WO2001041765A1 - 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 PDF

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WO2001041765A1
WO2001041765A1 PCT/KR1999/000854 KR9900854W WO0141765A1 WO 2001041765 A1 WO2001041765 A1 WO 2001041765A1 KR 9900854 W KR9900854 W KR 9900854W WO 0141765 A1 WO0141765 A1 WO 0141765A1
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Prior art keywords
itraconazole
spray
composition
water
set forth
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PCT/KR1999/000854
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French (fr)
Korean (ko)
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Jong-Won Kwon
Jung-Hun Kim
Hun-Sik Wang
Sun-Woo Jang
Woong-Tak Bae
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Dong A Pharm. Co., Ltd.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1641Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1611Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats

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 is 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

BIOAVAI ABILITY AND NARROW 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 m the absorption into the body and to a preparation method thereof Itraconazole-containmg composition of the present invention comprises itraconazole, water-soluble macromolecules at the amount of 10-1,000% w/w based on the weight of itraconazole, solubilizmg agents at an amount of 0 1-100% 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 solubilizmg agents

In the spray drying technique, the characteristic ordered crystalline structure of itraconazole could be turned into the disordered one and the water-soluble macromolecule converts the resulting disordered structure of particles into more hydrophilic one while the solubilizmg agent couldact to make the composition itself soluble and to improve the wettability. In addition, the spray- drying technique results producing particles as small as several microns m size. Thus, there can be provided a composition, which is greatly improved the bioavailability of itraconazole, a practically insoluble drug. Furthermore, itraconazole-containmg composition prepared according to the present invention shows almost constant solubility at the pH variation which may occur m 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 mvention, no interactions occur between the particles, allowing the specific area of particles to be enlarged without making them hydrophobic

DESCRIPTION OF THE PRIOR ART

In spite of its excellent m vitro anti-fungal effect itraconazole is hard to dissolve m water, which could not satisfy the first step for the absorption of drug into the body fluid. It has been reported that itraconazole could be relatively a little soluble very acidic aqueous solution, but it s just only 1 ^g/ml or less even in a strong acidic condition (e.g , pH 1 2) That is, m order to solubilize 100 mg of itraconazole, it needs at least 100 liters of a strong acidic solution. In fact, itraconazole itself is practically impossible to apply to the body.

In addition, although being m a dosage form which is designed to be readily absorbed into the body, drugs that are sparingly soluble and/or practically insoluble water show a serious absorption variation between individuals and may vary even in the same individual Itraconazole, which is relatively a little soluble m the stomach under a strong acidic condition, is made more serious absorption variation depending upon gastric pH and gastric emptying time

As widely known, the gastrointestinal pH condition is changed even m the same individual In particular, the characteristic pH fluctuation within the stomach is known to be very large, that is, from 1 to 3.5 Further, even m the same individual, greatly different gastric emptying times are observed Generally, a fasting condition, the period of time it takes for orally administered tablets to pass through the stomach into the small intestine is reported to be as short as 10 mm and as long as 2 hours or more

Accordingly, the absorption of itraconazole could be seriously improved if the gastric emptying time is extended with the gastric pH maintaining at a strong acidity Indeed, when commercially available itraconazole-containmg formulation agents were administered to persons mated condition, their adsorption was reported to increase twice or more compared with that m a fasting condition The reason was estimated that food intake stimulated gastric acid secretion and delayed the gastric emptying time (Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole, Eur J Cl Pharmacol , 1994, 46, pl47, The effects of food and dose of the oral systemic availability of itraconazole healthy subjects, Eur J Cl 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 order to extend the gastric emptying time and/or reduce the variation of passage into the small intestine as well as employ water-soluble macromolecules so as to hydrophilize ltra-conazole Therefore, order to develop excellent itraconazole-containmg compositions not only must th= solubility of the drug itself be increased, but also the tia- and inter- individual aosorption variation has to be lowered

Recently, extensive research has been conducted to develop techniques of improving the solubility of itraconazole water to facilitate its absorption into the body, reporting the increase m the water solubility of cyclodextrm inclusion complexes of itraconazole with the improved bioavailability (WO 85/02767, US-4,764,604) , bead dosage forms using water-soluble macromolecules (WO 94/05263, KR 95-702826) and inclusion compounds using cyclodextrm (WO 95/08993) for oral admmstration, and suggesting topical dosage forms using liposomes (WO 93/15719) 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 m 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 , ataroundpH2, itraconazole is not dissolved even at an amount of 1 ug/ml When considering on the basis of the research result m which humans have a normal pH range of about 1 to 3 5 and 16 % of adults is revealed to have over 3 0 the solubility reduction 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 m drug delivery systems, J. M. Anderson and S W Kim eds , Elsevier, Amsterdam, 1986, p27-38, Comportment pharmacocmetigue des spheroides apport et mteret en clmique- 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 % of that of normal persons (The pharmacokmetics of oral itraconazole m 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 mtra- or inter- individual difference of gastrointestinal physiology

According to the melt extrusion method (WO 97/44014) , which is one of the techniques or formulating itraconazole , the drug and a macromolecule are melted simultaneously and congealed In this case, the difference between 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 crystalline structure , i e , from amorphous state to crystalline one The resulting size of particles considerably increases up to 600 μ and their distribution is wide , so that it is difficult to obtain uniform particles

When serious account is taken of the fact that the dissolution of drugs is usuallyproportional to the specific area of particles, the above events may be problematic

Irrespective of their sizes, the particles which experience pulverization m the melt extrusion method could be aggregated and reduced m wettability and thus, a further process of removing these phenomena should be needed m the method

The spray-drying method has been widely used m the pharmaceutical industry or other manufacturing industries by virtue of its ability to solidify materials dissolved m solvent through only one process In addition, this method can produce fine particles as final products , modify the properties of mam ingredients by addition of other ingredients into the liquid phase. (EP00436373A1 ) This could be conducted at relatively low temperatures enough to evaporate solvents within a very short time, and has no serious bad influence on the properties of drugs or other excip ents because , even if 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 mter-particular reaction as well as requiring no additional processes such as the pulverization of particles or granulation

It was proposed that spray-dπedmaterials 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 m this technique are problematic m that they cannot guarantee the drug solubility large enough for the drug to be adsorbed m the normal variation of gastric pH, I . e , 1 -3 5 because not only itraconazole itself, but also the macromolecules are greatly decreased m solubility when tne pH moves toward the neutral even if it still remains acidic

Leading to the present invention, the effort of the 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 the finding that, when itraconazole is dissolved along with macromolecules and solubilizmg agents and then added with pharmaceutically acceptable excipients, there could be obtained itraconazole-containmg compositions m which the above-mentioned problems can be solved

SUMMARY OF THE INVENTION

The present invention is aimed to provide 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 solubilizmg agent. These properties could make the bioavailability of itraconazole be enhanced and moreover, would minimize mtra- and inter- individual absorption difference

In order to achieve the above object, the present invention provides an itraconazole-containmg compositions, which comprises itraconazole , water-soluble macromolecules at an amount of 10 to 1,000 %w/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 mvention provides a method for preparing an itraconazole-containmg 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 of itraconazole , solubilizmg agents 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 m the present invention include cellulose derivatives, polyvmyl alcohol, polyv yl acetate, polyvmylpyrro1Idone , polyalkylene oxide or polyalkylene glycol and one or more selected from these compounds may be used.

Examples of the cellulose useful m the present invention include methylcellulose , ethylcellulose , hydroxymethylcellulose , hydroxyethylcellulose , hydroxyethylmethylcellulose , hydroxypropylmethyl cellulose, carboxymethylcellulose , sodium carboxymethylcellulose , carboxymethylethylcellulose Examples of the solubilizing agent available m the present invention include surfactants or amphiphiles.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors used water-soluble macromolecules m order to get the crystalline structure of itraconazole eliminated m the final material and establish hydrophillic conditions around the drug molecules orparticles . On the purpose of obtainingprevious both properties the said macromolecules must be added more than a critical portion. However, adding the said macromolecules m relatively excess would bring the increase of the hardness of the final product , e.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 m such a range that the composition is not difficult to formulate into a dosage form

The most characteristic feature of the above formulation design is that itraconazole molecules are surrounded by water- soluble polymers with the aim of losing the crystallmity of the itraconazole and improving its hydrophilicity . However, the resulting spray-dried composition shows a large solubility difference over the general gastric pH range (pH 1-3 5) therefore, it is unsuitable to reduce the absorption variation. This problem results from the fact that the spray-dried composition, on the contrary to the expectation, still retains the characteristic crystallmity of 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 dependent 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, 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 solubilizmg agents were added for the purpose of the solubilization of an ordered drug

As the solubilizmg agents useful m tne present invention, surfactants and amphiphiles are exemplified Examples of the surfactants available 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 m the present invention include sodium docusate and sodium lauryl sulfate while benzalkonium chloride, benzethonium chloride and cetπmide 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 m the present invention are polyethylene -polypropylene copolymer and polyoxyethylene-polyoxypropylene copolymer (Poloxamer) , Gelucire1 such as propylene glycol monocaprylate , oleoyl macrogol - 6 -glyceπde , lmoleoyl macrogol -6-glycerιde , caprylocaproyl macrogol-8 -glyceride , propylene glycol monolaurate and polyglyceryl-6-dιoleate

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 m the solubilization than the wettability Therefore, by adding 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 improved by the composition of the present invention when being compared with 5 3 which is the solubility ratio Sporanox™, a commercially available itraconazole capsule Therefore, the composition of the present invention can greatly decrease the bioavailability variation of itraconazole, which is supposed to originate from characteristic mtra- and mter-mdividual gastric pH fluctuation as well as properties of food

In the case that these materials were added to sole itraconazole prior to the spray- drying, a slightly improved effect was obtained, but was very low, compared with that obtained when applied to the spray-dried material It is believed that the solubilizmg effect of the added materials hardly acts to reduce the crystallization energy of itraconazole itself Thus this shows that the solubility - increasing effect resulting from 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-dry g 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-drieα along with itraconazole Upon spray-drymg, 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 so forth The reason is that, if the spray-dried material, even though showing highest solubility, shows very poor pharmaceutical features, it is severely difficult to commercialize with good pharmacokmetic properties, which is indicative of its good absorption into the body

In the present invention, therefore, there are suggested the spray drying condition which are optimal

ID to improve the solubility of itraconazole and to provide pharmaceutically acceptable properties for itraconazole .

1) Preparation of Spray-Drying Solution

Itraconazole, the water-soluble macromolecule and the solubilizmg agents were dissolved a single or mixed solvent system composed of dichloromethane , chloroform, ethanol and/or methanol , and then an excιpιent(s) selected from salts such as sodium chloride or saccharides such as sugai and lactose or other pharmaceutical diluents such as microcrystallme cellulose, dibasic calcium phosphate, starch or manmtol is/are added at an amount of 0-100 %w/w based on the weight of itraconazole and finally a lubricant such as magnesium stearate, talc, glyceryl behenate and etc , is added at an amount of 0-50 %w/w based on the weight of itraconazole

2) Spray-Drying Condition

Upon spray-drymg, 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-drymg The inlet air temperature should be determined m such a range that itraconazole, the macromolecules and the solubilizmg agents are not physicochemically changed at all The feeding rate and atomizing pressure of the solution should be set on the basis of the evaporating capacity of the spray-dryer used In particular, since the outlet air temperature is 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-drymg solution, the smaller are the particles of the spray-dried material Higher air temperatures improved the flowability of the spray-dried particles, but resulted increase of the bulk density m the particles Despite of being reported that the increase of specific areas of particles brings about the increase of dissolution rate or solubility, spray-dπedmaterials containing a severely fine particles of several nm m the present invention showed rather decreased solubility, which is considered to result from mter-particular agglomeration or aggregation

As a result of repetitive applications for the optimal spray-drymg condition, such is the best that the feeding rate of the spray-drymg solution is preferably 40-700 ml/mm, the spray-drymg pressure 0 5-7 kg/cm2, the inlet air temperature 90-250 °C, the outlet air temperature

40-150 C and the solid content of the spray-drymg solution 0 5-20 0 %w/w respectively

Below, the present invention will be m more detail described through preferable examples These examples intend to be more descriptive of but not to limit the 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 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 homogeneous spray-drymg solution This solution was spray-dried at feeding rate of 150 ml/mm, 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 m similar manners to that of Example 1 while the amounts of water-soluble macromolecules and solubiliz g agents per 100 g of itraconazole were used as indicated m Table 1, below

TABLE 1 Compositions of Spray-Dried Materials

Figure imgf000020_0001
Figure imgf000021_0001

Hydroxypropylmethy1cellulose -Hydroxypropylcellulose

EXPERIMENTAL EXAMPLE 1 Solubilities of Spray-Dried Materials

The spray-dried materials of Examples 1 to 23 v/ere formulated into tablets with good disintegration 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 centπfuged The concentration of itraconazole m its supernatant was measured

TABLE 2 Solubilities of Spray-Dried Materials

Figure imgf000022_0001
*Eudragit™ E was added at an amount of 15% 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. Inparticular , cellulose derivatives brought about better improvement 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 the stomach of normal adults.

When sodium lauryl sulfate or Poloxamer 1 , which both showed the best effects among the solubilizing agents used, gradually increased m their amounts , the solubility of itraconazole increased However, when the amounts of sodium lauryl sulfate or Poloaxamerτ was over critical points, the solubility decreased unexpectedly Thus, it is necessary to appropriately control the amount of the solubilizmg agents

When serious attention is paid that the solubility of tne composition of Example 1 increased by about three times at pH 1 6 and by about twelve times at pH 2 4 , compared with that m the composition of Example 3 , the solubilizmg agent functions more critically m relatively high pH ranges

On the other hand, when Eudrag 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 mtra- 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, m particular, the capsules showed a solubility ratio of five, reflecting the mtra and inter- individual absorption differences of traconazole as they are

EXPERIMENTAL EXAMPLE 2 Dissolution of Spray-Dried Materi a l s

Using suitable excipients, spray-dried materials were manufactured into tablets and then, subjected to an dissolution test m a pH 1 2 buffer After 30 mm, more than 90% of itraconazole was released in the entire compositi ons

EXPERIMENTAL EXAMPLE 3 Relative Bioavailability of Itraconazole-Contammg Spray Dr±ed Materials

Compared with a commercially available Sporanox capsule, the composition of Example 1 was tested for relative bioavailability m ten healthy volunteers m the fasting condition To each group (n=5), the Sporanoxτt capsule with 100 mg of itraconazole and the composition of Example 1 with 50 mg of itraconazole were administered and tested m a crossover The concentration of itraconazole m blood thus obtained was given m Table 3 , below

TABLE 3 Concentration of Itraconazole m Blood

Level m Blooding/ml

Hours

Example 1 Sporanox Capsule itraconazole 50mg Itraconazole lOOmq)

2-±

Figure imgf000026_0001

* Parentheses indicate standard deviation ** Cmax indicates the maximum concentration *** AUC indicates the area under the plasma concentation - time curve

As seen m the data of Table 3, the composition of Example 1 containing 50 mg of itraconazole showed almost the same values m AUC - which is one of indices for the extent of drug absorption - and m C with the Sporanox™ capsule containing 100 mgof itraconazole , which is prepared 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 m the individual variation, the composition of the present mvention 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 mtra- and inter- individual gastric pH fluctuation can be attenuated

EXAMPLE 4 Relative Bioavailability of Itraconazole-Contammg Spray-Dried Material

Compared with a commercially available Sporanox' tablet , the composition of Example 1 was tested for relative bioavailability ten healthy volunteers m the fasting condition To each group (n=5) , the Sporanox™ tablet with 100 mg of itraconazole and the composition of Example 1 with 100 mg of itraconazole were administered and tested m a crossover The concentration of itraconazole m blood thus obtained was given m Table 4, below

TABLE 4 Itraconazole Level in Blood

Figure imgf000028_0001

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 Sporanox™ tablet containing the same amount of itraconazole. In the light of the mention of WO 97/44014 that the bioavailability of the Sporanox'' tablet is twice as high as that of the Sporanoxτ capsule, the composition of Example 1 containing 100 mg of itraconazole has an excellent effect when compared with the Sporanox™ tablet as well as the Sporanox" capsules which are now commercially available. The itraconazole-containmg compositions of the present invention increase the solubility of itraconazole, which is water-msoluble, thereby improve its absorption into the body In more detail, by reducing the absorption difference of itraconazole, which is attributed to the characteristic mtra- or mter-mdividual 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-containmg compositions m accordance with the present mvention 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 ιn vi vo application

Claims

WHAT IS CLAIMED IS :
1. An itraconazole-containmg composition prepared by spray-drymg itraconazole along with water-soluble macromolecules , solubilizmg agents and pharmaceutically acceptable additives
2. The itraconazole-containmg composition as set forthm claim 1 , wherein said water-soluble macromolecules are selected from the group consisting of cellulose derivatives, poly (vinyl alcohol) , poly (vinyl pyrrolidone) ; poly (vinyl acetate) ; poly (alkylene oxide) ,- and poly (alkylene glycol) , and mixtures thereof.
3 The itraconazole-containmg composition as set forth m claim 2, wherein said cellulose derivatives are methylcellulose , ethylcellulose , hydroxymethylcellulose , hydroxyethylcellulose , hydroxyethylmethylcellulose , hydroxypropylmethylcellulose , carboxymethylcellulose , sodium carboxymethylcellulose, or carboxymethylethyl cellulose
4. The itraconazole-containmg composition as set forth claim 1 , wherein said water-soluble macromolecules are pH- independent and areusedm 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" comprising caprylocaproyl macrogol- 8 -glyceride ; propylene glycol monolaurate ; and polyglyceryl-6 -dioleate .
8. The itraconazole-containing composition as set forth m claim 1, wherein said solubilizmg agents are used at an amount of 0 1-100 %w/w based on the weight of itraconazole
9 The itraconazole-containmg composition as set forthmclaiml, wherein the range of spray- dried particles , m size, from 10 nm to 100 ^m
10 The itraconazole-contain g composition as set forthmclaiml, wherein said water-soluble macromolecules are hydroxypropyl methylcellulose and said solubilizmg agents are Poloxamer
11 The itraconazole-containmg composition as set forth m 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-containmg composition as set forth m claim 1, wherein the composition is m a form of tablet, coated tablet, hard capsule, soft capsule, suspension, suspending syrup, dry syrup, paste, lmiment and spray
13 A method for preparing an itraconazole-containmg 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.
PCT/KR1999/000854 1999-12-08 1999-12-31 Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption WO2001041765A1 (en)

Priority Applications (2)

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KR19990055802A KR100694667B1 (en) 1999-12-08 1999-12-08 Antifungal compositions containing itraconazole with both improved bioavailability and narrow intra- and inter-individual variation of its absorption
KR1999/55802 1999-12-08

Applications Claiming Priority (4)

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AU1896400A AU1896400A (en) 1999-12-08 1999-12-31 Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption
JP2001543110A JP2003516354A (en) 1999-12-08 1999-12-31 Improved bioavailability, itraconazole-containing composition absorbed deviation interpersonal and intrapersonal is narrowed
CA 2393737 CA2393737A1 (en) 1999-12-08 1999-12-31 Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption
EP19990962555 EP1274432A4 (en) 1999-12-08 1999-12-31 Compositions containing itraconazole with improved bioavailability and narrow intra- and inter-individual variation of its absorption

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JP (1) JP2003516354A (en)
KR (1) KR100694667B1 (en)
CN (1) CN1398184A (en)
CA (1) CA2393737A1 (en)
WO (1) WO2001041765A1 (en)

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WO2001085135A1 (en) * 2000-04-21 2001-11-15 Dong A Pharma. Co., Ltd. PHARMACEUTICAL COMPOSITION CONTAINING ITRACONAZOLE WITH GASTRIC pH-INDEPENDENTLY IMPROVED SOLUBILITY AND PREPARATION METHOD THEREOF
WO2003017986A1 (en) * 2001-08-27 2003-03-06 Won Jin Biopharma Co., Ltd. Compositions containing itraconazole and their preparation methods
WO2005002553A2 (en) * 2003-07-02 2005-01-13 EGIS Gyógyszergyár Rt. Fluconazole capsules with improved release
WO2005023262A1 (en) * 2003-09-09 2005-03-17 Hanmi Pharm. Co., Ltd. Oral itraconazole composition which is not affected by ingested food and process for preparing same
JP2005521674A (en) * 2002-02-01 2005-07-21 ディポメド,インコーポレイティド Manufacture of an oral dosage form to deliver immediate and sustained-release drug
WO2007110878A1 (en) * 2006-03-27 2007-10-04 Panacea Biotec Ltd Sustained release pharmaceutical composition on the basis of a release system comprising an acid-soluble polymer and a ph-dependent polymer.
WO2008006712A2 (en) * 2006-07-13 2008-01-17 Unilever Plc Preparation of nanodispersions
US7507823B2 (en) 2004-05-06 2009-03-24 Bristol-Myers Squibb Company Process of making aripiprazole particles
WO2010020518A2 (en) * 2008-08-18 2010-02-25 Unilever Plc Improvements relating to nanodisperse compositions
WO2010137888A3 (en) * 2009-05-27 2011-04-21 주식회사 삼양사 Microspheres with improved bioavailability containing poorly water-soluble drugs, and method for preparing same
EP1438960B2 (en) 2003-01-14 2012-12-19 Acino Pharma AG Compostion of itraconazole dispersed in a hydrophilic polymer having enhanced bioavailability
EP1438961B2 (en) 2003-01-14 2014-08-20 Acino Pharma AG Bioequivalent composition of itraconazole dispersed in a hydrophilic polymer
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials

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CN1285590C (en) * 2004-02-23 2006-11-22 上海医药工业研究院 Itraconazole hydrochloride oral solid composition and preparation method
KR100555794B1 (en) 2005-03-17 2006-02-21 삼천당제약주식회사 Composition comprising itraconazole for oral administration
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

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085135A1 (en) * 2000-04-21 2001-11-15 Dong A Pharma. Co., Ltd. PHARMACEUTICAL COMPOSITION CONTAINING ITRACONAZOLE WITH GASTRIC pH-INDEPENDENTLY IMPROVED SOLUBILITY AND PREPARATION METHOD THEREOF
WO2003017986A1 (en) * 2001-08-27 2003-03-06 Won Jin Biopharma Co., Ltd. Compositions containing itraconazole and their preparation methods
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
JP2005521674A (en) * 2002-02-01 2005-07-21 ディポメド,インコーポレイティド Manufacture of an oral dosage form to deliver immediate and sustained-release drug
EP1438960B2 (en) 2003-01-14 2012-12-19 Acino Pharma AG Compostion of itraconazole dispersed in a hydrophilic polymer having enhanced bioavailability
EP1438961B2 (en) 2003-01-14 2014-08-20 Acino Pharma AG Bioequivalent composition of itraconazole dispersed in a hydrophilic polymer
WO2005002553A3 (en) * 2003-07-02 2005-03-24 Egyt Gyogyszervegyeszeti Gyar Fluconazole capsules with improved release
WO2005002553A2 (en) * 2003-07-02 2005-01-13 EGIS Gyógyszergyár Rt. Fluconazole capsules with improved release
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
USRE47033E1 (en) 2003-08-04 2018-09-11 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
WO2005023262A1 (en) * 2003-09-09 2005-03-17 Hanmi Pharm. Co., Ltd. Oral itraconazole composition which is not affected by ingested food and process for preparing same
US7507823B2 (en) 2004-05-06 2009-03-24 Bristol-Myers Squibb Company Process of making aripiprazole particles
WO2007110878A1 (en) * 2006-03-27 2007-10-04 Panacea Biotec Ltd Sustained release pharmaceutical composition on the basis of a release system comprising an acid-soluble polymer and a ph-dependent polymer.
EP2387992A1 (en) * 2006-07-13 2011-11-23 Iota NanoSolutions Limited Improvements relating to nanodispersions
WO2008006712A3 (en) * 2006-07-13 2009-02-26 Unilever Plc Preparation of nanodispersions
WO2008006712A2 (en) * 2006-07-13 2008-01-17 Unilever Plc Preparation of nanodispersions
WO2010020518A3 (en) * 2008-08-18 2010-10-14 Unilever Plc Improvements relating to nanodisperse compositions
WO2010020518A2 (en) * 2008-08-18 2010-02-25 Unilever Plc Improvements relating to nanodisperse compositions
WO2010137888A3 (en) * 2009-05-27 2011-04-21 주식회사 삼양사 Microspheres with improved bioavailability containing poorly water-soluble drugs, and method for preparing same
US9511026B2 (en) 2009-05-27 2016-12-06 Samyang Biopharmaceuticals Corporation Poorly soluble drug containing microspheres with improved bioavailability and method of preparing the same

Also Published As

Publication number Publication date Type
CN1398184A (en) 2003-02-19 application
CA2393737A1 (en) 2001-06-14 application
KR100694667B1 (en) 2007-03-14 grant
JP2003516354A (en) 2003-05-13 application
EP1274432A1 (en) 2003-01-15 application
EP1274432A4 (en) 2004-11-10 application
KR20010054823A (en) 2001-07-02 application

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