CA2393737A1 - Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption - Google Patents
Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption Download PDFInfo
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- CA2393737A1 CA2393737A1 CA002393737A CA2393737A CA2393737A1 CA 2393737 A1 CA2393737 A1 CA 2393737A1 CA 002393737 A CA002393737 A CA 002393737A CA 2393737 A CA2393737 A CA 2393737A CA 2393737 A1 CA2393737 A1 CA 2393737A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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Abstract
The present invention relates to agent containing itraconazole - with both improved bioavailability, due to higher water-solubility and impressively reduced difference of pH-dependent solubility, and narrow intra- and inter- individual variation of its absorption- and a manufacturing method thereof. Agent containing itraconazole of the present invention consists of itraconazole, water-soluble macromolecule of 10-100 % w/w to itracotazole, solubilizing agent of 0.1-100 % w/w to itraconazole and pharmaceutically allowed additives. Agent containing itraconazole of the present invention minimizes absorption variation by dozing time after food intake as well as i s available for adults with hypoacidity, AIDS patients and normal people. In addition, the manufacturing method introduces the elementary process, the spray drying, thereby control of physical properties of particles containing drug is easier and economy/production is improved.
Description
COMPOSITIONS CONTAINING ITRACONAZOLE WITH IMPROVED
BIOAVAILABILITY AND NARROYv' INTRA- AND
INTER-INDIVIDUAL VARIATION OF ITS ABSORPTION
FIELD OF THE INVENTION
The present invention relates to a composition containing itraconazole, which shows both high water solubility and narrow difference of its solubility according to pH, thereby representing excellent bioavailability and a narrow intra- and inter-individual variation range in the absorption into the body and to a preparation method thereof. Itraconazole-containing composition of the present invention comprises itraconazole, water-soluble macromolecules at the amount of 10-1,OOOo w/w based on the weight of itraconazole, solubilizing agents at an amount of 0.1-1000 w/w based on the weight of itraconazole, and pharmaceutically acceptable additives. It is prepared by spray-drying itraconazole along with the water-soluble macromolecules and the solubilizing agents.
In the spray-drying technique, the characteristic ordered crystalline structure of itraconazoie could be turned into the disordered one and the water-soluble macromoieculeconvertsthe resulting disordered structure of particles into more hydrophilic one while the WO 01141?65 PCT/KR99100854 solubilizing agent could act to make the composition itself soluble and to improve the wettability. In addition, the spray-drying technique results in producing particles as small as several microns in size. Thus, there can be provided a composition, which is greatly improved in the bioavailability of itraconazole, a practically insoluble drug. Furthermore, itraconazole-containing composition prepared according to the present invention shows almost constant solubility at the pH variation which may occur in the stomach, so that the drug can be maximally absorbed into the body with a minimum of absorption variation. In addition, according to the present invention, no interactions occur between the particles, allowing the spec-fic area of particles to be enlarged without making them hydrophobic.
DESCRIPTION OF THE PRIOR ART
in spite of its excellent in vitro anti-fungal effect itracorazole is hard to dissolve in water, which could not sans-y the first step for the absorption of drug into the body fluid. It has been reported that itraccnazole could be re'-atively a little soluble in very acidic aqueous solution, but it is just only 1 ~g/ml or less even in a s~rorg acidic condition (e.g., pH 1.2j. That is, in order to solubilize 100 mg of itraconazole, it needs at a least 100 liters of a strong acidic solution. In fact, itraconazole itself is practically impossible to apply to the body.
In addition, although being in a dosage form which is designed to be readily absorbed into the body, drugs that are sparingly soluble and/or practically insoluble in water show a serious absorption variation between individuals and may vary even in the same individual.
Itraconazole, which is relatively a little soluble in the stomach under a strong acidic condition, is made more serious in absorption variation depending upon gastric pH and gastric emptying time.
As widely known, the gastrointestinal pH condition is changed even in the same individual. In particular, the characteristic pH fluctuation within the stomach is known to be very large , that is , f rom 1 to 3 . 5 . Further, even in the same individual, greatly different gastric emptying times are observed. Generally, in a fasting condition, the period of time it takes for orally administered tableLS to pass through the stomach into the small intestine is reported to be as short as 10 min.
and as long as 2 hours or more.
Accordingly, the absorption o~ itraconazole could WO 01141765 PCT/KIt99100854 be seriously improved if the gastric emptying time is extended with the gastric pH maintaining at a strong acidity.
Indeed, when commercially available itraconazole-containing formulation agents were administeredto personsin afed condition,their adsorption was reported to increase twice or more comcared with that in a fasting condition. The reason was estimated that food intake stimulated gastric acid secretion and delayed the gastric emptying time (Influence ef concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluccnazole, Eur. J. Clin.
Pharmacol. , 1994, 46, p147; The effects of food and dose of the oral systemic availabilityof itraconazole in healthy subjects, Eur. J. Clin. Pharmacol., 1989, 36, p423).
Such results show that conventional formulations still suffer from being unable to reduce the intra- and inter-individual absorption variation, although they adopt multiple-unit dosage forms in order to extend the gastric emptying time and/or reduce the variation of passage into the small intestine as well as emplcy water-soluble macromolecules so as to hydrophilize i~ra-conazole.
Therefore, ir_ order to develop exceller_t r 'traconazole-containing compcs-Lions, not only must the solubility of the drug itself be increased, bu~~ also tre intra- and inter-ir_dividual absorption variation has to be lowered.
Recently, extensive research has been conducted to develop techniques of improving the solubility of itraconazole in water to facilitate its absorption into the body, reporting the increase in the water solubility of cyclodextrin inclusion complexes of itraconazole with the improved bioavailability (W085/02767, US-4,764,604), bead dosage forms using water-soluble macromolecules (WO
94/05263, KR 9'~-'702826) and inclusion compounds using cyclodextrin (WO 95/08993) for oral adminstration, and suggesting topical dosage forms using liposomes (WO
93/1571 9) . In a recent few years, the method to increase the solubility of itraconazole by use of spray-drying technique (WO 98/57967, KR 99-1564) or melt extrusion technique in combination with water-soluble macromolecules (WO 97/44014) have been developed.
According to the above techniques, the solubility of itraconazole increased to some extent, but there remains the drawback that the solubility of itraconazole itself is greatly lowered even upon a little increase of pH.
In particular, at around pH 2 , itraconazole is not dissolved even at an amount of 1 ~~g/ml. When considering on the basis of the research result in which humans have a normal ~H range of about 1 tc 3 . 5 and 15 0 of adults is revea 1 ed to have over 3 . 0, the solubility redaction of itraconazole due to the pH change could provide a factor of causing the intra- and inter-individual absorption variation of itraconazole (The design and evaluation of controlled release systems for the gastro-intestinal tract-In:
Advances in drug delivery systems, J. M. Anderson and S. W. Kim eds., Elsevier, Amsterdam, 1986, p27-38;
Comportment pharmacocinetigue des spheroides: apport et interet en clinique-Proceed. Symp. Capsugel, Paris, 1987, pp.73-81).
It was observed that persons with insufficient amounts of gastric acid could not absorb ketoconazole and itraconazole easily. As for AIDS patients, for example, their absorption of itraconazole was reported to be no more than 50 0 of that of normal persons (The pharmacokinetics of oral itraconazole in AIDS patients, J. Pharm. Pharmacol., 44, 1992, p618).
Therefore, there still remains an urgent need for dosage forms, which could surmount the absorption difference of itraconazole resulting from the intra- or inter-individual difference of gastrointestinal physiology.
According to the melt extrusion method (WO 97/44014 ) , which is one of the techniques for formulating itraconazole, the drug and a macromolecule are melted simultaneously anc congealed. In this case, the difference betcaeen the melting temperature and the decomposition temperature of the drug or the macromolecule is not so large, scrupulous care must be taken of temperature control. The fact that macromolecules with greater average molecular weights have a higher melting temperature makes the range of selectable macromolecules narrower. In addition, the heat or physical abrasion generated during the pulverization of the molten material is highly apt to make the drug' s crystal l ine structure , i . a . , f rom amorphous state to crystalline one. The resulting size of particles considerably increases up to 600 ~m and their distribution is wide, so that it is difficult to obtainuniformparticles .
When serious account is taken of the fact that the dissoiutionof drugs is usuallyproportional to the specific area of particles, the above events may be problematic.
Irrespective of their sizes, the particles which experience pulverization in the melt extrusion method could be aggregated and reduced in wettability and thus, a further process of removing these phenomena should be needed in the method.
The spray-drying method has been widely used in the pharrraceuticalindustry or other manufacturingindustr-es by virtue ef its ability to solidify materials dissolved ~n solvent through only one process. In addition, this r method can produce fine particles as f final products, modify the properties of main ingredients by addition of other ingredients into the liquid phase. (EP00436373AI) This could be conducted at relatively low temperatures enougr to evaporate solvents within a very short time, and has no serious bad influence on the properties of drugs or other excipi.ents because, even if in a very high temperature condition, the exposure time is no more than 1 sec. In addition, this method has advantages of being capable of improving the flowability of spray-dried materials and showing little inter-particular reaction as well as requiring no additionalprocessessuch asthe pulverization of particles or granulation.
Itwasproposedthatspray-dried materials containing itraconazole could be obtained by using pH-dependently soluble macromolecules, that is, macromolecules which could be dissolved at below pH 5 (WO 9933467A1).
However, the above macromolecules used in this technique are problematic in that they cannot guarantee the drug solubility large enough for the drug to be adsorbed in the normal variation of gastric pH, i . a . , 1 -3 . 5 because not only itraconazole itself , but also the macromolecules are great7.y decreased in solubility when tre pH moves toward the neutral even if it stile remains acidic.
Leading to the present invention , the ef fort of the WO 011417b5 PCTIKR99/00854 present inventors, which has been made to develop itraconazole dosage forms with improved solubility of ' water-insoluble itraconazole and reduced difference of solubility according to pH change, resulted in the finding that, when itraconazole is dissolved along with macromolecules and solubilizing agents and then added with pharmaceutically acceptable excipients, there could be obtaineditraconazole-containing compositionsin which the above-mentioned problems can be solved.
SUMMARY OF THE INVENTION
The present invention is aimed toprovide compositions containing itraconazole with improved solubility and its narrow variation according to normal change of gastric pH by spray-drying along with at least one water-soluble macromolecule and at least one solubilizing agent . These properties could make the bioavailability of itraconazole be enhanced and moreover, would minimize intra- and inter-individual absorption difference.
In order to achieve the above object, the present invention provides an itraconazole-containing compositicns,whichcemprisesi~racenazole,water-soluble macromolecu_es at an amount of 10 to 1,000 ow/w based on the weight of itraconazole, solubilizing agents at an amount of 0.1 to 100 %w/w based on the weight of itraconazole, and pharmaceutically acceptable additives.
In addition, the present invention provides a method for preparing an itraconazole-containing compositions characterized as following; itraconazole is mixed up with water-soluble macromolecules at an amount of 10 to 1,000%w/wbased on the weight ofitraconazole, solubilizing ager_ts at an amount of 0. 1 to 100 %w/w based on the weight of itraconazole and pharmaceutically acceptable additives and then spray-dried.
Examples of the water-soluble macromolecule available in the present invention include cellulose derivatives, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polyalkylene oxide or polyalkylene glycol and one or more selected from these compounds may be used.
Examples of the cellulose useful in the present invention include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethyl cel,~ulose, carboxymethylcellulose, sodium carboxymethylcell~alose, carboxymethylethylcellulose.
WO 01!41765 PCT/KR99/00854 Examples of the solubilizing agent available in the present invention include surfactants or amphiphiles.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors used water-soluble macromolecules in order to get the crystalline structure of itraconazole eliminated in the final material and establish hydrophillic conditions around the drug molecules or particles . On the purpose of obtaining previous both properties the said macromolecules must be added more than a critical portion. However, adding the said macromolecules in relatively excess would bring the increase of the hardness of the final product , a . g . , tablet .
This property itself can lead poor disintegration of the final product when exposed into water and moreover, the macromolecule is excessively swollen to form a membrane surrounding the final product, thereby preventing water from penetrating it . Therefore, the portion of the said macromolecule must be determined in such a range that the composition is not difficult to formulate into a dosage form.
The most characteristic feature of the above formu-~ation design is that itraconazole molecules are surrounded by water-soluble polymers with the aim of losing the crvstallinity of the itraconazole and improving its li WO 01!41765 PCT/KR99100854 hydrophilicity. However, tre resulting spray-dried composition shows a large solubility difference over the general gastric pH range (pH _-3.5) therefore, it is unsuitable to reduce the absorption variation. This problem results from the fact chat the spray-dried composition, on the contrary to the expectation, still retainsthe characteristic crystallinity ef itraconazole.
When an ordered and a disordered type of a drug coexist , the maximum solubility and the maximum dissolution rate of the drug are greatly aependmt on the proportion of the disordered type (The effects of disordered structure on the solubility and dissolution rate of some hydrophilic, sparingly soluble drugs, Int. J. Pharm. 177, 1999, p29).
In this case, the solubility cannot outgo the limit of the disordered type. Therefore, in order to maximize the solubility, the physical properties of the remained ordered drug must be changed.
In the present invention, water-soluble macromolecules were used to improve the solubility and widely used common solubilizing agents were added for the purpose of the solubilization of an ordered drug.
As tre solubilizing agents useful in the present inve::tion, surfactants and amphiphiles are exemplified.
Examples of the surfactants available in the present invention include anionic surfactants, cationic surfactants, and non-ionic surfactants, and one or more selected from these can be used.
Examples of the anionic surfactants available in the present invention include sodium docusate and sodium lauryl sulfate while benzalkonium chloride, benzethonium chloride and cetrimide may be used as the cationic surfactants. As the non-ionic surfactants, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, and sorbitan esters are exemplified.
Available as the amphiphile in the present invention are polyethylene-polypropylene copolymer and polyoxyethylene-polyoxypropylene copolymer (Poloxamer);
Gelucire'IV' such as propylene glycol monocaprylate , oleoyl macrogol-5-glyceride, linoleoyl macrogol-6-glyceride, caprylocaproyl macrogol-e-glyceride; propylene glycol monolaurate and polyglyceryl-6-dioleate.
The addition of the surfactants or amphiphiles is generally known to improve wettability as well as solubilization of the sparingly soluble drug. In particular, the addition of surfactants or amphiphiles is reported to bring about a better improvement in she solubilizaticnthanthewettability. Therefore, by adding WO 01/41765 PCT/KIt99100854 such additives, the solubilization of disordered and ordered type itraconazole can be facilitated. Of the above-mentioned additives, cationic surfactants and Poloxamer particularly showed best results. When the two materials were added, the solubility was measured to increase by 1.1-3 times at pH 1.6 and by 2.5-12 times at pH 2.4 than when not used, so that the solubility ratio between the both pHs (pH 1.6/pH 2.4) could be reduced down to 1.4 . This value demonstrated that the solubility difference of itraconazole between the both pHs is remarkably imp=oved by the composition of the present invention when being compared with 5.3 which is the solubility ratio in SporanoxT"', a commercially available itraconazole capsule. Therefore, the composition of the presentinvention can greatly decrease the bioavailability variation of itraconazole, which is supposed to originate from characteristic intra- and inter-individual gastric pH fluctuation as well as properties of food.
In the case that these materials were added to sole itraconazole priortothespray-drying,aslightlyimproved effect was obtained, but was very low, compared with that obtair_ed when app~~ied to the spray-dried material. It is believed that the so-~ubi-~izing e'fect of the added materials hardly acts to reduce the crystallizatior_ er_ergy of itraconazole itself. Thus, this shows that the solubility-increasing effect resultingfrom the addition of such amphiphiles must be fundamentally accompanied by the method that can eliminate the ordered structure of itraconazole itself by such as spray-drying method.
Accordingly, the inventors of the present invention conducted research to seek for the suitable condition under which the water-soluble macromolecules and the surfactants or amphiphiles can be spray-dried along with itraconazole. Upon spray-drying, account must be taken of the viscosity and solid content of the spray drying solution, the shape and flowability of the spray-dried material, and the particle size and particle size distribution of the spray-dried material. In addition, when the final spray-dried material is formulated into tablets or capsules, it is important for the dosage forms to have the physical properties satisfying the pharmaceutical features, such as disintegration, dissolution and sc forth. The reason is that, if the spray-dried material, ever_ though showing highest solubility, shows very poor pharmaceutical reatures, it is severely difficult to commercialize with good pharmacokinetic properties, which is indicative of its good absorption into the body.
In the present invention, therefore, theme are suggested the spray drying condition wric:~ are optimal l~
to improve the solubility of itraconazole and to provide pharmaceutically acceptable propertiesfor itraconazole.
I) Preparation of Spray-Drying Solution Itraconazole, the water-soluble macromolecule and the solubilizing agents were dissolved in a single or mixed solvent system composed of dichloromethane, chloroform, ethanol and/or methanol, and then an excipient (s) selected from salts such as sodium chloride or saccharides such as sugar and lactose or other pharmaceutical diluents such as microcrystalline cellulose, dibasic calcium phosphate, starch or mannitol is/are added at an amount of 0-100 ow/w based on the weight of itraconazole and f finally a lubricant such as magnesium stearate, talc, glyceryi. behenate and etc., is added at an amount of 0-50 ow/w based on the weight of itraconazole.
BIOAVAILABILITY AND NARROYv' INTRA- AND
INTER-INDIVIDUAL VARIATION OF ITS ABSORPTION
FIELD OF THE INVENTION
The present invention relates to a composition containing itraconazole, which shows both high water solubility and narrow difference of its solubility according to pH, thereby representing excellent bioavailability and a narrow intra- and inter-individual variation range in the absorption into the body and to a preparation method thereof. Itraconazole-containing composition of the present invention comprises itraconazole, water-soluble macromolecules at the amount of 10-1,OOOo w/w based on the weight of itraconazole, solubilizing agents at an amount of 0.1-1000 w/w based on the weight of itraconazole, and pharmaceutically acceptable additives. It is prepared by spray-drying itraconazole along with the water-soluble macromolecules and the solubilizing agents.
In the spray-drying technique, the characteristic ordered crystalline structure of itraconazoie could be turned into the disordered one and the water-soluble macromoieculeconvertsthe resulting disordered structure of particles into more hydrophilic one while the WO 01141?65 PCT/KR99100854 solubilizing agent could act to make the composition itself soluble and to improve the wettability. In addition, the spray-drying technique results in producing particles as small as several microns in size. Thus, there can be provided a composition, which is greatly improved in the bioavailability of itraconazole, a practically insoluble drug. Furthermore, itraconazole-containing composition prepared according to the present invention shows almost constant solubility at the pH variation which may occur in the stomach, so that the drug can be maximally absorbed into the body with a minimum of absorption variation. In addition, according to the present invention, no interactions occur between the particles, allowing the spec-fic area of particles to be enlarged without making them hydrophobic.
DESCRIPTION OF THE PRIOR ART
in spite of its excellent in vitro anti-fungal effect itracorazole is hard to dissolve in water, which could not sans-y the first step for the absorption of drug into the body fluid. It has been reported that itraccnazole could be re'-atively a little soluble in very acidic aqueous solution, but it is just only 1 ~g/ml or less even in a s~rorg acidic condition (e.g., pH 1.2j. That is, in order to solubilize 100 mg of itraconazole, it needs at a least 100 liters of a strong acidic solution. In fact, itraconazole itself is practically impossible to apply to the body.
In addition, although being in a dosage form which is designed to be readily absorbed into the body, drugs that are sparingly soluble and/or practically insoluble in water show a serious absorption variation between individuals and may vary even in the same individual.
Itraconazole, which is relatively a little soluble in the stomach under a strong acidic condition, is made more serious in absorption variation depending upon gastric pH and gastric emptying time.
As widely known, the gastrointestinal pH condition is changed even in the same individual. In particular, the characteristic pH fluctuation within the stomach is known to be very large , that is , f rom 1 to 3 . 5 . Further, even in the same individual, greatly different gastric emptying times are observed. Generally, in a fasting condition, the period of time it takes for orally administered tableLS to pass through the stomach into the small intestine is reported to be as short as 10 min.
and as long as 2 hours or more.
Accordingly, the absorption o~ itraconazole could WO 01141765 PCT/KIt99100854 be seriously improved if the gastric emptying time is extended with the gastric pH maintaining at a strong acidity.
Indeed, when commercially available itraconazole-containing formulation agents were administeredto personsin afed condition,their adsorption was reported to increase twice or more comcared with that in a fasting condition. The reason was estimated that food intake stimulated gastric acid secretion and delayed the gastric emptying time (Influence ef concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluccnazole, Eur. J. Clin.
Pharmacol. , 1994, 46, p147; The effects of food and dose of the oral systemic availabilityof itraconazole in healthy subjects, Eur. J. Clin. Pharmacol., 1989, 36, p423).
Such results show that conventional formulations still suffer from being unable to reduce the intra- and inter-individual absorption variation, although they adopt multiple-unit dosage forms in order to extend the gastric emptying time and/or reduce the variation of passage into the small intestine as well as emplcy water-soluble macromolecules so as to hydrophilize i~ra-conazole.
Therefore, ir_ order to develop exceller_t r 'traconazole-containing compcs-Lions, not only must the solubility of the drug itself be increased, bu~~ also tre intra- and inter-ir_dividual absorption variation has to be lowered.
Recently, extensive research has been conducted to develop techniques of improving the solubility of itraconazole in water to facilitate its absorption into the body, reporting the increase in the water solubility of cyclodextrin inclusion complexes of itraconazole with the improved bioavailability (W085/02767, US-4,764,604), bead dosage forms using water-soluble macromolecules (WO
94/05263, KR 9'~-'702826) and inclusion compounds using cyclodextrin (WO 95/08993) for oral adminstration, and suggesting topical dosage forms using liposomes (WO
93/1571 9) . In a recent few years, the method to increase the solubility of itraconazole by use of spray-drying technique (WO 98/57967, KR 99-1564) or melt extrusion technique in combination with water-soluble macromolecules (WO 97/44014) have been developed.
According to the above techniques, the solubility of itraconazole increased to some extent, but there remains the drawback that the solubility of itraconazole itself is greatly lowered even upon a little increase of pH.
In particular, at around pH 2 , itraconazole is not dissolved even at an amount of 1 ~~g/ml. When considering on the basis of the research result in which humans have a normal ~H range of about 1 tc 3 . 5 and 15 0 of adults is revea 1 ed to have over 3 . 0, the solubility redaction of itraconazole due to the pH change could provide a factor of causing the intra- and inter-individual absorption variation of itraconazole (The design and evaluation of controlled release systems for the gastro-intestinal tract-In:
Advances in drug delivery systems, J. M. Anderson and S. W. Kim eds., Elsevier, Amsterdam, 1986, p27-38;
Comportment pharmacocinetigue des spheroides: apport et interet en clinique-Proceed. Symp. Capsugel, Paris, 1987, pp.73-81).
It was observed that persons with insufficient amounts of gastric acid could not absorb ketoconazole and itraconazole easily. As for AIDS patients, for example, their absorption of itraconazole was reported to be no more than 50 0 of that of normal persons (The pharmacokinetics of oral itraconazole in AIDS patients, J. Pharm. Pharmacol., 44, 1992, p618).
Therefore, there still remains an urgent need for dosage forms, which could surmount the absorption difference of itraconazole resulting from the intra- or inter-individual difference of gastrointestinal physiology.
According to the melt extrusion method (WO 97/44014 ) , which is one of the techniques for formulating itraconazole, the drug and a macromolecule are melted simultaneously anc congealed. In this case, the difference betcaeen the melting temperature and the decomposition temperature of the drug or the macromolecule is not so large, scrupulous care must be taken of temperature control. The fact that macromolecules with greater average molecular weights have a higher melting temperature makes the range of selectable macromolecules narrower. In addition, the heat or physical abrasion generated during the pulverization of the molten material is highly apt to make the drug' s crystal l ine structure , i . a . , f rom amorphous state to crystalline one. The resulting size of particles considerably increases up to 600 ~m and their distribution is wide, so that it is difficult to obtainuniformparticles .
When serious account is taken of the fact that the dissoiutionof drugs is usuallyproportional to the specific area of particles, the above events may be problematic.
Irrespective of their sizes, the particles which experience pulverization in the melt extrusion method could be aggregated and reduced in wettability and thus, a further process of removing these phenomena should be needed in the method.
The spray-drying method has been widely used in the pharrraceuticalindustry or other manufacturingindustr-es by virtue ef its ability to solidify materials dissolved ~n solvent through only one process. In addition, this r method can produce fine particles as f final products, modify the properties of main ingredients by addition of other ingredients into the liquid phase. (EP00436373AI) This could be conducted at relatively low temperatures enougr to evaporate solvents within a very short time, and has no serious bad influence on the properties of drugs or other excipi.ents because, even if in a very high temperature condition, the exposure time is no more than 1 sec. In addition, this method has advantages of being capable of improving the flowability of spray-dried materials and showing little inter-particular reaction as well as requiring no additionalprocessessuch asthe pulverization of particles or granulation.
Itwasproposedthatspray-dried materials containing itraconazole could be obtained by using pH-dependently soluble macromolecules, that is, macromolecules which could be dissolved at below pH 5 (WO 9933467A1).
However, the above macromolecules used in this technique are problematic in that they cannot guarantee the drug solubility large enough for the drug to be adsorbed in the normal variation of gastric pH, i . a . , 1 -3 . 5 because not only itraconazole itself , but also the macromolecules are great7.y decreased in solubility when tre pH moves toward the neutral even if it stile remains acidic.
Leading to the present invention , the ef fort of the WO 011417b5 PCTIKR99/00854 present inventors, which has been made to develop itraconazole dosage forms with improved solubility of ' water-insoluble itraconazole and reduced difference of solubility according to pH change, resulted in the finding that, when itraconazole is dissolved along with macromolecules and solubilizing agents and then added with pharmaceutically acceptable excipients, there could be obtaineditraconazole-containing compositionsin which the above-mentioned problems can be solved.
SUMMARY OF THE INVENTION
The present invention is aimed toprovide compositions containing itraconazole with improved solubility and its narrow variation according to normal change of gastric pH by spray-drying along with at least one water-soluble macromolecule and at least one solubilizing agent . These properties could make the bioavailability of itraconazole be enhanced and moreover, would minimize intra- and inter-individual absorption difference.
In order to achieve the above object, the present invention provides an itraconazole-containing compositicns,whichcemprisesi~racenazole,water-soluble macromolecu_es at an amount of 10 to 1,000 ow/w based on the weight of itraconazole, solubilizing agents at an amount of 0.1 to 100 %w/w based on the weight of itraconazole, and pharmaceutically acceptable additives.
In addition, the present invention provides a method for preparing an itraconazole-containing compositions characterized as following; itraconazole is mixed up with water-soluble macromolecules at an amount of 10 to 1,000%w/wbased on the weight ofitraconazole, solubilizing ager_ts at an amount of 0. 1 to 100 %w/w based on the weight of itraconazole and pharmaceutically acceptable additives and then spray-dried.
Examples of the water-soluble macromolecule available in the present invention include cellulose derivatives, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polyalkylene oxide or polyalkylene glycol and one or more selected from these compounds may be used.
Examples of the cellulose useful in the present invention include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethyl cel,~ulose, carboxymethylcellulose, sodium carboxymethylcell~alose, carboxymethylethylcellulose.
WO 01!41765 PCT/KR99/00854 Examples of the solubilizing agent available in the present invention include surfactants or amphiphiles.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors used water-soluble macromolecules in order to get the crystalline structure of itraconazole eliminated in the final material and establish hydrophillic conditions around the drug molecules or particles . On the purpose of obtaining previous both properties the said macromolecules must be added more than a critical portion. However, adding the said macromolecules in relatively excess would bring the increase of the hardness of the final product , a . g . , tablet .
This property itself can lead poor disintegration of the final product when exposed into water and moreover, the macromolecule is excessively swollen to form a membrane surrounding the final product, thereby preventing water from penetrating it . Therefore, the portion of the said macromolecule must be determined in such a range that the composition is not difficult to formulate into a dosage form.
The most characteristic feature of the above formu-~ation design is that itraconazole molecules are surrounded by water-soluble polymers with the aim of losing the crvstallinity of the itraconazole and improving its li WO 01!41765 PCT/KR99100854 hydrophilicity. However, tre resulting spray-dried composition shows a large solubility difference over the general gastric pH range (pH _-3.5) therefore, it is unsuitable to reduce the absorption variation. This problem results from the fact chat the spray-dried composition, on the contrary to the expectation, still retainsthe characteristic crystallinity ef itraconazole.
When an ordered and a disordered type of a drug coexist , the maximum solubility and the maximum dissolution rate of the drug are greatly aependmt on the proportion of the disordered type (The effects of disordered structure on the solubility and dissolution rate of some hydrophilic, sparingly soluble drugs, Int. J. Pharm. 177, 1999, p29).
In this case, the solubility cannot outgo the limit of the disordered type. Therefore, in order to maximize the solubility, the physical properties of the remained ordered drug must be changed.
In the present invention, water-soluble macromolecules were used to improve the solubility and widely used common solubilizing agents were added for the purpose of the solubilization of an ordered drug.
As tre solubilizing agents useful in the present inve::tion, surfactants and amphiphiles are exemplified.
Examples of the surfactants available in the present invention include anionic surfactants, cationic surfactants, and non-ionic surfactants, and one or more selected from these can be used.
Examples of the anionic surfactants available in the present invention include sodium docusate and sodium lauryl sulfate while benzalkonium chloride, benzethonium chloride and cetrimide may be used as the cationic surfactants. As the non-ionic surfactants, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, and sorbitan esters are exemplified.
Available as the amphiphile in the present invention are polyethylene-polypropylene copolymer and polyoxyethylene-polyoxypropylene copolymer (Poloxamer);
Gelucire'IV' such as propylene glycol monocaprylate , oleoyl macrogol-5-glyceride, linoleoyl macrogol-6-glyceride, caprylocaproyl macrogol-e-glyceride; propylene glycol monolaurate and polyglyceryl-6-dioleate.
The addition of the surfactants or amphiphiles is generally known to improve wettability as well as solubilization of the sparingly soluble drug. In particular, the addition of surfactants or amphiphiles is reported to bring about a better improvement in she solubilizaticnthanthewettability. Therefore, by adding WO 01/41765 PCT/KIt99100854 such additives, the solubilization of disordered and ordered type itraconazole can be facilitated. Of the above-mentioned additives, cationic surfactants and Poloxamer particularly showed best results. When the two materials were added, the solubility was measured to increase by 1.1-3 times at pH 1.6 and by 2.5-12 times at pH 2.4 than when not used, so that the solubility ratio between the both pHs (pH 1.6/pH 2.4) could be reduced down to 1.4 . This value demonstrated that the solubility difference of itraconazole between the both pHs is remarkably imp=oved by the composition of the present invention when being compared with 5.3 which is the solubility ratio in SporanoxT"', a commercially available itraconazole capsule. Therefore, the composition of the presentinvention can greatly decrease the bioavailability variation of itraconazole, which is supposed to originate from characteristic intra- and inter-individual gastric pH fluctuation as well as properties of food.
In the case that these materials were added to sole itraconazole priortothespray-drying,aslightlyimproved effect was obtained, but was very low, compared with that obtair_ed when app~~ied to the spray-dried material. It is believed that the so-~ubi-~izing e'fect of the added materials hardly acts to reduce the crystallizatior_ er_ergy of itraconazole itself. Thus, this shows that the solubility-increasing effect resultingfrom the addition of such amphiphiles must be fundamentally accompanied by the method that can eliminate the ordered structure of itraconazole itself by such as spray-drying method.
Accordingly, the inventors of the present invention conducted research to seek for the suitable condition under which the water-soluble macromolecules and the surfactants or amphiphiles can be spray-dried along with itraconazole. Upon spray-drying, account must be taken of the viscosity and solid content of the spray drying solution, the shape and flowability of the spray-dried material, and the particle size and particle size distribution of the spray-dried material. In addition, when the final spray-dried material is formulated into tablets or capsules, it is important for the dosage forms to have the physical properties satisfying the pharmaceutical features, such as disintegration, dissolution and sc forth. The reason is that, if the spray-dried material, ever_ though showing highest solubility, shows very poor pharmaceutical reatures, it is severely difficult to commercialize with good pharmacokinetic properties, which is indicative of its good absorption into the body.
In the present invention, therefore, theme are suggested the spray drying condition wric:~ are optimal l~
to improve the solubility of itraconazole and to provide pharmaceutically acceptable propertiesfor itraconazole.
I) Preparation of Spray-Drying Solution Itraconazole, the water-soluble macromolecule and the solubilizing agents were dissolved in a single or mixed solvent system composed of dichloromethane, chloroform, ethanol and/or methanol, and then an excipient (s) selected from salts such as sodium chloride or saccharides such as sugar and lactose or other pharmaceutical diluents such as microcrystalline cellulose, dibasic calcium phosphate, starch or mannitol is/are added at an amount of 0-100 ow/w based on the weight of itraconazole and f finally a lubricant such as magnesium stearate, talc, glyceryi. behenate and etc., is added at an amount of 0-50 ow/w based on the weight of itraconazole.
2) Spray-Drying Condition t;~pon spray-drying, the properties of the final spray-dried material are greatly dependent on inlet and outlet air temperature and the feeding rate and atomizing pressure of the solution for spray-drying . The inlet air temperature should be determined in such a range that itraconazole, the macromolecu~~es and the solubilizinc ager_ts are not p=~ysicochemicall-~r changed at all . The feeding rate and atomizing pressure of the solution should be set on she basis of the evaporating capacity of the 1 E.
spray-dryer used. In particular, since the outlet air temperatureis most critically related to the optimization of the total process, care must be taken of its control.
The higher is the atomizing pressure or the lower is the solid content of the spray-drying solution, the smaller are the particles of the spray-dried material. Higher air temperatures improved the flowability of the spray-dried particles, but resulted in increase of the bulk density in Lhe particles . Despite of being reported that the increase of specific areas of particles brings about the increase of dissolution rate or solubility, spray-dried materials containing aseverelyfine particles of several nm in the present invention showed rather decreased solubility, which is considered to result from inter-particular agglomeration or aggregation.
As a result of repetitive applications for the optimal spray-drying condition, such is the best that the feeding rate of the spray-drying solution is preferably 40-700 ml/min, the spray-drying pressure 0.5-? kg/cm2, the inlet air temperature 90-250 °C, the outlet air temperature 40-150 °C and the solid content of the spray-drying solution 0.5-20.0 %w/w, respectively.
Below, the present invention will be it more detail described through preferable examples. These examples intents to be more descriptive of, but not ~c limit the WO 01/41765 PCT/KR99100$54 scope of the present invention. It should be noted that various modifications could be made within the spirit and scope of the present invention.
EXAMPLE 1: Preparation of Spray-Dried Material 1 100 g of hydroxypropylmethylcellulose and 7 g of Poloxamer were dissolved in a mixture of ethanol and dichloromethane, and 100 g of itraconazole was added.
To the resulting solution, 1 g of sodium chloride and 1 g of magnesium stearate were added, and dispersed to produce homogeneousspray-dryingsolution. Thissolution was spray-dried at feeding rate of 150 ml/mir~, atomizing pressure of 0.5 kg/cm , inlet air temperature of 190 °C, and outlet air temperature of 110 °C.
EXAMPLES 2-23: Preparation of Spray-Dried Materials 2-23 Spray-dried materials were prepared in similar manners to that of Example 1 while the amounts of water-soluble macromolecules and solubilizing agents per 1C0 g cf itraconazole were used as indicated in Table 1, below.
Corr.positions cf Sp.ray-Dried Materials No. Drug Macromolecule(g) Solubilizing Component(g) Agent(g}
2 Itraconazole Methylcellulose (100) (100) 3 Itraconazole HPMC1 (100) (100) Itraconazole HPMC
(100) (150) Itraconazole Polyvinylpyrrolidone (100) (100) 6 Itraconazole Polyvinylalcohol (100) (100) 7 Itraconazole Polyvinylacetate (100) (100}
8 Itraconazole Polyethyleneoxide (100) (100) 9 Itraconazole HPCz (100} (100) Itraconazole HPMC Sodium lauryl (100) (100} sulfate(lj 11 Itraconazole HPMC Benzaliconium (100) (100) chloride(1) 12 Itraconazole HPMC Polyoxyethylene (100) (100) sorbitan ester(1) 13 Itraconazole HPMC(100) Sorbitan (100) ester(1) 14 Itraconazole HPMC Poloxamer (100) (100) (1) Itraconazole HPMC Gelucire (7.00) (100) (1) 16 Itraconazole HPMC Propylene (100) (100) glycol mor_claurate ( 1 j 17 Itraconazole HPMC Sodium lauryl (100 (100} sulfate(3) l raconazo a ~~ o mm aury (100) (100) sulfate (7) 19 Itraconazole HPMC Sodium lauryl (100) (100) sulfate (10) 20 Itraconazole HPMC Sodium lauryl (100) (100) sulfate (20) 2i Itraconazole HPMC Poloxamer (100) (100) (3) 22 Itraconazole HPMC Poloxamer (100) (100) (10) 23 Itraconazole HPMC Poloxamer (100) (1006 (20) =Hydroxypropylmethylcellulose Hydroxypropylcellulose EXPERIMENTAL EXAMPLE l: Sclubilities cf Spray-Dried Materials The spray-dried materials of Examples 1 tc 23 were formulated into tablets with good disintegratior_property and each of them was put into pH 1.6 and pH 2.4 buffer solutions, respectively. At predetermined time, samples were taken from the solutions, and centrifuged. The concentration of itraconazole ir_ its supernatant was measureu.
Solubiiities of Spray-Dried Materials Solubility(~g/ml) Solubility osition Ratio Com 6/pH 2.4}
(pH 1 p pH 1.6 pH 2.4 .
Exmp. 1 180 131 1.4 Exmp. 2 61 1 61.0 Exmp. 3 62 11 5.6 Exmp. 4 70 13 5.4 Exmp. 5 58 3 19.3 Exmp. 6 52 3 17.3 Exmp. 7 52 2 26.0 Exmp. 9 59 8 7.4 Exmp. 10 102 71 1.4 Exmp. 11 71 35 2.0 Exmp. 12 73 32 2.3 Exmp. 13 72 36 2.0 Exmp. 14 125 79 1.6 Exmp. 15 6B 27 2.5 Exmp. 16 75 31 2.4 Exmp. 17 137 B8 1.6 Exmp. 18 137 B5 1.6 Exmp. 19 124 78 1.6 Exmp. 20 120 78 1.5 Exmp. 21 161 108 1.5 Exmp. 22 178 128 1.4 Exmp. 23 172 115 1.5 SporanoxT'"capsule85 16 ~.3 Sporanox- n5 25 2.6 Tablet Eudragi t Tr ~ 3 14 4 . 5 E *
*EudragitT"' E was added at an amount of 15o based on the weight of itraconazole.
As apparent in the above results, the solubility of itraconazole was greatly improved when it was used together with water-soluble macromolecules than when used alone. In particular,cellulose derivatives brought about better impro~rement in the solubility than did other macromolecules. That is, when cellulose derivatives were added, higher solubility over the both pHs as well as far smaller differences in solubility between the both pHs were obtained than when other macromolecules were used.
Examples 10 to 16 in which surfactants and amphiphiles were used with the aim of solubilizing and improving the wettability, showed greatly increased solubilities compared with Example 3. Particularly at pH 2.4, the solubility of itraconazole increased 2.5 to 7 times.
From this, it is apparent that the solubilizing agents used give better effects as pH moves toward relatively higher regions. Consequently, these results indicate that the solubilizing agents are able to compensate for the characteristic pH fluctuation, which occurs within tre stomach of normal adults.
When sodium lauryl sulfate or Poloxamer '° , which both showed the best effects among the solubilizing agents used, gradually increased in their amounts, the solubility of itraconazole increased. However, when the amounts of sodium lauryl sulfate or PoloaxamerT~~' was over critical points, the solubility decreased unexpectedly. Thus, it is necessary to appropriate'_y control the amount of the solubilizing agents.
When serious attention is paid that the solubility of the composition of Exampl a 1 increased by about three times at p:~ 1 . 6 and by about twelve times at pH 2 . 4 , compared with that in the composition of Example 3, the solubilizing agent functions more critically in relatively high pH
ranges.
On the other hand, when Eudragit'T" E, a conventional pH-dependent macromolecule, was used, the solubility at pH 2.4 was only one fourth of that at pH 1.6. Thus, it is clearly evident that this conventional macromolecule still remains insufficient to overcome the variation due to the characteristic intra- and inter-individual gastric pH fluctuation. As for commercially available Sporanox~~' tablets and capsules, their solubility ratio between pH
1.6 and pH 2.4 was 2 or greater and, in particular, the capsules showed a solubility ratio of five, reflecting the i.ntra- and inter-individual absorption differencEs cf i~rGconazole as they are.
EXPERIMEI~TTA'~ EXAMPLE 2 : Di ssolution .,_ Spray-Dried G _~
Materials Using suitable excipients, spray-dried materials were manufactured into tablets and then, subjected to an dissolution test in a pH 1.2 buffer. After 30 min, more than 90% of itraconazole was released in the entire compositions.
EXPERIMENTAL EXAMPLE 3: Relative Bioavailability of Itraconazole-Containing Spray-Dried Materials Compared with a commercially available Sporanox~v capsule, the composition of Example 1 was tested for relative bioavailability in ten healthy volunteers in the fasting condition. To each group (n=5; , the SporanoxT~:
capsule with 100 mg of itraconazole and the composition of Example 1 with SO mg of itraconazole were administered and tested in a crossover. The concentration of itraconazole in blood thus obtained was given in Table 3, below.
Concentration of Itraconazole in Blood Level in Blood(ng/ml flours Example 1 Sporanox -~ Capsule (ltraccnazole 5Gmg) !Itraconazole 100mc) 2 =i 0.5 33 (36)* 11 (17) 1 91 (B1) 42 (63) 2 91 (42) 82 (83) 3 81 (40) 101 (83) 4 68 (32) 98 (66}
spray-dryer used. In particular, since the outlet air temperatureis most critically related to the optimization of the total process, care must be taken of its control.
The higher is the atomizing pressure or the lower is the solid content of the spray-drying solution, the smaller are the particles of the spray-dried material. Higher air temperatures improved the flowability of the spray-dried particles, but resulted in increase of the bulk density in Lhe particles . Despite of being reported that the increase of specific areas of particles brings about the increase of dissolution rate or solubility, spray-dried materials containing aseverelyfine particles of several nm in the present invention showed rather decreased solubility, which is considered to result from inter-particular agglomeration or aggregation.
As a result of repetitive applications for the optimal spray-drying condition, such is the best that the feeding rate of the spray-drying solution is preferably 40-700 ml/min, the spray-drying pressure 0.5-? kg/cm2, the inlet air temperature 90-250 °C, the outlet air temperature 40-150 °C and the solid content of the spray-drying solution 0.5-20.0 %w/w, respectively.
Below, the present invention will be it more detail described through preferable examples. These examples intents to be more descriptive of, but not ~c limit the WO 01/41765 PCT/KR99100$54 scope of the present invention. It should be noted that various modifications could be made within the spirit and scope of the present invention.
EXAMPLE 1: Preparation of Spray-Dried Material 1 100 g of hydroxypropylmethylcellulose and 7 g of Poloxamer were dissolved in a mixture of ethanol and dichloromethane, and 100 g of itraconazole was added.
To the resulting solution, 1 g of sodium chloride and 1 g of magnesium stearate were added, and dispersed to produce homogeneousspray-dryingsolution. Thissolution was spray-dried at feeding rate of 150 ml/mir~, atomizing pressure of 0.5 kg/cm , inlet air temperature of 190 °C, and outlet air temperature of 110 °C.
EXAMPLES 2-23: Preparation of Spray-Dried Materials 2-23 Spray-dried materials were prepared in similar manners to that of Example 1 while the amounts of water-soluble macromolecules and solubilizing agents per 1C0 g cf itraconazole were used as indicated in Table 1, below.
Corr.positions cf Sp.ray-Dried Materials No. Drug Macromolecule(g) Solubilizing Component(g) Agent(g}
2 Itraconazole Methylcellulose (100) (100) 3 Itraconazole HPMC1 (100) (100) Itraconazole HPMC
(100) (150) Itraconazole Polyvinylpyrrolidone (100) (100) 6 Itraconazole Polyvinylalcohol (100) (100) 7 Itraconazole Polyvinylacetate (100) (100}
8 Itraconazole Polyethyleneoxide (100) (100) 9 Itraconazole HPCz (100} (100) Itraconazole HPMC Sodium lauryl (100) (100} sulfate(lj 11 Itraconazole HPMC Benzaliconium (100) (100) chloride(1) 12 Itraconazole HPMC Polyoxyethylene (100) (100) sorbitan ester(1) 13 Itraconazole HPMC(100) Sorbitan (100) ester(1) 14 Itraconazole HPMC Poloxamer (100) (100) (1) Itraconazole HPMC Gelucire (7.00) (100) (1) 16 Itraconazole HPMC Propylene (100) (100) glycol mor_claurate ( 1 j 17 Itraconazole HPMC Sodium lauryl (100 (100} sulfate(3) l raconazo a ~~ o mm aury (100) (100) sulfate (7) 19 Itraconazole HPMC Sodium lauryl (100) (100) sulfate (10) 20 Itraconazole HPMC Sodium lauryl (100) (100) sulfate (20) 2i Itraconazole HPMC Poloxamer (100) (100) (3) 22 Itraconazole HPMC Poloxamer (100) (100) (10) 23 Itraconazole HPMC Poloxamer (100) (1006 (20) =Hydroxypropylmethylcellulose Hydroxypropylcellulose EXPERIMENTAL EXAMPLE l: Sclubilities cf Spray-Dried Materials The spray-dried materials of Examples 1 tc 23 were formulated into tablets with good disintegratior_property and each of them was put into pH 1.6 and pH 2.4 buffer solutions, respectively. At predetermined time, samples were taken from the solutions, and centrifuged. The concentration of itraconazole ir_ its supernatant was measureu.
Solubiiities of Spray-Dried Materials Solubility(~g/ml) Solubility osition Ratio Com 6/pH 2.4}
(pH 1 p pH 1.6 pH 2.4 .
Exmp. 1 180 131 1.4 Exmp. 2 61 1 61.0 Exmp. 3 62 11 5.6 Exmp. 4 70 13 5.4 Exmp. 5 58 3 19.3 Exmp. 6 52 3 17.3 Exmp. 7 52 2 26.0 Exmp. 9 59 8 7.4 Exmp. 10 102 71 1.4 Exmp. 11 71 35 2.0 Exmp. 12 73 32 2.3 Exmp. 13 72 36 2.0 Exmp. 14 125 79 1.6 Exmp. 15 6B 27 2.5 Exmp. 16 75 31 2.4 Exmp. 17 137 B8 1.6 Exmp. 18 137 B5 1.6 Exmp. 19 124 78 1.6 Exmp. 20 120 78 1.5 Exmp. 21 161 108 1.5 Exmp. 22 178 128 1.4 Exmp. 23 172 115 1.5 SporanoxT'"capsule85 16 ~.3 Sporanox- n5 25 2.6 Tablet Eudragi t Tr ~ 3 14 4 . 5 E *
*EudragitT"' E was added at an amount of 15o based on the weight of itraconazole.
As apparent in the above results, the solubility of itraconazole was greatly improved when it was used together with water-soluble macromolecules than when used alone. In particular,cellulose derivatives brought about better impro~rement in the solubility than did other macromolecules. That is, when cellulose derivatives were added, higher solubility over the both pHs as well as far smaller differences in solubility between the both pHs were obtained than when other macromolecules were used.
Examples 10 to 16 in which surfactants and amphiphiles were used with the aim of solubilizing and improving the wettability, showed greatly increased solubilities compared with Example 3. Particularly at pH 2.4, the solubility of itraconazole increased 2.5 to 7 times.
From this, it is apparent that the solubilizing agents used give better effects as pH moves toward relatively higher regions. Consequently, these results indicate that the solubilizing agents are able to compensate for the characteristic pH fluctuation, which occurs within tre stomach of normal adults.
When sodium lauryl sulfate or Poloxamer '° , which both showed the best effects among the solubilizing agents used, gradually increased in their amounts, the solubility of itraconazole increased. However, when the amounts of sodium lauryl sulfate or PoloaxamerT~~' was over critical points, the solubility decreased unexpectedly. Thus, it is necessary to appropriate'_y control the amount of the solubilizing agents.
When serious attention is paid that the solubility of the composition of Exampl a 1 increased by about three times at p:~ 1 . 6 and by about twelve times at pH 2 . 4 , compared with that in the composition of Example 3, the solubilizing agent functions more critically in relatively high pH
ranges.
On the other hand, when Eudragit'T" E, a conventional pH-dependent macromolecule, was used, the solubility at pH 2.4 was only one fourth of that at pH 1.6. Thus, it is clearly evident that this conventional macromolecule still remains insufficient to overcome the variation due to the characteristic intra- and inter-individual gastric pH fluctuation. As for commercially available Sporanox~~' tablets and capsules, their solubility ratio between pH
1.6 and pH 2.4 was 2 or greater and, in particular, the capsules showed a solubility ratio of five, reflecting the i.ntra- and inter-individual absorption differencEs cf i~rGconazole as they are.
EXPERIMEI~TTA'~ EXAMPLE 2 : Di ssolution .,_ Spray-Dried G _~
Materials Using suitable excipients, spray-dried materials were manufactured into tablets and then, subjected to an dissolution test in a pH 1.2 buffer. After 30 min, more than 90% of itraconazole was released in the entire compositions.
EXPERIMENTAL EXAMPLE 3: Relative Bioavailability of Itraconazole-Containing Spray-Dried Materials Compared with a commercially available Sporanox~v capsule, the composition of Example 1 was tested for relative bioavailability in ten healthy volunteers in the fasting condition. To each group (n=5; , the SporanoxT~:
capsule with 100 mg of itraconazole and the composition of Example 1 with SO mg of itraconazole were administered and tested in a crossover. The concentration of itraconazole in blood thus obtained was given in Table 3, below.
Concentration of Itraconazole in Blood Level in Blood(ng/ml flours Example 1 Sporanox -~ Capsule (ltraccnazole 5Gmg) !Itraconazole 100mc) 2 =i 0.5 33 (36)* 11 (17) 1 91 (B1) 42 (63) 2 91 (42) 82 (83) 3 81 (40) 101 (83) 4 68 (32) 98 (66}
5 46 (21) 78 (51) 6 40 (18) 65 (45) 8 33 (19) 53 (38) Mean C 114 (67) 109 (83) ma::
Mean AUC**521 (242) 547 (426) * Parentheses indicate standard deviation ** Cmax indicates the maximum concentration *** AUC indicates the area under the plasma concentation - time curve As seen in the data of Table 3, the composition of Example 1 containing 50 mg of itraconazole showed almost the same values in AUC - which is one of indices for the extent of drug absorption - and in C with the Sporanox'T' ma>:
capsulecontaininglOUmgof itraconazole, whichisprepared on the basis of WO 94/05263. Therefore, the composition of the present invention can reduce the administration dose of itraconazole to half of the control drug.
Particularly in the individual variation, the composition of the present invention was conspicuously improved compared with the control drug. By minimizing the solubility difference of itraconazole between the both pHs, the difference of drug absorption attributed to the characteristic intra- and inter-individual gastric pH fluctuation can be attenuated.
EXAMPLE 4: Relative Bioavailability of Itraconazole-Containing Spray-Dried Material Compared with a commercially available SporanoxT'v tablet, the composition of Example 1 was tested for relative bioavailability in ten healthy volunteers in the fasting condition. To each group (n=5) , the SporanoxT~' tablet with 100 mg of itraconazole and the composition of Example 1 with 100 mg of itraconazole were administered and tested in a crossover . The concentration of itraconazole in blood thus obtained was given in Table 4, below.
Itraconazole Level in Blood Level in Bl ood(ng/ml) Hours Example 1 Sporanox T"' Tablet (Itraconazole 100mg)(Itraconazole 100mg) 0.5 16 (6) 20 (16) 1 60 (35) 41 (27) 2 174 (71) 56 {21) 3 174 (40) 74 (34) 4 147 (29) 84 (36) 5 115 {27) 68 (35) 6 92 (27) 64 (35) 8 80 (26} 46 (25) Mean 193 (50) 90 (34) C
ma::
Mean BBO{247) 466(194) AUC
As apparent from the data of Table 4, the composition of Example 1 containing 100 mg of itraconazole showed improved bioavailability by two times under the fasting condition as compared with that of the SporanoxT'~ tablet containing the same amount of itraconazole . In the light of the mention of WO 97/44014 that the bioavailability of the Sporanox"r tablet is twice as high as that of the Sporanox-~~~ capsule, the composition of Example 1 containing 100 ma of itraconazole has an excel lent effect when compared with the Sporanox=''tablet as well as the SporanoxTv capsules which are now commercially available.
2?
The itraconazole-containing compositions o~ the presentinventionincrease the solubility ofitraconazole, which is water-insoluble, thereby improve its absorption into the body. In more detail, by reducing the absorption difference of itraconazole, which is attributed to the characteristic intra- or inter-individual gastric pH
fluctuation. and to food intake, the compositions of the present invention could be effectively applied for normal adults as well as persons with hypochlorhydria or AIDS
patients. In addition, the method for preparing itraconazole-containing compositions in accordance with the present invention adopts just a single process - spray drying -, which could be readily industrialized and control the physical properties of drug particles into the most suitable conditions for in vivo application.
Mean AUC**521 (242) 547 (426) * Parentheses indicate standard deviation ** Cmax indicates the maximum concentration *** AUC indicates the area under the plasma concentation - time curve As seen in the data of Table 3, the composition of Example 1 containing 50 mg of itraconazole showed almost the same values in AUC - which is one of indices for the extent of drug absorption - and in C with the Sporanox'T' ma>:
capsulecontaininglOUmgof itraconazole, whichisprepared on the basis of WO 94/05263. Therefore, the composition of the present invention can reduce the administration dose of itraconazole to half of the control drug.
Particularly in the individual variation, the composition of the present invention was conspicuously improved compared with the control drug. By minimizing the solubility difference of itraconazole between the both pHs, the difference of drug absorption attributed to the characteristic intra- and inter-individual gastric pH fluctuation can be attenuated.
EXAMPLE 4: Relative Bioavailability of Itraconazole-Containing Spray-Dried Material Compared with a commercially available SporanoxT'v tablet, the composition of Example 1 was tested for relative bioavailability in ten healthy volunteers in the fasting condition. To each group (n=5) , the SporanoxT~' tablet with 100 mg of itraconazole and the composition of Example 1 with 100 mg of itraconazole were administered and tested in a crossover . The concentration of itraconazole in blood thus obtained was given in Table 4, below.
Itraconazole Level in Blood Level in Bl ood(ng/ml) Hours Example 1 Sporanox T"' Tablet (Itraconazole 100mg)(Itraconazole 100mg) 0.5 16 (6) 20 (16) 1 60 (35) 41 (27) 2 174 (71) 56 {21) 3 174 (40) 74 (34) 4 147 (29) 84 (36) 5 115 {27) 68 (35) 6 92 (27) 64 (35) 8 80 (26} 46 (25) Mean 193 (50) 90 (34) C
ma::
Mean BBO{247) 466(194) AUC
As apparent from the data of Table 4, the composition of Example 1 containing 100 mg of itraconazole showed improved bioavailability by two times under the fasting condition as compared with that of the SporanoxT'~ tablet containing the same amount of itraconazole . In the light of the mention of WO 97/44014 that the bioavailability of the Sporanox"r tablet is twice as high as that of the Sporanox-~~~ capsule, the composition of Example 1 containing 100 ma of itraconazole has an excel lent effect when compared with the Sporanox=''tablet as well as the SporanoxTv capsules which are now commercially available.
2?
The itraconazole-containing compositions o~ the presentinventionincrease the solubility ofitraconazole, which is water-insoluble, thereby improve its absorption into the body. In more detail, by reducing the absorption difference of itraconazole, which is attributed to the characteristic intra- or inter-individual gastric pH
fluctuation. and to food intake, the compositions of the present invention could be effectively applied for normal adults as well as persons with hypochlorhydria or AIDS
patients. In addition, the method for preparing itraconazole-containing compositions in accordance with the present invention adopts just a single process - spray drying -, which could be readily industrialized and control the physical properties of drug particles into the most suitable conditions for in vivo application.
Claims (13)
1. An itraconazole-containing composition prepared by spray-drying itraconazale along with water-soluble macromolecules, solubilizing agents and pharmaceutically acceptable additives.
2. The itraconazole-containing composition as set forth in claim 1, wherein said water-soluble macromolecules are selected from the group consisting of cellulose derivatives; polyvinyl alcohol); polyvinyl pyrrolidone); polyvinyl acetate); poly(alkylene oxide);
and poly(alkylene glycol), and mixtures thereof.
and poly(alkylene glycol), and mixtures thereof.
3. The itraconazole-containing composition as set forth in claim 2, wherein said cellulose derivatives are methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, or carboxymethylethyl cellulose.
4. The itraconazole-containing composition as set forth in claim 1,wherein said water-soluble macromolecules are pH-independent and are used in the range of 10-1,000 %w/w based on the weight of itraconazole.
5. The itraconazole-containing composition as set forth in claim 1, wherein said solubilizing agents are surfactants or amphiphiles.
6. The itraconazole-containing composition as set forth in claim 5, wherein said surfactants are anionic surfactants comprising sodium docusate and sodium lauryl sulfate; cationic surfactants comprising benzalkonium chloride, benzethonium chloride and cetrimide; and non-ionic surfactants comprising glyceryl monooleate, polyoxyethylene sorbitan fatty acid ester and sorbitan ester.
7. The itraconazole-containing composition as set forth in claim 5, wherein said amphiphiles are prepared by using one or more materials selected from the group consisting of polyethylene-polypropylene copolymers and polyoxyethylene-polyoxypropylene copolymers (Poloxamer); propylene glycol monocaprylate, oleoyl macrogol-6-glyceride, linoleoyl macrogol-6-glyceride;
Gelucire TM comprising caprylocaproyl macrogol-8-glyceride; propylene glycol monolaurate; and polyglyceryl-6-dioleate.
Gelucire TM comprising caprylocaproyl macrogol-8-glyceride; propylene glycol monolaurate; and polyglyceryl-6-dioleate.
8. The itraconazole-containing composition as set forth in claim 1, wherein said solubilizing agents are used at an amount of 0.1-100 %w/w based on the weight of itraconazole.
9. The itraconazole-containing composition as set forth in claim 1, wherein the range of spray-dried particles, in size, from 10 nm to 100 µm.
10. The itraconazole-containing composition as set forth in claim 1, wherein said water-soluble macromolecules are hydroxypropyl methylcellulose and said solubilizing agents are Poloxamer.
11. The itraconazole-containing composition as set forth in claim 1, wherein 100 weight parts of itraconazole, 100 weight parts of hydroxypropyl methylcellulose, and 7 weight parts of Poloxamer were spray-dried.
12. The itraconazole-containing composition as set forth in claim 1, wherein the composition is in a form of tablet, coated tablet, hard capsule, soft capsule, suspension, suspending syrup, dry syrup, paste, liniment and spray.
13. A method for preparing an itraconazole-containing composition comprising the steps of:
1) Dissolving itraconazole, a water-soluble macromolecule and a solubilizing agent in a solvent and adding a pharmaceutically acceptable additive to give a spray-drying solution; and 2) Spray-drying the above solution at feeding rate of 40-700 ml/min, atomizing pressure of 0.5-7 kg/cm2, inlet air temperature of 90-250 °C, outlet air temperature of 40-150 °C, and solid content of the spray-drying solution of 0.5-20.0 %w/w.
1) Dissolving itraconazole, a water-soluble macromolecule and a solubilizing agent in a solvent and adding a pharmaceutically acceptable additive to give a spray-drying solution; and 2) Spray-drying the above solution at feeding rate of 40-700 ml/min, atomizing pressure of 0.5-7 kg/cm2, inlet air temperature of 90-250 °C, outlet air temperature of 40-150 °C, and solid content of the spray-drying solution of 0.5-20.0 %w/w.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019990055802A KR100694667B1 (en) | 1999-12-08 | 1999-12-08 | Itraconazole-containing antifungal agents that improve bioavailability and reduce absorption variation between and in individuals |
| KR1999/55802 | 1999-12-08 | ||
| PCT/KR1999/000854 WO2001041765A1 (en) | 1999-12-08 | 1999-12-31 | Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2393737A1 true CA2393737A1 (en) | 2001-06-14 |
Family
ID=19624262
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002393737A Abandoned CA2393737A1 (en) | 1999-12-08 | 1999-12-31 | Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1274432A4 (en) |
| JP (1) | JP2003516354A (en) |
| KR (1) | KR100694667B1 (en) |
| CN (1) | CN1398184A (en) |
| AU (1) | AU1896400A (en) |
| CA (1) | CA2393737A1 (en) |
| WO (1) | WO2001041765A1 (en) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010097244A (en) * | 2000-04-21 | 2001-11-08 | 유충식 | Pharmaceutical composition containing itraconazole with gastric ph-independently improved solubility and preparation method thereof |
| KR100432949B1 (en) * | 2000-06-13 | 2004-05-31 | 코오롱제약주식회사 | Itraconazole composition of the powders and granules type, its pharmaceutical preparation and method |
| KR100438485B1 (en) * | 2001-08-13 | 2004-07-09 | 한국디디에스제약 주식회사 | Pharmaceutical compositions containing of azole antifungal drugs |
| KR100425755B1 (en) * | 2001-08-27 | 2004-04-03 | 주식회사 원진신약 | Compositions containing itraconazole and their preparation methods |
| KR100441745B1 (en) * | 2001-11-30 | 2004-07-27 | 환인제약 주식회사 | Composition of itraconazole for oral administration and process for preparing thereof |
| WO2003063833A1 (en) | 2002-02-01 | 2003-08-07 | Pfizer Products Inc. | Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials |
| US6682759B2 (en) * | 2002-02-01 | 2004-01-27 | Depomed, Inc. | Manufacture of oral dosage forms delivering both immediate-release and sustained-release drugs |
| KR100557680B1 (en) * | 2002-11-23 | 2006-03-07 | 한국유나이티드제약 주식회사 | Pellets for the solubility improvement of itraconazole and preparation method thereof |
| ES2283725T5 (en) † | 2003-01-14 | 2014-11-28 | Acino Pharma Ag | Bioequivalent composition of itraconazole dispersed in a hydrophilic polymer |
| DE60312635T3 (en) † | 2003-01-14 | 2013-05-08 | Cimex Pharma Ag | A composition in the form of a solid dispersion containing itraconazole and a hydrophilic polymer having improved bioavailability |
| HU227142B1 (en) * | 2003-07-02 | 2010-08-30 | Egis Gyogyszergyar Nyilvanosan | Capsule of improved release containing fluconazole |
| CA2532931A1 (en) | 2003-08-04 | 2005-02-10 | Pfizer Products Inc. | Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials |
| US20050058670A1 (en) * | 2003-09-09 | 2005-03-17 | Jong-Soo Woo | Oral itraconazole composition which is not affected by ingested food and process for preparing same |
| CN1285590C (en) * | 2004-02-23 | 2006-11-22 | 上海医药工业研究院 | Itraconazole hydrochloride, oral solid combination and preparation method |
| US7507823B2 (en) | 2004-05-06 | 2009-03-24 | Bristol-Myers Squibb Company | Process of making aripiprazole particles |
| KR100555794B1 (en) * | 2005-03-17 | 2006-03-03 | 삼천당제약주식회사 | Oral Compositions Containing Itraconazole |
| MX2008012486A (en) * | 2006-03-27 | 2008-10-10 | Panacea Biotec Ltd | Sustained release pharmaceutical composition on the basis of a release system comprising an acid-soluble polymer and a ph-dependent polymer. |
| GB0613925D0 (en) * | 2006-07-13 | 2006-08-23 | Unilever Plc | Improvements relating to nanodispersions |
| GB0814953D0 (en) * | 2008-08-18 | 2008-09-24 | Unilever Plc | Improvements relating to nanodisperse compositions |
| WO2010137888A2 (en) * | 2009-05-27 | 2010-12-02 | 주식회사 삼양사 | Microspheres with improved bioavailability containing poorly water-soluble drugs, and method for preparing same |
| CN102309488A (en) * | 2010-07-02 | 2012-01-11 | 北京京卫燕康药物研究所有限公司 | Itraconazole medicinal composition and preparation method thereof |
| JP6730315B2 (en) * | 2015-01-20 | 2020-07-29 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Solid dispersion of compounds using polyvinyl alcohol as carrier polymer |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH30929A (en) * | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
| SK177598A3 (en) * | 1996-06-28 | 1999-07-12 | Schering Corp | Oral composition comprising a triazole antifungal compound |
| FR2758461A1 (en) * | 1997-01-17 | 1998-07-24 | Pharma Pass | PHARMACEUTICAL COMPOSITION HAVING HIGH BIOAVAILABILITY AND PROCESS FOR PREPARING THE SAME |
| KR19990001564A (en) * | 1997-06-16 | 1999-01-15 | 유충식 | Azole antifungal agents with improved solubility and preparations containing them |
| KR19990055802A (en) * | 1997-12-27 | 1999-07-15 | 김영환 | Semiconductor device manufacturing method |
| PT1039909E (en) * | 1997-12-31 | 2003-02-28 | Choongwae Pharma Corp | METHOD OF PRODUCTION AND COMPOSITION OF AN ORAL PREPARATION OF ITRACONAZOLE |
| KR100288890B1 (en) * | 1997-12-31 | 2001-05-02 | 최현식 | Itraconazole oral preparation and preparation method thereof |
| US7939105B2 (en) * | 1998-11-20 | 2011-05-10 | Jagotec Ag | Process for preparing a rapidly dispersing solid drug dosage form |
-
1999
- 1999-12-08 KR KR1019990055802A patent/KR100694667B1/en not_active Expired - Lifetime
- 1999-12-31 JP JP2001543110A patent/JP2003516354A/en not_active Withdrawn
- 1999-12-31 EP EP99962555A patent/EP1274432A4/en not_active Withdrawn
- 1999-12-31 AU AU18964/00A patent/AU1896400A/en not_active Abandoned
- 1999-12-31 CA CA002393737A patent/CA2393737A1/en not_active Abandoned
- 1999-12-31 CN CN99817076A patent/CN1398184A/en active Pending
- 1999-12-31 WO PCT/KR1999/000854 patent/WO2001041765A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| JP2003516354A (en) | 2003-05-13 |
| CN1398184A (en) | 2003-02-19 |
| EP1274432A4 (en) | 2004-11-10 |
| KR20010054823A (en) | 2001-07-02 |
| WO2001041765A1 (en) | 2001-06-14 |
| AU1896400A (en) | 2001-06-18 |
| KR100694667B1 (en) | 2007-03-14 |
| EP1274432A1 (en) | 2003-01-15 |
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