AU2002321061A1 - Process of thermodynamical activation of water-insoluble drugs loaded into cross linked polymers - Google Patents
Process of thermodynamical activation of water-insoluble drugs loaded into cross linked polymersInfo
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Description
PROCESS OF THERMODYNAMICAL ACTIVATION OF WATER-INSOLUBLE DRUGS LOADED INTO CROSS-LINKED POLYMERS State of the art
Oral delivery of poorly soluble drugs has become, in the last years, one of the most challenging problems for advanced pharmaceutical research. Usually, drugs with low water solubility show poor bioavailability and a high variability of plasma levels among subjects. This in turn leads to formulations with high drug content which often must be delivered repeatedly to obtain and maintain therapeutic plasma levels. Several studies have been made with the purpose of improving the solubility of these drugs by physical means, without resorting e.g. to chemical derivatisation or the use of additional chemicals.
The unfavourable biopharmaceutical behaviour of poorly soluble drugs is strictly correlated with well defined physical-chemical characteristics. Drug uptake can occur in different ways but, for small synthetic molecules, absorption via a non- saturable passive process (diffusion through the Gl barrier) plays a primary role. The ability of poorly water soluble drugs to be passively absorbed is strictly dependent on their physical properties, such as steric hindrance, crystal form, solubility, lipophily, wettability and surface area. Due to their organised lattice-like structures, drug crystals require a large amount of energy to completely dissolve. The total energy required for dissolving a solid drug is the sum of many contributions, namely surface interaction (generation of a new solid-liquid interface), fusion (crystal lattice fracture), solvation of each single solute molecule and mass transfer or diffusion into the solvent (D.C. Hsia et al., J. Pharm. Sci. 66, 961 , 1977).
The first two energy steps (surface interaction and fusion) necessary to reach the drug dissolution can be eliminated by forming an amorphous phase of the drug (state with an increased thermodynamic activation) or strongly reduced by the presence of drug nanocrystals (crystals having dimensions of nanometers). Amorphisation, and formation of nanocrystals at a less extent, results in drug solubilisation kinetic, having dissolution rate and supersaturation concentrations, that is much higher than that obtainable with the differently formulated drug in its
crystalline state. This allows a strong increase of the drug effects "in vivo" by enhanced bioavailability, reduction of the onset of action (tmax) and decrease of the variability between subjects. From these considerations, the following rank of solid state thermodynamic activation can be described: amorphous > nanocrystals > crystals, which is paralleled by the enhancement of the biopharmaceutical properties such as dissolution rate, supersaturation and bioavailability.
The presence of amorphous, nanocrystalline or crystal phase can be detected by means of Differential Scanning Calorimetry (DSC). Compared to the sharp melting peak of the drug crystal, the nanocrystals present a broader peak with a markedly lower maximum of temperature. Moreover, a decrease of the temperature maximum related to the nanocrystal melting peak is observed when the nanocrystals size decreases (I. Colombo et al. 4th Int. Conf. Pharm. Technol., 1986; F. Carli et al. Ada Pharm. Jugosl. 38, 361 , 1988). The amorphous phase does not show any thermal event. The fraction of nanocrystals or crystals is determined by the melting enthalpy relative to melting peak relative to each form. A technique to enhance the solubility of poorly soluble or insoluble drugs of reduced particle size consists in incorporating them into water-swellable but insoluble polymer by means of polymer swelling with a solution of the drug in a solvent; the solvent is thus removed and the drug precipitates in small particles within the polymer network; an example of such processes is described in DE 2 634 004 and DE 3 320 583, resulting in a uniform dispersion of the drug, mainly in the crystalline or nanocrystalline form. An number of studies have been performed on the activation of drugs by high- energy co-grinding processes, i.e. by grinding together, in the same grinding chamber, both the drug and the supporting polymer; grinding is performed under high-energy conditions. For instance, US 4,639,670 describes the conversion of crystalline drugs into a more activated form, obtained by co-grinding a crystalline drug with a swellable polymer such as cross-linked polyvinylpyrrolidone: this process is performed in dry conditions. In a modification of this process, US 5,449,521 teaches that when co-grinding of drug and polymer is performed in a solvent-enriched environment, e.g. in presence of solvent vapours able to dissolve
the active principle, a higher activation of the active principle is obtained. In US Patent 5,225,192 (M.L. Lovrecich) a process is claimed in which a polymer is first loaded with a drug by co-grinding in dry conditions; the product is then treated with a non-aqueous organic solvent in gaseous or liquid form: this process obtains a composite where the drug is mainly concentrated on the outer surface of the particles of polymeric carrier; with respect to its starting composition, the thus treated drug is present with an increased nanocrystal fraction and a reduced amorphous fraction: as a result the drug is more stabilised, but its activation level is lowered. Although some improvement have been reported in the ability to activate poorly soluble drugs, a constant need is still present for pharmaceutical compositions with improved dissolution times and improved bioavailability. In particular, the need is highly felt for compositions with a higher the level of drug amorphisation, thus with increased solubility and bioavailability. Summary of the invention
The present inventors have obtained composites of water-insoluble drugs with a very high level of activation, by a process comprising co-grinding a mixture of said drug with a cross-linked polymeric carrier, followed by contacting the resulting co- ground material with water or aqueous vapours. With respect to the drug in its original state, this process causes the substantial disappearance of the insoluble crystalline fraction, increases the amorphous fraction, and reduces both the nanocrystal fraction and the nanocrystals size. The composites obtainable by this process show increased dissolution properties and a high bioavailability. The composites further show an excellent flowability, which allows them to be processed easily into pharmaceutical formulations. Detailed description of the invention
Object of the present invention is a process to prepare a highly activated composite of one or more water-insoluble drugs, said process comprising the steps of :(a) subjecting said water-insoluble drug and a cross-linked polymer to co- grinding; (b) exposing the ground product of step a. to contact with water or water vapours. The resulting composite contains large amounts of drug in the easily soluble amorphous form, reduced amounts of drug in the nanocrystalline form, and
is substantially free from practically insoluble drug crystals. Water-insoluble drug useful for the present invention are those drugs belonging to the "class II" or "class IV" molecules, as defined in FDA/CDER Guidance for Industry. Waiver of in-vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutical Classification Sysytem. August 2000. Examples of water-insoluble drugs belonging to this class are cox-2 inhibitors, antiinflammatory drugs such as nimesulide, piroxicam, naproxene, ketoprofen, ibuprofen and diacerheine, antifungal drugs such as griseofulvin, itraconazole, fluconazole, miconazole and ketonazole, bronchodilators/anti-asthmatic drugs such as zafrilukast, salbutamol, beclomethasone, flunisolide, clenbuterol, salmeterol and budesonide, steroids such as estradiol, estriol, progesterone, megestrol acetate, medroxyprogesterone acetate, antihypertensive /antithrombotic/ vasodilator drugs such as nefedipine, nicergoline, nicardipine, lisinopril, enalapril, nicorandil, celiprolol and verapamil, benzodiazepines such as temazepam, diazepam, lorazepam, fluidiazepam, medazepam and oxazolam, anti-migraine drugs such as zolmithptan and sumatriptan, antilipoproteinemic drugs such as fenofibrate, lovastatin, atorvastatin, fluvastatin, and simvastatin, anti-viral / antibactetial drugs such as tosufloxacin, ciprofloxacin, ritonavir, saquinavir, nelfinavir, acyclovir and indinavir, immunodepressant drugs such as tacrolimus, rapamycine and didanisine, anti- histaminic drugs such as loratadine, antitumour drugs such as etoposide, bicalutamide, tamoxifen, doclitaxel and paclitaxel, anti-psychotic drugs such as speridone, antiosteoporotic drugs such as raloxifene, anti-convulsant drugs such as carbamazepin and phenytoin, analgetic/narcotic drugs such as oxycodone, hydrocodone, morphine and butorpanol, muscle relaxant such as tinazadine, anti- ulcerative drugs such as famotidine.
Typical of these drugs is their substantial insolubility in water: when administered orally, they present marked problems in dissolution, thus failing to exert any appreciable systemic pharmacological action. The activation profile obtained by the present process is limited to and peculiar of water insoluble drugs. Nevertheless, drugs having higher solubility in water may optionally be used, in admixture with the water insoluble drug(s), in the process of
the invention.
The cross-linked polymer used in the process of the present invention is chosen among those cross-linked polymers commonly used as pharmaceutical carrier; these polymers are water swellable but water-insoluble: examples are cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, starch (as known, starch is a naturally cross-linked product), sodium starch glycolate, pregelatinized starch, polacrilin potassium; preferred polymer is cross-linked polyvinylpyrrolidone; According to the process of the invention (step a.), the drug and the cross-linked PVP (optionally pre-mixed) are loaded into a suitable grinding apparatus and are subjected to co-grinding; preferably the two powders are added separately into the mill. The cross-linked PVP and the water-insoluble drug are used in a ratio preferably comprised between 12:1 and 0.5:1 , more preferably between 5:1 and 1 :1. The grinding apparatus is chosen among those conventionally available, e.g. a ball mill, an air jet mill, rotary mill, vibration mill, roller mill, mortar mill, planetary mill, etc. However, the co-grinding is most preferably performed under high-energy conditions, e.g. using a high-energy mill, for example a Sweco DM 3 mill. The co- grinding is suitably performed at normal conditions (i.e. at room temperature and atmospheric pressure). Said co-grinding is performed in dry conditions: by "dry conditions" it is meant that there is no addition of any solvents or solvents vapours into the grinding chamber before and during the grinding process, nor the process is performed in a solvent-enriched environment; grinding at normal conditions of ambient humidity (usually lower than 75% relative humidity) is considered as a dry condition for the purpose of the present invention.
Preferably, the co-grinding (step a.) is continued until particles having an average grain size comprised between 0.1 and 500 microns are obtained. As an example, if cross-linked PVP is used, grinding times comprised between 1 and 6 hrs, e.g. 3 hrs. are in general sufficient. Once the grinding step is concluded, the ground material is contacted with water or aqueous vapour (step b.). This step can be performed in the same grinding chamber (though in absence of grinding action), or in any other suitable reactor;
the chamber or reactor can be equipped with systems to supply the water / water vapour, such as openings or nozzles connected to a water supply ; if necessary, a compressing device is present to favour the solvent input; when water vapours are supplied, an apart water heater or supply of heated water / water vapours (temperature > 40°C) is preferably connected to said opening / nozzles; in alternative, the water is heated directly when fed by suitable heating means, e.g. when passing through the opening / nozzle. Alternatively, the ground powder may be transferred into a chamber already saturated with water vapours or containing the required amount of water. During the step b., the powder is preferably maintained in an agitated status, e.g. by stirring, vibration, rotation or suspension in a fluidised bed. The step b can be performed in a single process step or in two or more independent wetting steps, using identical or different wetting techniques. The water/aqueous vapour is added to the ground powder at least until a wetted mass is obtained; preferably however, larger amounts of water are added, since the activation and the flowability increase according to the amount of added water; as an example, a powdeπwater weight ratio comprised between 1 :0.05 and 1 :5, preferably between 1 :0.1 and 1 :3 can be used; higher amounts of water are also contemplated by the present invention. The time of contact between the drug and the water / aqueous vapours can be broadly varied; preferably the contact is continued until a homogeneously wetted mass is obtained; a contact time of 5-120 min, preferably 10-40 min is normally sufficient to achieve these conditions.
As mentioned above, the above process causes a substantial increase of the amorphous fraction of water-insoluble drugs and strongly reduces or eliminates any residual original crystalline form (; it also reduces the nanocrystal fraction and the nanocrystals size. Altogether, these features ensure complete and quick dissolution in-vivo, and thus an enhanced bioavailability of the active principle. The resulting activated composites show a high dissolution rate of the water-insoluble agent, a rapid distribution of the drug throughout the various body compartments, a quick access to the target receptors, a quick onset of action and an intense effect. The increased amorphisation of the product of the present process can be
experimentally proved by the reduction of the heat of fusion relative to the nanocrystals, and by the disappearance of the melting peak relative to the original crystal (DSC analysis). The reduction of nanocrystals size is indicated by the decrease of their melting temperature. By "amorphous drug" it is meant a state of molecular dispersion into the polymer crosslinks (no melting peak is detected by Differential Scanning Calorimetry (DSC)).
By "nanocrystals" it is meant drug particles having an average particle size which allows a lowering of the maximum of the drug melting peak of at least 0.5°C, measured by DSC, according to the following works: J.R. Blachere et al J. Am. Cer. Soc. 55, 306, 1972; M. Brun et al. J. Chim. Phys. 70, 973, 1973; M. Brun et al. J. Chim. Phys. 70, 979, 1973.
The product resulting from the step b. (preferably dried in order to eliminate the absorbed water) can easily be processed further into pharmaceutical formulations by techniques known in the art. The optional drying step can be performed by techniques known in the art, e.g. by drying under vacuum, heating under vacuum, freeze-drying, etc.
The product of step b. shows, once dried, a very high flowability, i.e. a flowability index of < 26 mm, preferably of < 20 mm, as measured with a Flotest tester (Tecnogalenica, l-Cernusco sul Naviglio): this allows an easier processing into the final pharmaceutical form. (e.g. by allowing a more precise dosage, a higher recovery of product from the reactor walls, a quicker production cycle, etc.). The processing into final pharmaceutical form may include adding, to the product of step b., conventional additives for pharmaceutical use, such as diluents, disintegrants, effervescent agents, suspending agents, lubricants, flavours, antioxidants, etc. Examples of such final pharmaceutical forms are tablets, minitablets, capsules, microcapsules, granules, pellets, soluble or dispersible powders, sachet dosage forms, suspensions, solutions, creams, ointments, implantable articles, programmed release devices, etc; where appropriate, said formulations may be provided with a polymeric coating, allowing to mask the taste of the drug and/or to maintain integrity of the drug after administration until the target site for delivery is reached within the organism.
The present invention is now described with reference to the following non limiting examples.
EXPERIMENTAL PART
Materials and methods Differential Scanning Calorimetry is performed at a temperature ranging from 20 to
230°C and a scan rate of 10°C/min in a nitrogen atmosphere. Samples of 3-6 mg are used. The following experimental data are determined:
Maximum temperature of the melting peak relative to the nanocrystalline (T1 ) and original crystalline (T2) forms. Melting enthalpy relative to the nanocrystalline (ΔH1 ) and original crystalline (ΔH2) forms.
Temperature (T150%) relative to 50% of the melting transition relative to the nanocrystalline form.
Amount of the nanocrystalline (% Crist. 1 ) and original crystalline (% Crist. 2) fractions, expressed as a percent of drug on total dry product. These fractions are determined from a calibration curve taking into account the water content.
The % of amorphous phase can be calculated with the formula 100 - [ % Crist 1 + (% Crist 2(*)) ] (*): if present. The determination of flowability is based upon the ability of the powder to fall freely from a cylinder through a hole in a plate. The flowability index is given in millimeter diameter of the smallest hole through which the powder falls freely. The flowability index is determined using a Flotest tester (Tecnogalenica, l-Cernusco sul
Naviglio). EXAMPLE 1
1.A (reference)
3.75 g of megestrol acetate (class II drug) and 11.25 g of crosslinked polyvinylpyrrolidone (PVP-CL) are poured into the grinding chamber of a Fritsch
Pulverisette 5 mill together with the grinding balls. The process time is 15 minutes. B
5 g of the preparation 1.A are kneaded into a mortar with 4.95 g of water and dried. The powder/water ratio is 1 :0.9 w/w.
The products of examples 1.A-B were subjected to DSC analysis. The results are shown in the following table. TABLE 1
Compared to the reference 1.A, the preparation 1 B shows a marked decrease of the nanocrystals size (T150%, higher activation),. The melting peak of the crystalline drug (T2) is 217°C.
EXAMPLE 2
2.A (reference)
3.75 g of griseofulvin (class II drug) and 11.25 g of crosslinked polyvinylpyrrolidone
(PVP-CL) are poured into the grinding chamber of a Fritsch Pulverisette 5 mill togheter with the grinding balls. The process time is 15 minutes. (Reference)
2.B
5 g of the preparation 2.A are kneaded into a mortar with 4.95 g of water and dried. The powder/water ratio is 1 :0.9 w/w.
The products of examples 2.A-B were subjected to DSC analysis. The results are shown in the following table.
TABLE 2
Compared to the reference, the preparation 2.B shows a marked decrease of the nanocrystalline fraction and a reduction of the nanocrystals size (higher activation). The melting peak of the crystalline drug (T2) is 218°C.
EXAMPLE 3 (reference example: no class II drug)
3.A
2.5 g of theophylline (no class II drug) and 12.5 g of crosslinked polyvinylpyrrolidone (PVP-CL) are poured into the grinding chamber of a Fritsch
Pulverisette 5 mill together with the grinding balls. The process time is 15 minutes.
3.B
5 g of the preparation 3.A are kneaded into a mortar with 4.95 g of water and dried. The powder/water ratio is 1 :0.9 w/w.
3.C
5 g of the preparation 3.A are poured into a chamber saturated with methylene chloride vapours (organic solvent) for 24 hours, and dried.
3.D
5 g of the preparation 3.A are poured into a chamber saturated with acetone vapours (organic solvent) for 24 hours and dried.
The products of examples 3.A-D were subjected to DSC analysis. The results are shown in the following table.
TABLE 3
Compared to the reference 3.A, the preparations 3.B, 3.C and 3.D show an increase of the nanocrystallinity fraction (lower activation). The melting peak of the crystalline drug (T2) is 272°C.
EXAMPLE 4 (reference example: class II drug / post-tratment with organic solvent)
4.A
3.75 g of griseofulvin (class II drug) and 11.25 g of crosslinked polyvinylpyrrolidone
(PVP-CL) are poured into the grinding chamber of a Fritsch Pulverisette 5 mill together with the grinding balls. The process time is 15 minutes.
4.B
5 g of the preparation 4.A are poured into a chamber saturated with methylene chloride vapours (organic solvent) for 24 hours, and dried.
The products of examples 4.A-B were subjected to DSC analysis. The results are shown in the following table.
TABLE 4
nanocrystalline fraction and of the nanocrystals size (lower activation). The melting peak of the crystalline drug (T2) is 218°C.
The examples 3C, 3D and 4B show that when the wetting treatment is performed with organic solvents, the resulting effect is a generalised increase in nanocrystal fraction and of nanocrystals size, i.e. a lowering of the activation state, indiscriminately for both class II drugs (griseofulvin) and non-class II drugs
(theophylline).
The example 4B shows that when the wetting treatment of class II drugs is performed with an organic solvent in place of water, no increase in the activation is present, on the contrary the activation level is lowered.
Altogether, these data highlight the criticality and selectivity of the claimed process, with respect to the activation of water-insoluble drugs.
Claims (1)
- CLAIMS i 1. Process to prepare a highly activated composite of one or more water-insoluble2 drugs, comprising the following steps:3 (a) subjecting said water-insoluble drug and a cross-linked polymer to co-grinding;4 (b) exposing the ground product of step a. to contact with water or water vapours.1 2. Process according to claim 1 , where said co-grinding is performed under high2 energy conditions.1 3. Process according to claim 1-2, where said cross-linked polymer is chosen from2 cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose,3 starch, sodium starch glycolate, pregelatinized starch, polacrilin potassium.1 4. Process according to claim 1-3, where said cross-linked polymer and said drug2 are used in a weight ratio comprised between 12:1 and 0.5:1 , preferably between3 5:1 and 1 :11 5. Process according to claim 1-4, where said step a. is performed in a period2 comprised between 1 hour and 6 hours.1 6. Process according to claim 1-5, where said step b. is performed in a period2 comprised between 5 minutes and 120 minutes.1 7. Process according to claim 1-6 where, in step b., said ground powder is2 maintained in an agitated status.1 8. Process according to claim 1-7, where in step b. the powder / water weight ratio2 is comprised between 1 :0.05 and 1 :51 9. Process according to claim 1-7, where in step b. the powder / water weight ratio2 is comprised between 1 :0.1 and 1 :31 10. Process according to claim 1-9, where the product of step b., optionally dried,2 is further processed into a pharmaceutical form.1 11. A highly activated composite of a water-insoluble drug, obtainable by the2 process of claims 1-10. l 12. A composite according to claim 11 , formulated for pharmaceutical use.1 13. A composite according to claims 11-12, in the form of tablets, minitablets,2 capsules, microcapsules, granules, pellets, soluble or dispersible powders, sachet dosage forms, suspensions, solutions, creams, ointments, implantable articles, programmed release devices.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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IE2001/0628 | 2001-06-29 | ||
IE20010628 | 2001-06-29 | ||
PCT/EP2002/006052 WO2003002097A1 (en) | 2001-06-29 | 2002-06-03 | Process of thermodynamical activation of water-insoluble drugs loaded into cross-linked polymers |
Publications (2)
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AU2002321061A1 true AU2002321061A1 (en) | 2003-05-15 |
AU2002321061B2 AU2002321061B2 (en) | 2006-08-24 |
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AU2002321061A Ceased AU2002321061B2 (en) | 2001-06-29 | 2002-06-03 | Process of thermodynamical activation of water-insoluble drugs loaded into cross linked polymers |
Country Status (11)
Country | Link |
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US (1) | US8889182B2 (en) |
EP (1) | EP1414414B1 (en) |
JP (1) | JP2005503360A (en) |
AT (1) | ATE377413T1 (en) |
AU (1) | AU2002321061B2 (en) |
CA (1) | CA2452575C (en) |
DE (1) | DE60223382T2 (en) |
DK (1) | DK1414414T3 (en) |
ES (1) | ES2295379T3 (en) |
NZ (1) | NZ530826A (en) |
WO (1) | WO2003002097A1 (en) |
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WO2003086354A1 (en) * | 2002-04-12 | 2003-10-23 | Elan Pharma International Ltd. | Nanoparticulate megestrol formulations |
US9101540B2 (en) | 2002-04-12 | 2015-08-11 | Alkermes Pharma Ireland Limited | Nanoparticulate megestrol formulations |
US8754238B2 (en) | 2003-07-22 | 2014-06-17 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
US7535456B2 (en) * | 2004-04-30 | 2009-05-19 | Hillcrest Laboratories, Inc. | Methods and devices for removing unintentional movement in 3D pointing devices |
GB0516604D0 (en) * | 2005-08-12 | 2005-09-21 | Sandoz Ag | Rapidly dispersing/disintegrating compositions |
TWI415845B (en) | 2006-10-03 | 2013-11-21 | Arena Pharm Inc | Pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto |
ES2421237T7 (en) | 2007-08-15 | 2013-09-30 | Arena Pharmaceuticals, Inc. | Imidazo [1,2-a] pyridine derivatives as modulators of the serotonergic 5ht2a receptor in the treatment of disorders related thereto |
WO2009123714A2 (en) | 2008-04-02 | 2009-10-08 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-ht2a serotonin receptor |
CA2725578A1 (en) * | 2008-04-24 | 2009-10-29 | Evestra, Inc. | Oral contraceptive dosage forms comprising a progestogen dispersed in an enteric polymer and further comprising an estrogen |
PL2364142T3 (en) | 2008-10-28 | 2018-09-28 | Arena Pharmaceuticals, Inc. | Compositions of a 5-ht2a serotonin receptor modulator useful for the treatment of disorders related thereto |
US9126946B2 (en) | 2008-10-28 | 2015-09-08 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto |
ITMI20120092A1 (en) | 2012-01-26 | 2013-07-27 | Micro Macinazione S A | PHARMACO-CARRIER INCLUSION COMPOSITES PREPARED WITH MECHANICAL-CHEMICAL ACTIVATION PROCESS BY HIGH-ENERGY JET FLUID MILLS |
CA2989343A1 (en) | 2015-06-12 | 2016-12-15 | Yandong Wen | Diaryl and arylheteroaryl urea derivatives useful for the prophylaxis and treatment of rem sleep behavior disorder |
US10034859B2 (en) | 2015-07-15 | 2018-07-31 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
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Publication number | Priority date | Publication date | Assignee | Title |
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DE2634004B2 (en) | 1976-07-29 | 1978-08-10 | Bernhard Dr. 8000 Muenchen Lippold | Process for accelerating the dissolution and improving the solubility of poorly soluble drugs intended for oral administration |
DE3320583A1 (en) | 1983-06-08 | 1984-12-13 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW GALENIC PREPARATION FORMS OF ORAL ANTIDIABETICS AND METHOD FOR THE PRODUCTION THEREOF |
GB8403359D0 (en) * | 1984-02-08 | 1984-03-14 | Erba Farmitalia | Pharmaceutical compositions |
US5225192A (en) * | 1988-10-17 | 1993-07-06 | Vectorpharma International S.P.A. | Poorly soluble medicaments supported on polymer substances in a form suitable for increasing their dissolving rate |
IT1227626B (en) * | 1988-11-28 | 1991-04-23 | Vectorpharma Int | SUPPORTED DRUGS WITH INCREASED DISSOLUTION SPEED AND PROCEDURE FOR THEIR PREPARATION |
IT1241417B (en) * | 1990-03-06 | 1994-01-14 | Vectorpharma Int | THERAPEUTIC COMPOSITIONS WITH CONTROLLED RELEASE OF DRUGS SUPPORTED ON CROSS-LINKED POLYMERS AND COATED WITH POLYMER FILM, AND THEIR PREPARATION PROCESS |
IT1246188B (en) * | 1990-07-27 | 1994-11-16 | Resa Farma | PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS HAVING INCREASED SPEED OF DISSOLUTION OF THE ACTIVE SUBSTANCE AND COMPOSITIONS OBTAINED. |
IT1298574B1 (en) * | 1998-02-06 | 2000-01-12 | Vectorpharma Int | PHARMACEUTICAL COMPOSITIONS IN THE FORM OF POLYMER-BASED MICROPARTICLES OBTAINED BY EXTRUSION AND SPHERONIZATION |
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2002
- 2002-06-03 ES ES02754615T patent/ES2295379T3/en not_active Expired - Lifetime
- 2002-06-03 US US10/481,938 patent/US8889182B2/en active Active
- 2002-06-03 DK DK02754615T patent/DK1414414T3/en active
- 2002-06-03 WO PCT/EP2002/006052 patent/WO2003002097A1/en active IP Right Grant
- 2002-06-03 AT AT02754615T patent/ATE377413T1/en not_active IP Right Cessation
- 2002-06-03 AU AU2002321061A patent/AU2002321061B2/en not_active Ceased
- 2002-06-03 CA CA2452575A patent/CA2452575C/en not_active Expired - Fee Related
- 2002-06-03 JP JP2003508336A patent/JP2005503360A/en active Pending
- 2002-06-03 EP EP02754615A patent/EP1414414B1/en not_active Expired - Lifetime
- 2002-06-03 DE DE60223382T patent/DE60223382T2/en not_active Expired - Lifetime
- 2002-06-03 NZ NZ530826A patent/NZ530826A/en not_active IP Right Cessation
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