Patent Application
20120196873
The present invention is in the field of drug formulation. In particular the present invention relates to the stabilization of the amorphous state of drugs using sponge-like carrier matrices.
The enhancement of dissolution and bioavailability is desired for drugs with low solubility. Amorphous forms of drugs often have a higher bioavailability than crystalline forms of the same drug. The crystalline form of the solid state of poorly water-soluble components influences both, the dissolution kinetics and the limiting drug concentration. Amorphous forms however perform best in both parameters as there is no lattice energy which needs to be overcome. Technical concepts for stabilisation of the amorphous state suffer from high energy inputs (e.g. melt extrusion with polymers), which may cause side reactions and degradation of the poorly water soluble compound. In other cases the mechanical properties of the product are poor as they are waxy solids or viscous liquids. Porous particles are also used to interrupt crystallisation due to interactions with the surface of the particle. Obviously this method leads to small amounts of loading, which is also a disadvantage for further applications. The choice of appropriate carrier matrix materials is therefore crucial for practical considerations. Takeuchi et al. (Int. J. Pharm. 293 (2005) 155-164) describe the use of porous silica for the formation of solid dispersion particles with Indomethacin (IMC).
WO 2005/051358 A1 describes pharmaceutical compositions comprising porous particle carriers and a water-soluble polymer for increasing the bioavailability of water-insoluble drugs. EP 0 454 044 B1 describes pharmacological compositions comprising polyelectrolyte complexes in microparticulate form.
The present invention relates to the stabilization of amorphous states of drugs using sponge-like carrier matrices. Amorphous states of drugs herein relate to states of drugs that lack crystalline structure or that have a very small portion of residual crystalline structure, preferably below about 15%, more preferably below about 10%, even more preferably below about 1% and most preferably no residual crystalline structure. The degree of amorphous states and crystalline structure in a sample of a drug or active ingredient can be determined using X-ray powder diffraction (XRPD). Pharmaceutical compositions and methods for their production are provided by the present invention. The sponge-like carrier matrices of the pharmaceutical compositions of the invention can be used as scaffold for the deposition of poorly soluble drugs in the amorphous state.
These compositions can be used for the stabilisation of drugs in the amorphous state, for rheology improvement and for solubilisation enhancement or combinations thereof. The sponge-like carrier matrix mentioned above may comprise polyelectrolyte complexes (ITC) formed by the electrostatic interaction between a polyanion and a polycation. The assembly mentioned above may also comprise inorganic carriers.
These carriers can be loaded with an active compound, combinations of excipient and active ingredients or combinations of polyelectrolytes and active ingredients provided that excipient or polyelectrolyte and active ingredient are soluble or molecular dispersed in the same solvent or solvent mixture. The scaffold (i.e. the carrier) itself may also be formed during the loading process with the active ingredient.
The present invention relates to a pharmaceutical composition comprising
In a first particular aspect the present invention relates to a pharmaceutical composition comprising
The polyelectrolyte complex preferably comprises
In a second particular aspect, the present invention relates to a pharmaceutical composition to comprising
This second aspect provides a carrier, particularly porous particles, with a high inner surface.
In one particularly preferred embodiment of the second aspect of the present invention, the pharmaceutical composition comprises one or more low molecular weight excipients.
In another particularly preferred embodiment of the second aspect of the present invention, the pharmaceutical composition comprises no further low or high molecular weight excipients.
The present invention also relates to a method for producing a pharmaceutical composition according to the first aspect of the pharmaceutical composition, comprising the steps of
The polyelectrolyte complex can be prepared by a method comprising the steps of
The present invention relates to a method for producing a pharmaceutical composition according to the second aspect of the pharmaceutical composition, comprising the steps of
The present invention also relates to a pharmaceutical composition obtainable by any of the methods of the present invention.
The present invention relates to a pharmaceutical composition comprising
The sponge-like carrier matrix herein alone or together with the excipient stabilises the amorphous active ingredient (i.e. the drug, particularly drugs with a low solubility in water), thereby facilitating the delivery of the active ingredient to its target and enhancing the bioavailability as compared to the unformulated drug substance or compared to existing carrier systems. The present invention relates in a first aspect to a pharmaceutical composition as defined above, wherein the sponge-like carrier matrix comprises polyelectrolyte complexes. In a second aspect the present invention relates to a pharmaceutical composition as defined above, wherein the sponge-like carrier matrix comprises porous particles. Porous particles are preferably microparticles with pores and/or holes. The have preferably dimensions in the μm range, preferably in the range of from about 1 to 700 μm, more preferably 1 to 250 μm, even more preferably 1 to 250 μm and most preferably 75 to 250 μm. The sponge-like, cavernous carrier matrices are preferably in form of supramolecular structures, particles, flakes and/or bricks (e.g. amorphous matrices of brittle nature). The sponge-like carrier matrices described herein preferably improve the rheology of the drug formulation.
The optional excipient may be a low molecular weight excipient or a high molecular weight excipient. A low molecular weight excipient herein refers to an excipient with a molecular mass of below about 1500 Da, preferably below 1400 Da, more preferably below 1200 Da, more preferably below 1000 Da, more preferably below 800 Da, even more preferably below 750 Da and most preferably below 500 Da. A high molecular weight excipient herein refers to an excipient with a molecular mass of about 1500 Da or above 1500 Da. A polymeric excipient comprises repetitive covalent bounds between one or more monomers. Typically each monomer is present multiple times in the polymer in a statistical or block wise manner. Therefore polymers typically belong to the class of high molecular weight excipients as defined above. Synthetic polymers are synthesized using polymerisation reactions, in which the product has no uniform molecular weight, but a molecular weight distribution. In contrast, natural polymers such as proteins and nucleic acids usually have a defined structure and molecular weight. In the context of the second aspect of the invention (i.e. the pharmaceutical composition comprising porous particles), the excipient is preferably a low molecular weight excipient.
Low molecular weight excipient are for example selected from the group comprising sorbitan monopalmitates (SPAN), polysorbates (TWEEN®), surfactants in general, polyalcohols as e.g. glycerole, manniole, monosaccharides (e.g. glucose, lactose), amino acid and peptide. Preferred polysorbates are selected from the group comprising TWEEN® 80, TWEEN® 65, TWEEN® 60, TWEEN® 40 and TWEEN® 20. The low molecular weight excipient may be a permeation enhancer or a solubiliser.
High molecular weight excipient are for example selected from the group comprising poly(vinylpyrrolidone) (PVP), poly(ethyleneglycole) (PEG), poly(propylenglycole) (PPG), polyvinyl alcohol, Eudragit E, and Eudragit S, polysaccaride such as dextran, starch, cellulose derivatives or chitosan, polypeptide such as poly-lysine or protein such as albumin, e.g. human serum albumin (HSA).
The excipient may in one embodiment be a monomer or in another embodiment be a polymer comprising repetitive structural units.
In some particular embodiments the excipient is insoluble in water. In further embodiments the excipient is insoluble in water but soluble in diluted acids (preferably with a pH below about 4.5) or diluted bases (preferably with a pH above about 8).
It is preferred that the ratio between the low molecular weight excipient or the high molecular weight excipient with respect to the amount of drug in the pharmaceutical composition is in the range of from about 0 to 50% (w/w), preferably below 50% (w/w), more preferably below 20% (w/w) and most preferably below 5% (w/w).
The active ingredient in the context of the present invention is preferably a low solubility drug according to groups II or IV of the Biopharmaceutics Classification System (BCS) (FDA). Low solubility drugs are all drugs that are not high solubility drugs according to the following definition of the FDA. A drug substance is considered highly soluble when the highest dose strength is soluble in ≦250 ml water over a pH range of 1 to 7.5.
The active ingredient may for example be selected from the group comprising
Preferred active ingredients of the above list that do not form salts at any pH.
In preferred embodiments of the invention, the concentration of the active ingredient in the pharmaceutical composition is in the range of from 0 to 90% (w/w), preferably 0 to 50%, more preferably between about 5 and 25% (w/w), even more preferably in the range of from about 10 to 20% (w/w) and most preferably between about 8 and 20% (w/w). All concentration percentages herein refer to weight-per-weight (w/w) unless otherwise stated. (w/v) relates to weight-per volume.
Preferably, the active ingredient is located on the inner surfaces of the porous particles of the pharmaceutical composition and not on the outer surface.
Preferably, residual organic solvents, particularly class 3 solvents (solvent with low toxic potential) as defined in the The European Pharmacopoeia (Ph. Eur.) 5 (EDQM 2007), paragraph 5.4 solvents, are present at a concentration of less than 5%, less than 4%, less than 3%, less than 2% or less than 1% (w/w).
The pharmaceutical composition of the present invention is not limited to a particular way of administration. The administration may for example be an intramuscular, subcutaneous, parenteral, ophthalmic or oral administration.
As mentioned above, in the first aspect the present invention relates to a pharmaceutical composition comprising
The polyelectrolyte complex preferably comprises
Polyelectrolytes are polymers whose repeating units, or at least one of the repeating units, bear an electrolyte group. An electrolyte is any substance dissociating in an appropriate medium (e.g. water) into ions of opposite charge. A polymer is a macromolecule composed of repeating structural units connected by covalent chemical bonds. There are heteropolymers (comprising two or more kinds of structural units) and homopolymers (comprising only one kind of structural units). A polyelectrolyte may contain negatively and positively charge groups. These polyelectrolytes are called ampholytes. A skilled person knows that the net charge of an ampholytic compound in aqueous solutions depends on its isoelectrical point and on the pH of the solution. A polycation has an overall positive charge and comprises structural units with a net positive charge, whereas polyanions have an overall negative charge and comprises structural units with a net negative charge. A polyelectrolyte may also be considered as comprising a polyacid and a polybase.
The polyanion is preferably selected from the group comprising xylan polysulfate, dextran sulfate, poly(amino acids) such as polyaspartic acid or polyglutamic acid, polysaccharide polysulfate such as sulfate of starch hydrolysate, inulin, hydroxyethylstarch, polysaccharide polysulfonate, polysaccharide polyphosphate, carboxymethylcellulose, gelatin B, collagen, HSA (Human Serum Albumin) or other albumins, Eudragit S and polyphosphates.
The polycation is preferably selected from the group comprising poly-L-lysine, poly-α, β-(2-dimethylaminoethyl)-D,L-aspartamide, chitosan, lysine octadecyl ester, aminated dextran, aminated cyclodextrin, aminated cellulose ether, protamine (sulfate), gelatin A, Eudragit E, HSA (Human Serum Albumin) or other albumins, casein, nucleic acid (e.g. DNA, RNA, LNA or PNA) and aminated pectin.
Preferred polyelectrolyte combinations in the context of the first aspect of the present invention are:
The polyelectrolyte complex may additionally comprise inorganic or organic ions and/or salts, e.g. sodium chloride and antifoam agents, such as polypropylene glycol, polyethylene glycol, polyvinyl alcohol and non-complexed polymers.
In the second aspect, the present invention relates to a pharmaceutical composition comprising
In one particularly preferred embodiment of the second aspect of the present invention, the pharmaceutical composition comprises one or more low molecular weight excipients.
In another particularly preferred embodiment of the second aspect of the present invention, the pharmaceutical composition comprises no further low or high molecular weight excipients.
The porous particles preferably comprise a carrier material selected from the group comprising magnesium aluminometasilicate (MAS), anhydrous dibasic calcium phosphate, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, soy bean hull fiber, and agglomerated silicon dioxide.
Magnesium aluminometasilicate is available from Fuji Chemicals Co. under the name Neusilin®. Different forms of Neusilin® are available. However, the preferred magnesium aluminometasilicate preparation in the context of the present invention is Neusilin® US2. Unless otherwise stated, “Neusilin®” and “Neusilin® US” herein refers to Neusilin® US2, particularly in the examples.
Agglomerated silicon dioxide is available from Evonik under the trade name Aerosil®.
It has surprisingly been found in the present invention that the porous particles stabilize the amorphous drugs even without the addition of further high molecular weight excipients or without the addition of excipients at all. Further it has surprisingly been found that the polyelectrolyte complex carriers even stabilize active ingredients that do not form salts at any pH and/or that are low solubility drugs according to groups II or IV of the Biopharmaceutics Classification System (BCS) (FDA). The use of polyelectrolyte complexes enables new routes of administrations for such classes of active ingredients. The choice of the polyelectrolyte allows for a targeting of the active ingredient and for the use of a wide variety of active ingredients. Furthermore, the pharmaceutical compositions of the present invention enhance the bioavailability of the active ingredient.
The present invention also relates to methods for the production of the pharmaceutical compositions of the present invention. All definitions and embodiments, particularly those for the active ingredient, the excipient and the sponge-like matrix, also apply to the methods for the production of the pharmaceutical compositions.
The present invention relates to a method for producing a pharmaceutical composition according to the first aspect of the pharmaceutical composition, comprising the steps of
Polyelectrolyte complexes build amorphous matrices, which depending on the production method and composition may vary in the rheological behaviour, particle size, degree of porosity, pore size and in their mechanical properties in general. These polyelectrolyte matrices, as well as other inorganic carriers, are optimal scaffolds for the precipitation of a drug, previously dissolved in an organic solvent, into the amorphous state. These compositions besides from stabilizing the drug in the amorphous state also have the additional role of being appropriate filler excipients for solid dosage form development.
The polyelectrolyte complex can be prepared by a method comprising the steps of
Particular methods for the production of polyelectrolyte complexes are illustrated in examples 1 to 8. The solutions comprising the polyanionic or polycationic compounds may additionally comprise salts, e.g. sodium chloride, and preferably have ion strengths of in the range of from about 0 to 1 M, preferably in the range of from about 0.01 M to about 0.125 M. The polyelectrolyte may preferably have concentrations in the aqueous solution in a range in which the viscosity is not limiting the processability, preferably from about 1 to 2% (w/v).
The present invention relates to a method for producing a pharmaceutical composition according to the second aspect of the pharmaceutical composition, comprising the steps of
Mixing may for example be performed by stirring, vortexing, wet-milling or using a homogenizer.
Particular methods for the production of a pharmaceutical composition according to the second aspect are illustrated in examples 9 and 10 (Itraconanzole with Neusilin®) and examples 12 to 15 (Candesartan with Neusilin®) (also shown in polarisation microscopy images in
The resulting pharmaceutical composition preferably comprises porous microparticles that do not form superparticular structures or complexes. Further the method preferably results in porous particles in which the active ingredient (and optionally the excipient) is located on the inner surface of the particles and not on the outer surface.
During the method, the organic solvent comprising the active ingredient (and optionally the excipient) is preferably completely soaked into the porous particles. Furthermore, the method preferably results in amorphous particles with little to no residual crystal-like structure as judged from X-ray powder diffraction spectra.
The organic solvent in the context of the methods of this invention is preferably a class 3 solvent (solvent with low toxic potential) as defined in the The European Pharmacopoeia (Ph. Eur.) 5 (EDQM 2007), paragraph 5.4, or is selected from the group comprising acetic acid, heptane, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methylethyl ketone, tert-butylmethyl ether, methylisobutyl ketone, cumene, 2-methyl-1-propanol, dimethyl sulfoxide, pentanel, ethanol, 1-pentanol, ethyl acetate, 1-propanol, ethyl ether, 2-propanol, ethyl formate, propyl acetate and formic acid or is a mixture of two or more organic solvents selected from said group. Strong limitations apply to the presence of residual non-class 3 solvents in the final pharmaceutical composition. Therefore such solvents are less preferred. After removal of the organic solvent, the amount residual solvent needs to be in accordance with regulatory requirements. However, in some embodiments, the solvent may be identical to the low molecular weight excipient. In this particular case the organic solvent must not be removed. In all other cases the solvent is preferably removed. A skilled person is aware of the melting temperatures of the low molecular weight excipient above which it can act as a solvent for the active ingredient.
The active ingredients may preferably have concentrations in the organic solvent of more than about 20 mg/ml, more preferably more than about 50 mg/ml, most preferably more than about 100 mg/ml.
The low or high molecular weight excipient may preferably have concentrations in the organic solvent of more than about 2 mg/ml, more preferably more than about 15 mg/ml, most preferably more than about 25 mg/ml.
The organic solvent may for example be removed by freeze-drying, by spray-drying, by evaporation in a rotary evaporator, by heating, or by applying a vacuum or combinations thereof.
In particular embodiments, the organic solvent comprising the active ingredient is added dropwise under permanent mixing to the polyelectrolyte complex or to the porous particles comprising the carrier material.
The present invention also relates to a pharmaceutical composition obtainable by any of the methods of the present invention. All definitions and embodiments, particularly those for the active ingredient, the excipient and the sponge-like matrix, as outlined above also apply to the pharmaceutical compositions obtainable by the methods for the production of the pharmaceutical compositions.
In particular, the present invention relates—according to the first aspect of the present invention—to a pharmaceutical composition obtainable by a method comprising the steps of
The polyelectrolyte complex can be prepared by a method comprising the steps of
The solutions comprising the polyanionic or polycationic compounds may additionally comprise salts, e.g. sodium chloride, and preferably have ion strengths of in the range of from about 0 to 1 M, preferably in the range of from about 0.01 M to about 0.125 M. The polyelectrolyte may preferably have concentrations in the aqueous solution in a range in which the viscosity is not limiting the processability.
According to the second aspect of the present invention, the invention relates to a pharmaceutical composition obtainable by a method comprising the steps of
The organic solvent in the context of the pharmaceutical compositions obtainable by the methods of this invention is preferably a class 3 solvent (solvent with low toxic potential) as defined in the The European Pharmacopoeia (Ph. Eur) 5 (EDQM 2007), paragraph 5.4, or is selected from the group comprising acetic acid, heptane, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methylethyl ketone, tert-butylmethyl ether, methylisobutyl ketone, cumene, 2-methyl-1-propanol, dimethyl sulfoxide, pentanel, ethanol, 1-pentanol, ethyl acetate, 1-propanol, ethyl ether, 2-propanol, ethyl formate, propyl acetate and formic acid or is a mixture of two or more organic solvents selected from said group. Strong limitations apply to the presence of residual non-class 3 solvents in the final pharmaceutical composition. Therefore such solvents are less preferred. After removal of the organic solvent, the amount residual solvent needs to be in accordance with regulatory requirements. However, in some embodiments, the solvent may be identical to the low molecular weight excipient. In this particular case the organic solvent must not be removed. In all other cases the solvent is preferably removed. A skilled person is aware of the melting temperatures of the low molecular weight excipient above which it can act as a solvent for the active ingredient.
The active ingredients may preferably have concentrations in the organic solvent of more than about 20 mg/ml, more preferably more than about 50 mg/ml, most preferably more than about 100 mg/ml.
The low or high molecular weight excipient may preferably have concentrations in the organic solvent of more than about 2 mg/ml, more preferably more than about 15 mg/ml, most preferably more than about 25 mg/ml.
The organic solvent may for example be removed by freeze-drying, by spray-drying, by evaporation in a rotary evaporator, by heating, or by applying a vacuum or combinations thereof.
In particular embodiments, the organic solvent comprising the active ingredient is added dropwise under permanent mixing to the polyelectrolyte complex or to the porous particles comprising the carrier material.
The following examples illustrate particular embodiments and aspects of the present invention. However, they are not limiting the scope of the invention.
Examples 1 to 8 illustrate methods for the production of polyelectrolyte complexes.
Examples 9 and 10 illustrate amorphous formulations of Itraconazole.
Examples 11 to 18 illustrate amorphous formulations of Candesartan cilexetil.
A solution containing 2% (w/v) protamine sulfate with an ionic strength of 0.01 M was added to a solution containing 2% (w/v) carboxymethylcellulose with an ionic strength of 0.01 M under mixing with an ultra-Turrax®. The resulting suspension was lyophilised and stored at RT until further use.
A solution containing 2% (w/v) protamine sulfate with an ionic strength of 0.125 M was added to a solution containing 2% (w/v) carboxymethylcellulose with an ionic strength of 0.125 M under mixing with an ultra-Turrax®. The resulting suspension was lyophilised and stored at RT until further use.
A solution containing 2% (w/v) protamine sulfate with an ionic strength of 0.125 M was added to a solution containing 1% (w/v) carboxymethylcellulose with an ionic strength of 0.125 M under mixing with an ultra-turrax. The resulting suspension was lyophilised and stored at RT until further use.
u) A solution containing 2% (w/v) protamine sulfate with an ionic strength of 0.125 M and a concentration of 1% (w/v) of PPG was added to a solution containing 2% (w/v) carboxymethylcellulose with an ionic strength of 0.125 M and 1% (w/v) PPG under mixing with an ultra-Turrax®. The resulting suspension was lyophilised and stored at RT until further use.
Production of Polyelectrolyte Complexes
A solution containing 2% (w/v) protamine sulfate with an ionic strength of 0.01 M and a concentration of 1% (w/v) of PPG was added to a solution containing 2% (w/v) carboxymethylcellulose with an ionic strength of 0.01 M and 1% (w/v) PPG under mixing with an ultra-Turrax®. The resulting suspension was lyophilised and stored at RT until further use.
A solution containing 2% (w/v) protamine sulfate with an ionic strength of 0.01 M and a concentration of 1% (w/v) of PPG was added to a solution containing 1% (w/v) carboxymethylcellulose with an ionic strength of 0.01 M and 1% (w/v) PPG under mixing with an ultra-Turrax®. The resulting suspension was lyophilised and stored at RT until further use.
A solution containing 2% (w/v) protamine sulfate with an ionic strength of 0.125 M and a concentration of 1% (w/v) of PPG was added to a solution containing 1% (w/v) carboxymethylcellulose with an ionic strength of 0.125 M and 1% (w/v) PPG under mixing with an ultra-turrax. The resulting suspension was lyophilised and stored at RT until further use.
A solution containing 2% (w/v) protamine sulfate with an ionic strength of 0.125 M and a concentration of 1% (w/v) of PPG was added to a solution containing 2% (w/v) carboxymethylcellulose with an ionic strength of 0.125 M and 1% (w/v) PPG under mixing with an ultra-Turrax®. The resulting suspension was lyophilised and stored at RT until further use.
A Solution of 500 mg Itraconazole in 2.5 ml of dichloromethane was prepared. This clear solution was added dropwise to 2.5 g Neusilin® US under permanent mixing. If agglutination was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. The solvent was removed using a rotary evaporator. The amount of total Itraconazole was analysed using HPLC and found to be 17% (w/w). The formulation was analysed using x-ray powder diffraction (XRPD) measurements. No crystalline material was found, even about 1 year after preparation. See appended
A Solution of 500 mg Itraconazole and 200 mg PEG in 2.5 ml of dichloromethane was prepared. This clear solution was added dropwise to 2.5 g Neusilin® US under permanent mixing. If agglutination was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. The solvent was removed using a rotary evaporator. The amount of total Itraconazole was analysed using HPLC and found to be 16% (w/w). The formulation was analysed using XRPD measurements. No crystalline material was found even about 1 year after preparation. See appended
A Solution of 20 mg Eudragid E (EuE) and 200 mg candesartan-cilextil in 4 ml acetone was prepared. This clear solution was transferred to a rotary evaporator and the solvent was removed. The respective residue was examined with polarisation microscopy (see appended
A Solution of 50 mg Eudragid E and 100 mg candesartan-cilextil in 1 ml acetone was prepared. This clear solution was added dropwise to 0.5 g Neusilin® US under permanent mixing. If agglutination was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. A polarisation microscopy image showed no evidence for crystalline materials (see appended
A Solution of 50 mg Eudragid S (EuS) and 100 mg candesartan-cilextil in 1 ml acetone and 0.5 ml 2-propanol was prepared. This clear solution was added dropwise to 0.5 g Neusilin® US under permanent mixing. If agglutination was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. A polarisation microscopy image showed no evidence for crystalline materials (see appended
A Solution of 50 mg poly(ethylene glycol) (PEG) and 100 mg candesartan-cilextil in 1 ml dichloromethane was prepared. This clear solution was added dropwise to 0.5 g Neusilin® US under permanent mixing. If agglitunation was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. A polarisation microscopy image showed no evidence for crystalline materials (see appended
A Solution of 30 mg candesartan-cilextil in 300 ml dichloromethane was prepared. This clear solution was added dropwise to 0.15 g Neusilin® US under permanent mixing. If agglutination was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. In a XRPD study no crystalline materials could be found in the formulation (see appended
A Solution of 20 mg candesartan-cilextil in 200 ml dichloromethane was prepared. This clear solution was added dropwise to 0.1 g polyelectrolyte complex (PEC) under permanent mixing. If agglutination was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. In a XRPD study only weak reflexes were found (see appended
A Solution of 20 mg candesartan-cilextil and 10 mg PEG in 200 ml dichloromethane was prepared. This clear solution was added dropwise to 0.1 g PEC under permanent mixing. If agglutination was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. In a XRPD study only weak reflexes were found (see appended
A Solution of 20 mg candesartan-cilextil and 10 PVP in 200 ml dichloromethane was prepared. This clear solution was added dropwise to 0.1 g PEC under permanent mixing. If agglutination was observed mixing was continued until a fine powder was achieved, only than the next drop of solution was added. In a XRPD study only very weak reflexes were found (see appended
| Number | Date | Country | Kind |
|---|---|---|---|
| 08158678.6 | Jun 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2009/057688 | 6/19/2009 | WO | 00 | 12/22/2011 |
