glycol units and also contains approx. 0.3% colloidal silica to improve its flow properties.
- graft copolymers for present invention are the graft copolymers of vinyl acetate, crotonic acid and polyalkylene glycol as described in, for example, German Patent 1,077,430.
- Their viscosity is preferably of max. 250 mPa • s in a 20% solution in water (as determined according to EN ISO 2555 at 23 0 C using a shear rate of 100 rpm)
- a particularly preferred copolymer of vinyl acetate, crotonic acid and polyalkylene glycol is a graft copolymer of vinyl acetate, crotonic acid and polyethylene glycol, especially the graft copolymer prepared from 400 parts of vinyl acetate, 32 parts of crotonic acid and 40 parts of 20 polyethylene glycol with a molecular weight of 4,000.
- these copolymers there may be mentioned the product sold under the name Aristoflex A by Hoechts; its viscosity, in a 5% by weight solution in dimethyl formide at 35°C, is 0.0025 to 0.00028 Pa.s.
- Graft copolymer in which polyvinyl acetate and/or hydrolysed polyvinyl acetate (polyvinyl alcohol) groups are grafted onto a polyalkylene oxide (preferably polyethylene oxide) backbone.
- polyalkylene oxide preferably polyethylene oxide
- Polymers of this type are described and claimed in EP 219 048B (BASF). These polymers are obtainable by grafting a polyalkylene oxide of molecular weight (number average) 2000 - 100 000 with vinyl acetate, which may be hydrolysed to an extent of up to 15%, in a weight ratio of polyalkylene oxide to vinyl acetate of 1:0.2 to 1:10.
- the polyalkylene oxide may contain units of ethylene oxide, propylene oxide and/or butylene oxide; polyethylene oxide is preferred.
- the polyalkylene oxide has a number- average molecular weight of from 4000 to 50 000, and the weight ratio of polyalkylene oxide to vinyl acetate is from 1:0.5 to 1:6.
- the dosage form may be used for a wide range of low aqueous solubility and dissolution rate active agents or bioactive compounds of the group of ACE inhibitors, adenohypophoseal hormones, adrenergic neuron blocking agents, adrenocortical steroids, inhibitors of the biosynthesis of adrenocortical steroids, alpha-adrenergic agonists, alpha- adrenergic antagonists, selective alpha.sub.2-adrenergic agonists, analgesics, antipyretics and anti-inflammatory agents, androgens, anesthetics, antiaddictive agents, antiandrogens, antiarrhythmic agents, antiasthmatic agents, anticholinergic agents, anficholinesterase agents, anficoagulents, antidiabetic agents, antidiarrheal agents, antidiuretics, antiemetic and prokinetic agents, antiepileptic agents, antiestrogens, antifungal agents, antihyp
- the dosage form of present invention is used for the poorly soluble drug is selected from the group consisting of carbamazepin, dapsone, grisefulvin, indinavir, nifedipine, nitrofurantion, phentytoin, ritonavir, saquinavir, sulfamethoxazole, valproic acid and trimethoprin.
- the dosage form of the present invention can comprises a drug is elected from the group of compounds consisting of acetazolamide, azathioprine, iopanoic acid, nalidixic acid, nevirapine, praziquantel, rifampicin,
- the dosage form comprises a drug selected from the group of compounds consisting of albendazole, amitrptyline, artemether, lumefantrine, chloropromazine, ciprofloxacin, clofazimine, efavirenz, lopinavir, folic acid, glibenclamide, haloperidol, ivermectin, mebendazole, niclosamide, pyrantel, pyrimethamine, retinol vitamin, sulfadiazine, sulfasalazine, triclabendazole.
- a drug selected from the group of compounds consisting of albendazole, amitrptyline, artemether, lumefantrine, chloropromazine, ciprofloxacin, clofazimine, efavirenz, lopinavir, folic acid, glibenclamide, haloperidol, ivermectin, mebendazole
- Example 1 Materials Itraconazole (purity more than 99%) is obtainable from Molekula Ltd Technology House, Old Forge Road, Ferndown Industrial Estate, Wimborne, Dorset, Bh21 7RR, United Kingdom, Phone: +44(0) 1202 863000, Fax: +44(0) 1202 863003, Email: info@molekula.com; ANDAChem, Inc., 6 West Kouzhuang Road, Taiyuan, 030012, People's Republic of China, Phone: 01186-351-734-1915, Fax: 01186-350-202-9235, Email: sales@andachem.com; Sigma-Aldrich, P O Box 14508, St.
- Hot stage extrusion was performed with a co-rotating, fully intermeshing conical mini twin screw extruder (DSM laboratories, the Netherlands). The temperature was set at 180 0 C, the screw rate varied from 92 to 100 rpm thermogravimetric analysis showed that no decomposition of the polymer occurred). A load of 5 g per run was fed manually; after feeding the internal circulation time was 5 min. The extrudates were collected after cooling at ambient temperature on a conveyer belt. Extruded samples were subsequently milled for 4 min with a laboratory cutting mill (Kika, Germany) and sieved to exclude particles >355 ⁇ m. For two samples the influence of the particle size on the dissolution was investigated. Therefore two fractions were made using sieves of 355, 250 and 90 ⁇ m.
- DSC Differential scanning calorimetry
- MCS Modulated Temperature DSC
- DSC Differential scanning calorimetry
- MCS Modulated Temperature DSC
- Data were analysed mathematically using Thermal Solutions software (TA Instruments, Leatherhead UK). Dry nitrogen (5.0) at a flow rate of 50 mL/min was used as the purge gas through the DSC cell.
- TA Instruments (Leatherhead, UK) aluminium open pans were used for all calorimetric studies. The mass of the empty sample pan was matched with the mass of the empty reference pan within + 0.1 mg, the sample mass varied from 13 to 16 mg.
- the temperature scale and the enthalpic response was calibrated with an Indium standard.
- the heat capacity signal was calibrated by comparing the response of a sapphire disk with the equivalent literature value at 80°C. Validation of temperature, enthalpy and heat capacity measurement using the same standard materials showed that deviation of the experimental from the reference value was ⁇ 0.5°C for the temperature measurement, and ⁇ 1% for measurement of the heat capacity at 80°C.
- the amplitude used in the MTDSC experiment was 0.212 0 C, the period was 40 s, and the underlying heating rate was 2°C/min.
- the samples were measured from -8O 0 C to 180 0 C.
- the DSC thermogram of Kollicoat IR was recorded with a heating rate of 5°C/min and was measured from 20 to 400 0 C.
- Thermogravimetric analysis was performed with a TGA Q500 (TA-instruments, Leatherhead, UK) using a dry nitrogen purge of 100 ml per min.
- the 8 mg Kollicoat IR sample was placed in a 100 ⁇ l platinum cup and measured from 20 to 400 0 C with a heating rate of 5 0 C per min.
- Dissolution experiments were performed in triplicate on 15/85, 20/80, 25/75, 40/60, and 80/20 Itraconazole/Kollicoat IR (w/w) powdered extrudates and 20/80 Itraconazole/Kollicoat IR (w/w) physical mixtures with either crystalline or glassy Itraconazole.
- the tests were performed using the USP 24 method 2 (paddle method) in a Hanson SR ⁇ plus dissolution apparatus (Chatsworth, CA).
- 500 mL of simulated gastric fluid without pepsin (SGF; USP 24) was used as dissolution medium at a temperature of 37°C and a paddle speed of 100 rpm.
- Powdered extrudates and physical mixtures were added to the dissolution medium.
- Five-milliliter samples were taken and immediately replaced with fresh dissolution medium at 5, 10, 15, 30, 45, 60, 120, 180, and 240 min. These samples were filtered with 0.45 ⁇ m Teflon filters (Macherey-Nagel, D ⁇ ren, Germany). The filtrates were further analysed by high-performance liquid chromatography (HPLC) (Six et al., 2004).
- the solid dispersions were dissolved in dimethylsulfoxide and the Itraconazole content was determined using HPLC.
- the presence of two glass transitions indicates the existence of two amorphous phases which are miscible (Fig. 5a). If the concentration of Itraconazole is increased, the highest Tg (Glass Transition Temperature) increases until 40% of drug is reached.
- Tg remains constant around 52 ⁇ 0.4 0 C, which is slightly below the Tg of pure glassy Itraconazole, which is 59.4°C (Six et al., 2001).
- the highest Tg in the solid dispersions is most likely that of a phase containing Itraconazole. Since the Tg remains constant at a value which is just below that of pure glassy Itraconazole, this amorphous phase still contains a small amount of Kollicoat IR which acts as a plasticizer.
- the first Tg is situated at -52.55°C when the drug concentration in the solid dispersions is 5% and increases up to -32.5 ⁇ 2 0 C.
- This Tg already reaches a constant value from 15% of Itraconazole on. From that point on an endothermic peak at approximately 160 0 C is detected which, with increasing drug concentration, increases up to a temperature that corresponds to the melting point of pure Itraconazole.
- the course of the two Tg' s point to the fact that the first one is that of a phase which is rich in Kollicoat IR and the second Tg is that of a phase that is rich in Itraconazole.
- the two physical mixtures showed a significantly different release. From the physical mixture that was prepared with crystalline Itraconazole a maximum of 1.5% was dissolved after 30 min. The physical mixture that was prepared with glassy Itraconazole showed a release of 55% after 1 hour, which is much higher than the release of pure glassy Itraconazole, which has a release of 14% after 3 hours (Six et al., 2003). Still the maximum release was much lower than for the 20/80 Itraconazole / Kollicoat IR w/w solid dispersion and also the supersaturation could not be maintained. The explanation for the differences between the dissolution profiles can be found in the different physicochemical properties of the solid dispersions.
- the analysed samples can be divided into two groups: samples with less than 40% of Itraconazole and samples with 40% or more.
- the dissolution profile of the 15/85, 20/80, and 25/75 Itraconazole/Kollicoat IR w/w samples was more or less the same. For all these samples it was the case that no separate glassy drug phase was present, the drug and the carrier were mainly present in two separate amorphous phases, although a small crystalline drug fraction was present as well (Fig 5a, b). These physicochemical properties are reflected in the dissolution profile that shows that the drug dissolves very fast and remains solubilized in a supersaturated solution.
- Fig.l provides the chemical structure of Kollicoat IR, a polyvinyl alcohol-polyethylene glycol copolymer.
- Fig. 2. demonstrates the overlay of XRPD-spectra of milled Itraconazole/Kollicoat IR extrudates ⁇ 250 ⁇ m with decreasing amount of Itraconazole, 80 %, 40%, 20%, 10% to 0 %, from top to bottom and 100% pure crystalline Itraconazole (bottom).
- Fig. 3. demonstrates the overlay of XRPD-spectra of milled Kollicoat IR extrudates ⁇ 250 ⁇ m and pure untreated Kollicoat (bottom). The mixing times in the extruder decrease from top to bottom, 10, 5, 2, and 0 minutes.
- Fig. 4. demonstrates the overlay of XRPD spectra of pure unprocessed Kollicoat IR powder (bottom), pure Kollicoat IR that had been kept in the oven for 5 min at 150°C (middle), and pure Kollicoat IR that had been extruded (top).
- Fig. 5a demonstrates the reversing heat flow of solid dispersions made up of Itraconazole and Kollicoat IR. From top to bottom: 80%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, and 5% Itraconazole/Kollicoat IR w/w, all transitions are indicated by arrows.
- Fig. 5b demonstrates the total heat flow of solid dispersions made up of Itraconazole and Kollicoat IR. From top to bottom: 80%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, and 5% Itraconazole/Kollicoat IR w/w, all transitions are indicated by arrows.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/296,848 US20110059175A9 (en) | 2006-04-10 | 2007-04-10 | Enhancing solubility and dissolution rate of poorly soluble drugs |
EP07719197A EP2004142A2 (en) | 2006-04-10 | 2007-04-10 | Enhancing solubility and dissolution rate of poorly soluble drugs |
JP2009504531A JP2009533357A (en) | 2006-04-10 | 2007-04-10 | Method for improving solubility and dissolution rate in poorly soluble drugs |
CA002642757A CA2642757A1 (en) | 2006-04-10 | 2007-04-10 | Solid dispersion of poorly soluble drugs in graft copolymers |
CN2007800207895A CN101460148B (en) | 2006-04-10 | 2007-04-10 | Solid dispersion of poorly soluble drugs in graft copolymers |
IL194635A IL194635A0 (en) | 2006-04-10 | 2008-10-07 | Solid dispersion of poorly soluble drugs in graft copolymers |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0607105.4A GB0607105D0 (en) | 2006-04-10 | 2006-04-10 | Enhancing solubility and dissolution rate of poorly soluble drugs |
GB0607105.4 | 2006-04-10 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2007115381A2 true WO2007115381A2 (en) | 2007-10-18 |
WO2007115381A3 WO2007115381A3 (en) | 2007-12-06 |
WO2007115381B1 WO2007115381B1 (en) | 2008-02-14 |
Family
ID=36539598
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/BE2007/000033 WO2007115381A2 (en) | 2006-04-10 | 2007-04-10 | Solid dispersion of poorly soluble drugs in graft copolymers |
Country Status (9)
Country | Link |
---|---|
US (1) | US20110059175A9 (en) |
EP (1) | EP2004142A2 (en) |
JP (1) | JP2009533357A (en) |
CN (1) | CN101460148B (en) |
CA (1) | CA2642757A1 (en) |
GB (1) | GB0607105D0 (en) |
IL (1) | IL194635A0 (en) |
WO (1) | WO2007115381A2 (en) |
ZA (1) | ZA200808556B (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009042114A2 (en) | 2007-09-21 | 2009-04-02 | The Johns Hopkins University | Phenazine derivatives and uses thereof |
WO2009118356A3 (en) * | 2008-03-25 | 2010-02-18 | Formac Pharmaceuticals N.V. | Preparation method for solid dispersions |
CN102144982A (en) * | 2011-03-30 | 2011-08-10 | 江苏神龙药业有限公司 | Minodronate tablets and preparation method thereof |
WO2012085236A1 (en) | 2010-12-23 | 2012-06-28 | Abbott Gmbh & Co. Kg | Solid retard formulations based on solid dispersions |
WO2013189776A1 (en) * | 2012-06-22 | 2013-12-27 | Basf Se | Active ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers |
US20140356429A1 (en) * | 2010-07-20 | 2014-12-04 | Japan Tobacco Inc. | Tablet containing ferric citrate |
US9044734B2 (en) | 2011-09-23 | 2015-06-02 | Basf Se | Diesel oxidation catalyst with layered structure containing ceria composition as palladium support material for enhanced HC and CO gas conversion |
EP3037458A1 (en) * | 2014-12-24 | 2016-06-29 | Industrial Technology Research Institute | Polymer, and pharmaceutical composition employing the same |
CN108261401A (en) * | 2018-01-31 | 2018-07-10 | 佛山市南海东方澳龙制药有限公司 | Ivermectin solid dispersion body and ivermectin tablet |
US10668156B2 (en) | 2012-06-22 | 2020-06-02 | Basf Se | Active-ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers |
US10835495B2 (en) | 2012-11-14 | 2020-11-17 | W. R. Grace & Co.-Conn. | Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same |
WO2023025672A1 (en) * | 2021-08-25 | 2023-03-02 | Basf Se | Direct tableting auxiliary composition |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2009214307A1 (en) * | 2008-02-13 | 2009-08-20 | Bayer Intellectual Property Gmbh | Drug delivery system with stabilising effect |
US20140178479A1 (en) * | 2011-08-12 | 2014-06-26 | Perosphere, Inc. | Concentrated Felbamate Formulations for Parenteral Administration |
EP2649989B1 (en) | 2012-04-13 | 2017-10-18 | King Saud University | Method for preparing a solid dispersion, solid dispersion obtained thereby and use thereof |
AP2015008840A0 (en) * | 2013-04-11 | 2015-11-30 | Ctc Bio Inc | Tadalafil free base-containing film dosage form containing polyethylene glycol-based polymer and/or vinyl pyrrolidone-based polymer as dispersion stabilizer |
US11116769B2 (en) | 2013-04-11 | 2021-09-14 | Ctc Bio, Inc. | Tadalafil free base-containing film dosage form containing polyethylene glycol-based polymer and/or vinyl pyrrolidone-based polymer as dispersion stabilizer |
CN103330685B (en) * | 2013-07-08 | 2014-11-26 | 浙江昂利康制药有限公司 | Cefaclor granule and preparation method thereof |
CN103446075B (en) * | 2013-09-04 | 2016-05-18 | 回音必集团浙江亚东制药有限公司 | A kind of Cefaclor Capsules and preparation method thereof |
US20150231081A1 (en) * | 2014-02-20 | 2015-08-20 | Cadila Healthcare Limited | Delayed release posaconazole tablets |
WO2017094856A1 (en) * | 2015-12-02 | 2017-06-08 | 株式会社日本触媒 | Water-soluble film and manufacturing method therefor |
WO2017115746A1 (en) * | 2015-12-28 | 2017-07-06 | 沢井製薬株式会社 | Gefinitib-containing tablet |
CN105832680B (en) * | 2016-05-12 | 2018-12-25 | 沈阳药科大学 | A kind of pharmaceutical composition improving spirolactone In Vitro Dissolution and mobility |
JP6790244B2 (en) * | 2016-09-13 | 2020-11-25 | ザ プロクター アンド ギャンブル カンパニーThe Procter & Gamble Company | Process for Producing Compositions Containing Beneficial Agent Delivery Particles |
CN114736263B (en) * | 2022-03-08 | 2023-12-26 | 天津大学 | Binary co-amorphous material and application thereof |
WO2023187599A1 (en) * | 2022-03-27 | 2023-10-05 | Didenko Kirill | Methods and bioavailable highly permeable compounds for the treatment of viral diseases |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US15A (en) | 1836-08-31 | Cotton-planter | ||
US5633A (en) | 1848-06-13 | Improvement in water-wheels | ||
DE1077430B (en) | 1958-04-15 | 1960-03-10 | Hoechst Ag | Process for the production of graft polymers of polyvinyl esters |
EP0219048B1 (en) | 1985-10-12 | 1990-05-23 | BASF Aktiengesellschaft | Use of graft copolymers of polyalkylenoxides and vinyl acetate as anti-redeposition agents in the washing and post-treatment of textiles containing synthetic fibres |
WO1994027596A1 (en) | 1993-05-22 | 1994-12-08 | Rhône-Poulenc Rorer GmbH | Pharmaceutical preparation and method of producing it |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4957974A (en) * | 1988-03-29 | 1990-09-18 | Rohm And Haas Company | Graft copolymers and blends thereof with polyolefins |
IL124935A (en) * | 1996-05-20 | 2001-06-14 | Janssen Pharmaceutica Nv | Dispersible antifungal compositions comprising itraconazole with improved bioavailability |
ES2185238T3 (en) * | 1997-12-31 | 2003-04-16 | Choongwae Pharma Corp | ORAL PREPARATION OF ITRACONAZOL AND ITS PREPARATION PROCEDURE. |
US6630170B2 (en) * | 2001-04-26 | 2003-10-07 | Board Of Regents The University Of Texas System | Mesoporous compositions and method of preparation |
US20040208931A1 (en) * | 2002-12-30 | 2004-10-21 | Friend David R | Fast dissolving films for oral administration of drugs |
WO2004093786A2 (en) * | 2003-04-16 | 2004-11-04 | Corium International | Covalent and non-covalent crosslinking of hydrophilic polymers and adhesive compositions prepared therewith |
US20050013863A1 (en) * | 2003-07-18 | 2005-01-20 | Depomed, Inc., A Corporation Of The State Of California | Dual drug dosage forms with improved separation of drugs |
MXPA06000529A (en) * | 2003-07-18 | 2006-08-11 | Santarus Inc | Pharmaceutical composition for inhibiting acid secretion. |
US7914971B2 (en) * | 2005-08-12 | 2011-03-29 | Semiconductor Energy Laboratory Co., Ltd. | Light exposure mask and method for manufacturing semiconductor device using the same |
ES2427724T3 (en) * | 2006-02-03 | 2013-10-31 | Evonik Röhm Gmbh | Pharmaceutical compositions, containing mixtures of polymers and active substances hardly soluble in water |
-
2006
- 2006-04-10 GB GBGB0607105.4A patent/GB0607105D0/en not_active Ceased
-
2007
- 2007-04-10 CN CN2007800207895A patent/CN101460148B/en not_active Expired - Fee Related
- 2007-04-10 JP JP2009504531A patent/JP2009533357A/en active Pending
- 2007-04-10 US US12/296,848 patent/US20110059175A9/en not_active Abandoned
- 2007-04-10 CA CA002642757A patent/CA2642757A1/en not_active Abandoned
- 2007-04-10 EP EP07719197A patent/EP2004142A2/en not_active Withdrawn
- 2007-04-10 WO PCT/BE2007/000033 patent/WO2007115381A2/en active Application Filing
-
2008
- 2008-01-01 ZA ZA200808556A patent/ZA200808556B/en unknown
- 2008-10-07 IL IL194635A patent/IL194635A0/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US15A (en) | 1836-08-31 | Cotton-planter | ||
US5633A (en) | 1848-06-13 | Improvement in water-wheels | ||
DE1077430B (en) | 1958-04-15 | 1960-03-10 | Hoechst Ag | Process for the production of graft polymers of polyvinyl esters |
EP0219048B1 (en) | 1985-10-12 | 1990-05-23 | BASF Aktiengesellschaft | Use of graft copolymers of polyalkylenoxides and vinyl acetate as anti-redeposition agents in the washing and post-treatment of textiles containing synthetic fibres |
WO1994027596A1 (en) | 1993-05-22 | 1994-12-08 | Rhône-Poulenc Rorer GmbH | Pharmaceutical preparation and method of producing it |
Non-Patent Citations (16)
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009042114A2 (en) | 2007-09-21 | 2009-04-02 | The Johns Hopkins University | Phenazine derivatives and uses thereof |
US8216495B2 (en) | 2008-03-25 | 2012-07-10 | Formac Pharmaceuticals N.V. | Preparation method for solid dispersions |
WO2009118356A3 (en) * | 2008-03-25 | 2010-02-18 | Formac Pharmaceuticals N.V. | Preparation method for solid dispersions |
JP2011515444A (en) * | 2008-03-25 | 2011-05-19 | フォーマック ファーマシューティカルズ ナムローゼ フェンノートシャップ | Method for preparing solid dispersion |
US20140356429A1 (en) * | 2010-07-20 | 2014-12-04 | Japan Tobacco Inc. | Tablet containing ferric citrate |
WO2012085236A1 (en) | 2010-12-23 | 2012-06-28 | Abbott Gmbh & Co. Kg | Solid retard formulations based on solid dispersions |
US10463739B2 (en) | 2010-12-23 | 2019-11-05 | AbbVie Deutschland GmbH & Co. KG | Solid retard formulations based on solid dispersions |
CN102144982B (en) * | 2011-03-30 | 2012-12-12 | 江苏神龙药业有限公司 | Minodronate tablets and preparation method thereof |
CN102144982A (en) * | 2011-03-30 | 2011-08-10 | 江苏神龙药业有限公司 | Minodronate tablets and preparation method thereof |
US9044734B2 (en) | 2011-09-23 | 2015-06-02 | Basf Se | Diesel oxidation catalyst with layered structure containing ceria composition as palladium support material for enhanced HC and CO gas conversion |
WO2013189776A1 (en) * | 2012-06-22 | 2013-12-27 | Basf Se | Active ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers |
US10668156B2 (en) | 2012-06-22 | 2020-06-02 | Basf Se | Active-ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers |
US10835495B2 (en) | 2012-11-14 | 2020-11-17 | W. R. Grace & Co.-Conn. | Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same |
EP3037458A1 (en) * | 2014-12-24 | 2016-06-29 | Industrial Technology Research Institute | Polymer, and pharmaceutical composition employing the same |
US9737607B2 (en) | 2014-12-24 | 2017-08-22 | Industrial Technology Research Institute | Polymer, and pharmaceutical composition employing the same |
CN108261401A (en) * | 2018-01-31 | 2018-07-10 | 佛山市南海东方澳龙制药有限公司 | Ivermectin solid dispersion body and ivermectin tablet |
CN108261401B (en) * | 2018-01-31 | 2021-01-08 | 佛山市南海东方澳龙制药有限公司 | Ivermectin solid dispersion and ivermectin tablet |
WO2023025672A1 (en) * | 2021-08-25 | 2023-03-02 | Basf Se | Direct tableting auxiliary composition |
Also Published As
Publication number | Publication date |
---|---|
WO2007115381A3 (en) | 2007-12-06 |
EP2004142A2 (en) | 2008-12-24 |
US20110059175A9 (en) | 2011-03-10 |
WO2007115381B1 (en) | 2008-02-14 |
CA2642757A1 (en) | 2007-10-18 |
IL194635A0 (en) | 2009-08-03 |
GB0607105D0 (en) | 2006-05-17 |
US20090311325A1 (en) | 2009-12-17 |
JP2009533357A (en) | 2009-09-17 |
CN101460148B (en) | 2012-11-14 |
ZA200808556B (en) | 2009-11-25 |
CN101460148A (en) | 2009-06-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20090311325A1 (en) | Enhancing solubility and dissolution rate of poorly soluble drugs | |
US8216495B2 (en) | Preparation method for solid dispersions | |
EP2599486B1 (en) | Dronedarone solid dispersion and preparation method thereof | |
TW201019938A (en) | Pharmaceutical formulations of an HCV protease inhibitor in a solid molecular dispersion | |
EP2218718A1 (en) | Amorphous form of heterocyclic compound, solid dispersion and medicinal preparation each comprising the same, and process for production of the same | |
RU2526914C2 (en) | Compositions of telmisartan in form of nanoparticles, and method for preparing them | |
CN101232870A (en) | Nanoparticulate imatinib mesylate formulations | |
US10688110B2 (en) | Complexes of Celecoxib and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
WO2016155655A1 (en) | Solid pharmaceutical dosage form of parp inhibitor, and application of solid pharmaceutical dosage form of parp inhibitor | |
WO2015152433A1 (en) | Amorphous solid dispersion comprising paclitaxel, tablet comprising the same, and method for preparing the same | |
US20120148637A1 (en) | Nanoparticulate olmesartan medoxomil compositions, process for the preparation thereof and pharmaceutical compositions containing them | |
Verreck et al. | The use of three different solid dispersion formulations—melt extrusion, film-coated beads, and a glass thermoplastic system—to improve the bioavailability of a novel microsomal triglyceride transfer protein inhibitor | |
WO2012159511A1 (en) | Azilsartan solid dispersion, preparation method and pharmaceutical compositions thereof | |
EP3548029A1 (en) | Pharmaceutical formulation containing tadalafil | |
Tripathy et al. | Solid dispersion: A technology for improving aqueous solubility of drug | |
EP2637643B1 (en) | Pharmaceutical composition for treating hcv infections | |
Miller et al. | Solid dispersion technologies | |
EP3820451A1 (en) | Solid dispersion comprising an anticancer compound with improved solubility and efficacy | |
Wagh et al. | Alternative Strategies in Solid Dispersion Manufacturing | |
Bompelwar et al. | ENHANCEMENT OF SOLUBILITY OF NEVIRAPINE BY USING HPMC BY SOLID DISPERSION METHOD | |
Srividya | In-Vitro Dissolution and In-Vivo Bioavailability of a Novel Solid Dispersion of Losartan Potassium and Hydrochlorothiazide. | |
MXPA00006574A (en) | Method and composition of an oral preparation of itraconazole |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200780020789.5 Country of ref document: CN |
|
DPE1 | Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 194635 Country of ref document: IL Ref document number: 2642757 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 8483/DELNP/2008 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009504531 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007719197 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12296848 Country of ref document: US |