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`(cid:47)(cid:88)(cid:83)(cid:76)(cid:81)(cid:3)(cid:89)(cid:17)(cid:3)(cid:76)(cid:38)(cid:72)(cid:88)(cid:87)(cid:76)(cid:70)(cid:68)
`(cid:56)(cid:54)(cid:3)(cid:51)(cid:68)(cid:87)(cid:72)(cid:81)(cid:87)(cid:3)(cid:49)(cid:82)(cid:17)(cid:3)(cid:27)(cid:15)(cid:28)(cid:28)(cid:28)(cid:15)(cid:22)(cid:27)(cid:26)
`Page 1
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`

`
`1
`
`PROCESS FOR MICRONIZING
`SLIGHTLY-SOLUBLE DRUG
`
`5,202,129
`
`BACKGROUND OF THE INVENTION
`
`3
`
`1. Field of the invention
`The present invention relates to a procas for micron-
`izing a slightly-soluble drug. More specifically, it relates
`to a process for microttizing a slightly-soluble drug.
`which comprises grinding said drug in the presence of a
`sugar or sugar alcohol of a lower molecular weight as a
`grinding aid, and to a pharmaceutical formulation con-
`taining the resultant ultrafine drug as an active ingredi-
`CD1.
`
`2. Description of the Related Arts
`When a pharmaceutical formulation containing a_
`drug is orally administered to subjects, a dissolution step
`is essential for the drug to be absorbed through gastroin-
`testinal tract. It has long been recognized that a slightly-
`aoluble drug often shows insullicient bioavailability
`because of the poor solubility in gastroirttestirtal fluids.
`which compels said drug to pass through the site of
`absorption before it completely dissolves in the fluids.
`Various attempts have been made from the aspect of
`pharmaceutics to improve and increase the absorption
`efficiency of a slightly-soluble drug in gastrointestinal
`tract.
`
`20
`
`25
`
`Specific examples of said attempts employed for pre-
`paring improved formulations include following coun-
`termeasures.
`
`1) Providing a soft gelatin capsule containing a solu-
`tion of said drug in a nonaqueous solvent.
`2) Providing a water-soluble salt of said drug.
`3) Providing a solid solution which is prepared by
`dissolving the drug with a suitable polymer in an or-
`ganic solvent and drying the solution promptly (see,
`reference 1 listed at the end of this specification).
`4) A drug is dissolved in an organic solvent and ad-
`sorbed on a porous material in the form of ultrafine
`particles so that the surface area may be increased.
`5) A drug is pulverized in the presence of an appro-
`priate adduct to obtain an amorphous powder (see,
`references 3, 4 and 5).
`6) A drug is just ground into a fine powder (see,
`reference 2).
`The above countermeasures l) to 5) are associated
`with alteration of properties of a drug in molecular
`level. These countermeasures, although advantageous
`in some aspects. have several disadvantages described
`below.
`In the method of the above item 1), it is not always
`easy to find out a suitable nonaqueous solvent. In addi-
`tion, the capsule size may become too big for oral ad-
`ministration. Furthermore, the production cost may be
`high.
`The second method of the above item 2, where the
`drug is convened into a water-soluble salt, is not appli-
`cable to all kinds of drugs because many drugs may not
`form such salts. Additionally, formation ofa water-solu-
`ble salt may be often accompanied by alteration ofpha.r-
`maceutical activity of the drug and/or decrease its sta-
`bility. Therefore, this method is just applicable to lim-
`ited drugs.
`The methods of the above items 3 and 4 are not appli-
`cable to every drug and the methods require the use of
`organic solvents which may be harmful to living bodies.
`Production cost may also be high in these methods.
`
`2
`In the method of the above item 5, a s1ightly—soluble
`drug is mixed with an adduct such as (1);! -l,-II-glucan,
`(2) adsorbent, or (3) polyvinylpyrrolidone. The drug is
`pulverized in the presence of such adduct to obtain the
`drug in the form of amorphous powder which may
`exhibit improved dissolution rate and bioavailability.
`However, the amorphous form is not physically stable
`and often converted reversibly to more stable crystal
`form. Consequently, the dispersion or dissolution prop-
`erties ofthe drug may be changed as time passes.
`‘fire method of the above item 6) differs from those of
`items 1) to 5) which all change the properties of a drug
`in molecular level, in that the former contemplates to
`improve bioavailability of a drug through microniza-
`tion. The micronization has the following advantages.
`a) The alteration of crystal form of a drug is slight or
`moderate;
`'
`b) The operation is safe because no organic solvent is
`employed;
`c) The production cost is low; and
`d) The operation is easy.
`In general, a milling process (it is also referred to as
`grinding, pulverizatiou, and the like) is essential in the
`process of the production of pharmaceutical formula-
`tions. Examples of mills commonly used involve dry-
`type mills, such as jet, ball, vibration, and hammer mill.
`These dry-type mills are used to grind a drug alone to
`afford particles of several pm in diameter. However, it
`is difficult
`to obtain liner particles by conventional
`means. Especially. preparation of submicron particles of
`less than 1 tun in diameter is almost impossible.
`This difliculty is associated with peculiar nature in-
`herent to micronized particles that such particles have a
`tendency to aggregate, adhere, or solidify as the particle
`size decreases. Thus, it is extremely difficult to grind a
`drug into ultrafine particles having a diameter of less
`than several pm by conventional milling procedures.
`Accordingly, a practically applicable process for pre-
`paring ultraftne particles of a drug has long been
`needed.
`
`SUMMARY OF THE INVENTION
`
`The present inventors have found that ultrafine parti-
`cles of a slightly-soluble drug, whose average diameter
`is less than about 2-to 3 pm, preferably less than 1 pm,
`can be easily obtained by grinding the drug in the pres-
`ence of a grinding aid selected from a sugar and a sugar
`alcohol by means of a high-speed stirring mill or impact
`mill.
`Accordingly, in one aspect, this invention provides a
`process for micronizing slightly-soluble drug character-
`ized by subjecting a mixture of said drug and a sugar or
`sugar alcohol to high-speed stirring comminutiom or
`impact comminution.
`This invention also provides a pharmaceutical formu-
`lation which comprises, as an active ingredient, a mi-
`cronized drug produced according to the above process
`together with suitable excipients or diluents therefor.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The term “slightly-soluble drug" herein used refers to
`a pharmaceutical compound which dissolves in water.
`particularly at 20' C., at the ratio of 5 mg/ml or less and
`which is insufficiently absorbed at gastrointestinal tract
`when it is administered in the form of conventional solid
`formulations. Specific examples of the alightlyaoluble
`drugs are coronary vasodilators such as nifedipine,
`
`S5
`
`65
`
`Page 2
`Page 2
`
`

`
`I0
`
`25
`
`30
`
`35
`
`3
`nicardipine, nimo-dipine, dipyridamole, disopyramide,
`prenylamine lactate, and efloxate; antihypertensives
`such as dihydroergotoxine and prazosin; steroidal anti-
`inflammatory agents such as cortisone, dexamethasone,
`betamethasone, and fluo-cinolone acetonide; non-steroi-
`dal anti-inflammatory agents such as indomethacin,
`naproxen, and ketoprofen; psychoneurotic agents such
`as phenytoin, phenacemide, ethylphenacemide, etho-
`toin, primidone. phensuximide, diazepam, nitrazepam,
`and clonazepam; cardiacs such as digoxin, digitoxin,
`and ubidecarenon; diuretics such as spironolactoue,
`triainterene, chlorthalidone, polythiazide, and benzthia-
`zide; chemotherapeutics such as griseofulvin, nalidixic
`acid, and chloramphenicol; skeletal muscle relaxants
`such as chlorzoxazone, phenprobamate, and carisopro-
`dol; anticonvulsants such as etomidoline; antihistaminic
`agents
`such
`as
`diphenhydramine,
`prometha.zine,'
`mequitazine, hisbenthiamine, and clemastine fumarate.
`Sugars and sugar alcohols used as a grinding aid are
`selected from pharmaceutically acceptable sugars and
`sugar alcohols having no influence on the medical ef-
`fects of an active ingredient. For the purpose of the
`invention, it is preferable to use sugars or sugar alcohols
`having a molecular weight of less than 500, and capable
`of easily dispersing and dissolving in water, whereby
`improving dissolution rate of the active ingredient.
`Examples of sugars and sugar alcohols usable in the
`present
`invention include xilitol, mannitol, solbitol,
`arabinose, ribose, xylose, glucose, mannose, galactose,
`sucrose, lactose. and the like. They can be used alone, or
`as a mixture of two or more of these compounds. The
`most preferable sugar is mannitol.
`In the process of the invention, one part by weight of
`an active ingredient is combined with about 2.5 to about
`50 parts, preferably about 2.5 to about 20 parts, more
`preferably about 5 to about 10 parts by weight, of a
`sugar.
`Mills employable in the present process are, for exam-
`ple, dry mills capable of grinding a material into ultra-
`‘fine particles through a mechanical impact and!or attri-
`tion, which are called high-speed stirring mills and
`impact mills. Specific examples of the preferred mills
`are cylinder-type mills such as rotating ball mill, vibrat-
`ing ball mill, tube mill, rod mill, and the like.
`The time required for the completion of the present
`process depends on the properties of the drug and sugar
`or sugar alcohol, function of the mill, content of the
`sugar or sugar alcohol in the mixture, and total amount
`of the mixture to be treated. The grinding time may also
`be changed according to the strength of impact, and it
`is generally between 5 to 30 minutes under a strong
`impact, while it is between 8 to 1(1) hours under a weak
`impact. The drug and sugar or sugar alcohol can be
`used in the present procedure without pre-treatment,
`but they can be coarsely ground before use.
`The mixture which have undergone micronizing
`treatment according to the process of the present inve|:t- '
`lion contains ultrafine particles of the drug having an
`average diameter ofless than 1 pm. Coexistence of the
`sugar or sugar alcohol in the mixture after the treatment
`is advantageous because it has high solubility in water
`and can disperse into water, whereby increasing disso-
`lution rate of the drug.
`_
`The mixture treated according to the process of the
`invention can be used as such for the preparation of
`pharmaceutical compositions. Alternatively, after dis-
`persing the mixture into water, the resulting suspension
`can be subjected to ultrafiltration to remove the sugar
`
`i202J29
`
`4
`or sugar alcohol and subsequently dried to yield a mi-
`cronized slightly-soluble drug in high purity.
`The micronized drug obtained by the invention can
`be formulated in the form of powders, tablets, granules,
`capsules. aerosols, suspensions, syrups, ointments, sup-
`positories, and the like, with one or more pharmaceuti-
`cally acceptable excipients and/or diluents.
`The following examples further illustrate the present
`invention. The examples are not intended to be limiting
`the scope of the invention in any respect and should not
`be so construed.
`
`EXAMPLE 1
`
`Microniaation of Naproxene in the Presence of
`D-Mannitol
`
`Naproxene (1 3), a slightly-soluble pharmaceutical
`compound, was mixed with D-mannitol (9 g, Katayama
`Chemicals, Ltd.). The mixture was then ground for one
`hour in a sealed stainless steel vibrational ball mill
`(Specks, 00., volume: 50 ml) with the aid of two stain-
`less steel balls of 9 mm in diameter.
`The size distribution of naproxene iii the resultant
`rnicronized product was determined in the following
`manner:
`
`The product obtained above (sample 1), a mixture of
`separately ground naproxene and D-mannitol (control
`1), and naproxeue powder (untreated raw material}
`(control 2) were employed in the experiment. The mea-
`surement was conducted using a centrifugal particle
`size analyzer (SA-CP2, Shimazu Seisaltusyo, Japan).
`The 50% average diameter of naproxene was deter-
`mined on the basis of volume. The results are shown
`below:
`
`50% average diameter
`
` Sample of naproxene
`Sample 1
`0.32 um
`Control 1
`4.4 pm
`Control 2
`19 pm
`
`The influence of the duration of treating time on the
`particle size was investigated, and it was found that the
`size was reduced rapidly in the initial stage and almost
`reached to equilibrium within 30 minutes.
`EXAMPLE 2
`
`45
`
`Micronization of Various Slightly-Soluble Drugs in the
`Presence of D-mannitol
`
`Slightly-soluble pharmaceutical compounds (each I
`g) were subjected to the micro-grinding procedure as
`described in Example I in the presence ofD-maunitol (9
`g, Katayama Chemicals, Ltd.) (60 minutes, mixing ratio
`of 1:9).
`The size distribution of the each compound was de-
`termined and the 50% average diameter thereof was
`obtained in the same manner as above. For comparison,
`each pharmaceutical compound was ground alone. Ex-
`perimental results are shown in Table 1 below.
`
`TABLE I
`Particle Sin‘: of Various Compounds
`Micmnized in the Presence oi‘D-m.an.n.itol
`
`compound
`indornethac-in
`phenytoin
`
`50% Average Diameter gggl
`Before
`After Mllhng
`Milling
`alone
`mixture
`9
`‘L!
`0.35
`32
`17
`0.2‘!
`
`55
`
`65
`
`Page 3
`Page 3
`
`

`
`5
`
`TABLE l-continued
`
`5,202,129
`
`Particle Sites of Various Compounds
`‘Hicroniaed in the Pruence of D-mannitol
`
` % 5
`Before
`Alter M'dl_in'g
`
`compound
`Milling
`alone
`mixture
`aaproaene
`19
`4.4
`Q32
`12
`16
`0.42
`61
`11.0
`0.53
`5
`14.0
`0.25
`7
`3.4
`0.1
`
`chioramphenichol
`griaeofnlvin
`oaophoaphoric add
`
`10
`
`Table 1 shows that the particle size of each micron-
`ized compound is less than 1 pm and that the m.icroniz-
`ing process of the invention gives ultrafine particles
`compared with those obtained by grinding without
`D-mannitol.
`'
`
`EXAMPLE 3
`
`Micronization of Oxophosphoric Acid in the Prmence
`of Various Sugars or Sugar Alcohols
`Oxophosphric acid (1 8). I Slightly-soluble pharma-
`ceutical compound, was subjected to the micronizing
`procas as described in Example 1
`in the presence of 25
`each of various sugars (each 9 g) (60 minutes. mixing
`ratio of 1:9).
`The size distribution of oxophosphoric acid was de-
`terrrtined and the 50% average diameter thereof was
`obtained in the same manner as above. As a control,
`oxophosphoric acid was ground alone. Test results are
`shown in Table 2 below.
`
`TABLE 2
`
`30
`
`must Sines ofhlicronized oxggflhau-ac Acid
`
` Sugars 50% avenge diameter (um)
`None
`3.4
`glucose
`0.22
`iactoae
`0.22
`Iucroae
`0.22
`maltose
`I119
`ailitol
`lJ.2l
`aorbitol
`0.12
`D-mannilol
`0.15
`
`Table 2 shows that all of the listed sugars are effective
`to give a micronized oxophsphoric acid having a parti-
`cle size of less than I pm. It can be seen that D-mannitol
`is the most efficient sugar among others.
`EXAMPLE 4
`
`45
`
`Isolation of Micronized Oaophosphoric Acid
`
`To the micronized product comprising oJrophos-
`phoric acid and D-mannitol (I0 g, prepared in Example
`3) was added a distilled water (It!) 1111), and the mixture
`was stirred in order to disperse the acid and also to
`dissolve mannitol. The resultant
`suspension was
`charged in Ultrafltration System ( Model UHP-62'
`Toyo Paper, Japan. equipped with a ultrafilter UK-50,
`50,m0-molecular weight cutoff}. and uitrafiltered under
`pressure to remove dissolved D-mannitol. After the
`addition of distilled water (la) ml), the ultrafiltration
`was repeated under pressure with stirring. The solid
`residue left on the ultrafilter membrane was recovered
`and dried over phosphorus pentaoaide under reduced
`pressure for 24 hours at 50' C. to obtain oxophosphoric
`acid as a ultrafine powder with high purity (puri-
`ty:98%). Scanning electron microscope observation
`revealed that it consisted of particles in the form of line
`
`6
`prismatic crystals having an average diameter of from
`about 0.1 to 0.4 pm.
`The above test shows that the micronized oaophos-
`phoric acid can be purified by subjecting the product to
`dispersing, ultraliltering. and drying treatments.
`EXAMPLE 5
`
`Micronization of Phenytoin
`
`A mixture of phenytoin (10 g) and D-mannitol (90 g)
`was ground in a ceramic ball mill (volume: IL; 90 ee-
`ramic balls of 20 mm in diameter) at 120 rpm for 48
`hours. Sine distribution measurement was carried out in
`the same manner as Example I and the 50% average
`diameter was determined. The 50% average diameter of
`phenytoin before grinding was 3.2 pm. while it was 0.6
`pm after grinding.
`The influence of the duration of treating time on the
`particle size was investigated, and it was found that the
`size was reduced rapidly in the
`stage and almost
`reached to equilibrium within 48 hours. Further grind-
`ing up to 200 hours gave no change in the particle size.
`The following formulation examples are illustrative
`only and are not intend to limit the scope of the inven-
`tion.
`
`FORMULATION 1
`
`Suspension Syrups
`
`To a micronized product consisting of chloramphe-ni-
`col (10 g) and sucrose (90 g) prepared according to the
`procedure described in Example 4 were added methyl
`celulose and water, and the mixture was homogenized
`in a homomixer to obtain a suspension syrup or chlo-
`ramphenycol.
`The average diameters of chloratnphenycol particles
`before and after the micronization, and just after formu-
`lation to the suspension syrup, were determined accord-
`ing to the procedure described in Example 1. Average
`diameter of the particles was 10 um before microniz.a-
`tion, and 0.6 nm after micronization. In suspension
`syrup, the average diameter of the particles was 0.7 um
`when measured immediately after the preparation, and
`the size remained unchanged after keeping the syrup at
`room temperature. The test results show that formula-
`tion procedure gives no adverse effect to the micron-
`ized product, and a stable suspension syrup of chloram-
`phenycol can be obtained while keeping the particle
`size constant.
`
`FORMULATION 2
`
`Tablets
`
`To a micronized product consisting of griaeofulvin
`and D-mannitol {prepared in Example 2) were added
`corn starch as a disintegrator and polyvinylpyrroiidone
`as a binder. The mixture was subjected to a wet granula-
`tion. Granules so produced were mixed with magne-
`sium stearate, and the mixture was compressed by
`means of a tablet machine to yield tablets. The tablets
`were completely disintegrated in water within 10 min-
`utes when subjected to disintegration teat deacribed in
`the llth revised edition of Japanese p
`After the disintegration test. size distribution of gr'iaeo-
`fulvin in the solution was measured by scanning elec-
`tron micrographic method. The average diameter of
`griseofuibin in the solution was 0.4 pm.
`
`Page 4
`Page 4
`
`

`
`5
`
`Micronized product consisting of oxophosphoric acid
`and D-mannitol (prepared in Example 2) was admixed
`with hydroxypropyl cellulose as a binder. The mixture
`was granulated using a rotary granulator and dried to
`yield granules. The granules were completely disinte-
`grated in water within 10 minutes when subjected to
`disintegration test described in the llth revised edition
`of Japanese pharmaoopoeia. After the disintegration
`test, size distribution of oxophosphoric acid in the solu-
`tion was measured in the manner as in Example 1. The
`average diameter of oxophosphoric acid in the solution
`was 0.3 pm.
`
`REFERENCES
`
`25
`
`7
`
`FORNIULATION 3
`
`Granules
`
`5,202, 129
`
`8
`
`What is claimed is:
`1. A process for micronizing a slightly-soluble drug
`.oomprising subjecting a mixture of said drug and a
`sugar or sugar alcohol, the weight ratio of said sugar or
`sugar alcohol being at least 2.5 or more parts by weight
`to one part by weight of the drug, to high-speed stirring
`comminution or impact comminution to give a micron-
`ized drug having an average diameter of less than} pm.
`2. The process of claim 1, wherein the molecular
`weight of the sugar or sugar alcohol is less than $11!.
`3. The process of claim 1 or 2, wherein the sugar or
`sugar alcohol is selected from the group consisting of
`xylitol, mannitol, sorbitol, arabinose, ribose. xylose,
`glucose, mannose, galactose, sucrose and lactose.
`4. A pharmaceutical formulation which comprises, as
`an active ingredient, in micronized drug produced ac-
`cording to claim 1 together with suitable excipients or
`diluents therefor.
`.
`5. The process according to claim 1, wherein said
`l. H. Selcikawa, et aI., Chem.Pharm.Bull., vol.26, 3033
`weight ratio of sugar or sugar alcohol is about 2.5 to
`(1918)
`about 50 parts by weight to one part by weight of the
`2. R. M. Atkinson, et al., Nature, vol.193, 583 (1962)
`d.rI.Ig.
`3. Y. Naltai, Japanese Patent Publication (lrokai) No.
`6. The process according to claim 5, wherein said
`51-32718, and K. Takeo, et a.i., Japanese Patent Publi-
`weight ratio of sugar or sugar alcohol is about 2.5 to
`cation (kokai) No. 53-9315
`about 20 parts by weight to one part by weight of the
`4. M. Matsui, et al., Japanese Patent Publication (kokai)
`drug.
`No. 60-8220
`7. The process according to claim 6, wherein said
`5. N. Kaneniwa, et al., Cl1ern.Pharn:..Bu1l., vol.23, 2986
`weight ratio of sugar or sugar alcohol is about 5 to
`(1975)
`about 10 parts by weight to one part by weight of the
`6. K. Kigasawa. et al., Yakugaku-Zasshi, vol. 101(8), 30 drug.
`723-732 (1931)
`
`45
`
`55
`
`65
`
`Page 5
`Page 5