CA2022465C - Process for micronizing slightly-soluble drug - Google Patents
Process for micronizing slightly-soluble drugInfo
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- CA2022465C CA2022465C CA002022465A CA2022465A CA2022465C CA 2022465 C CA2022465 C CA 2022465C CA 002022465 A CA002022465 A CA 002022465A CA 2022465 A CA2022465 A CA 2022465A CA 2022465 C CA2022465 C CA 2022465C
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- sugar alcohol
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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
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
Abstract
The present invention is directed to a process for micronizing a slightly-soluble drug characterized by subjecting a mixture of said drug and a sugar or sugar alcohol to high-speed stirring comminution or impact comminution. Also provided is a pharmaceutical formulation which comprises the micronized drug.
Description
2()~4~) A PROCESS FOR MICRONIZING A SLIGHTLY-SOLUBLE DRUG
The present invention relates to a process for micronizing a slightly-soluble drug. More specifically, it relates to a process for micronizing a slightly-soluble drug, which comprises grinding said drug in the presence of a lower molecular weight sugar or sugar alcohol as a grinding aid, and to a pharmaceutical formulation containing the resultant ultrafine drug as an active ingredient.
When a pharmaceutical formulation containing a drug is orally administered, a dissolution step is essential for the drug to be absorbed through the gastrointestinal tract. It has long been recognized that a slightly-soluble drug often shows insufficient bioavailability because of poor solubility in gastrointestinal fluids. This compels the 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 the gastrointestinal tract.
Specific examples of said attempts employed for preparing improved formulations include the following countermeasures.
1) Providing a soft gelatin capsule containing a solution of said drug in a nonaqueous solvent.
2) Providing a water-soluble salt of said drug.
The present invention relates to a process for micronizing a slightly-soluble drug. More specifically, it relates to a process for micronizing a slightly-soluble drug, which comprises grinding said drug in the presence of a lower molecular weight sugar or sugar alcohol as a grinding aid, and to a pharmaceutical formulation containing the resultant ultrafine drug as an active ingredient.
When a pharmaceutical formulation containing a drug is orally administered, a dissolution step is essential for the drug to be absorbed through the gastrointestinal tract. It has long been recognized that a slightly-soluble drug often shows insufficient bioavailability because of poor solubility in gastrointestinal fluids. This compels the 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 the gastrointestinal tract.
Specific examples of said attempts employed for preparing improved formulations include the following countermeasures.
1) Providing a soft gelatin capsule containing a solution 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 organic 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 adsorbed 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 appropriate adduct to obtain an amorphous powder (see, references 3, 4 and 5).
6) A drug is simply ground into a fine powder (see, reference 2).
The above countermeasures 1) to 5) are associated with an alteration in the molecular level properties of the drug. These countermeasures, although advantageous in some aspects, have several disadvantages described below.
In the method of item (1) above, it is not always easy to find a suitable nonaqueous solvent. In addition, the capsule size may become too big for oral administration. Furthermore, the production cost may be high.
The second method (disclosed in reference 2), where the drug is converted into a water-soluble salt, is not applicable to all drugs as many drugs may not form such salts. Additionally, formation of a water-soluble salt may often be accompanied by alteration of the pharmaceutical activity of the drug and/or decrease its stability. Therefore, this method is only applicable to 20~2465 certain drugs.
The methods disclosed in references 3 and 4 are not applicable to every drug and the methods require the use of organic solvents which may be harmful to humans and animals. Production costs may also be high in these methods.
In the method disclosed in reference 5, a slightly-soluble drug is mixed with an adduct, e.g.
(1) ~-1,4-glucan, (2) adsorbent, or (3) polyvinylpyrrolidone. The drug is pulverized in the presence of such adduct to obtain the drug in the form of an amorphous powder which may exhibit improved dissolution rate and bioavailability. However, the amorphous form is not physically stable and often converted reversibly to a more stable crystal form. Consequently, the dispersion or dissolution properties of the drug may change as time passes.
The method of item (6) above differs from those of items (1) to (5) which all change the molecular level properties of the drug, in that the former contemplates bioavailability improvement of the drug through micronization. The micronization has the following advantages.
a) Alteration of crystal form of the drug is slight or moderate;
b) Operation is safe because no organic solvent is employed;
c) Production cost is low; and d) The operation is easy.
In general, a milling process (it is also referred to as grinding, pulverization, and the like) is essential in the process of the production of pharmaceutical formula-tions. Examples of mills commonly used involve dry-type mills, e.g. jet, ball, vibration, and hammer mill. These dry-type mills are used to grind a drug alone to afford particles of several ~m in diameter. However, it is difficult to obtain finer particles by conventional means.
Especially, preparation of submicron particles of less than 1 ~m in diameter is almost impossible.
This difficulty is associatedwith the peculiar nature inherent to micronized particles. Micronized ~ticles 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 ~m by conventional milling procedures. Accordingly, a practically applicable process for preparing ultrafine particles of a drug has long been needed.
The present inventors have found that ultrafine particles of a slightly-soluble drug, whose average diameter is less than about 2 to 3 ~m, preferably less than 1 ~m, can be easily obtained by grinding the drug in the presence of a grinding aid selected from a sugar and a sugar alcohol by means of a high-speed stirring mill or impact mill.
2~2465 Accordingly, in one aspect, this invention pro-vides a process for micronizing a slightly-soluble drug characterized by subjecting a mixture of said drug and a sugar or sugar alcohol to high-speed stirring comminution or impact comminution.
This invention also provides a pharmaceutical formulation which comprises, as an active ingredient, a micronized drug produced according to the above process together with suitable excipients or diluents therefor.
The term "slightly-soluble drug" herein used refers to a pharmaceutical compound which dissolves in water, particularly at 20 ~C, at a ratio of 5 mg/ml or less and which is insufficiently absorbed in the gastrointestinal tract when it is administered in the form of conventional solid formulations. Specific examples of the slightly-soluble drugs are coronary vasodilators, e.g.
nifedipine, nicardipine, nimodipine, dipyridamole, disopyramide, prenylamine lactate, and efloxate;
antihypertensives, e.g. dihydroergotoxine and prazosin;
steroidal anti-inflammatory agents, e.g. cortisone, dexamethasone, betamethasone, and fluocinolone acetonide;
non-steroidal anti-inflammatory agents, e.g. indomethacin, naproxen, and ketoprofen; psychoneurotic agents , e.g.
phenytoin, phenacemide, ethylphenacemide, ethotoin, primidone, phensuximide, diazepam, nitrazepam, and 2022 4 ~fi~, clonazepam; cardiacs, e.g. digoxin, digitoxin, and ubidecarenon; diuretics, e.g. spironolactone, triamterene, chlorthalidone, polythiazide, and benzthiazide;
chemotherapeutics, e.g. griseofulvin, nalidixic acid, and S chloramphenicol; skeletal muscle relaxants, e.g.
chlorzoxazone, phenprobamate, and carisoprodol;
anticonvulsants, e.g. etomidoline; antihistaminic agents, e-g- diphenhydramine, promethazine, mequitazine, bisbenthiamine, 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 effects of the 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, thus improving the dissolution rate of the active ingredient. Examples of sug~s and sug~ alcohols suitable for use in the present invention include xylitol, mannitol, sorbitol, 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 preferred sugar is mannitol.
In the process of the invention, one part by weight of an active ingredient is combined with about 2.5 to 2 ~ 6 5 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 example, dry mills capable of grinding a material into ultrafine particles through mechanical impact and/or attrition, which are called high-speed stirring mills and impact mills. Specific examples of the preferred mills are cylinder-type mills, e.g. rotating ball mill, vibrating 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 the 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 impact strength, and it is generally between 5 to 30 minutes under a strong impact, while it is between 8 to 100 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.
Mixtures which have undergone micronizing treatment according to the process of the present invention contain ultrafine particles of the drug having an average diameter of less than 1 ~m. Co-existence 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, thus increasing thedissolution 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 dispers-ing the mixture into water, the resulting suspension can be subjected to ultrafiltration to remove the sugar or sugar alcohol and is subsequently dried to yield a micronized 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, supposi-tories, and the like, with one or more pharmaceutically acceptable excipients and/or diluents.
The following examples further illustrate the present invention. The examples are-not intended to limit the scope of the invention in any respect and should not be so construed.
Example 1 Micronization of naproxene in the presence of D-mannitol Naproxene (1 g), a slightly-soluble pharmaceutical compound, was mixed with D-mannitol (9 g, Katayama Chemi-cals, Ltd.). The mixture was then ground for one hour in a sealed stainless steel vibrational ball mill (Specks, Co., 20~2$i3~
g volume: 50 ml) with the aid of two stainless steel balls of 9 mm in diameter.
The size distribution of naproxene in the resul-tant micronized 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 naproxene powder (untreated raw material) (control 2) were employed in the experiment. The measurement was conducted using a centrifugal particle size analyzer (SA-CP2*, Shimazu Seisakusyo, Japan). The 50% average diame-ter of naproxene was determined on the basis of volume. The results are shown below:
Sample50% average diameter of naproxene Sample 1 0.32 ~m Control 1 -4.4 ~m Control 2 19 ~m The influence of the treating time duration on the particle size was investigated, and it was found that the size was reduced rapidly in the initial stage and almost reached equilibrium within 30 minutes.
Example 2 Micronization of various slightly-soluble drugs in the presence of D-mannitol Slightly-soluble pharmaceutical compounds (each lg) were subjected to the micro-grinding procedure as *Trade Mark .~ . 'h described in Example 1 in the presence of D-mannitol (9 g, Katayama Chemicals, Ltd.) (60 minutes, miX;ng ratio of 1:9).
The size distribution of each compound was determined and the 50% average diameter thereof was obtained in the same manner as above. For comparison, each pharma-ceutical compound was ground alone. Experimental results are shown in Table 1 below.
Table 1 Particle Sizes of Various Compounds Micronized in the Presence of D-mannitol 50% Average Diameter (~m) Before Milling After Milling compound alone mixture indomethacin 9 1.3 0.35 phenytoin 32 2.7 0.27 naproxene 19 4.4 0.32 bisbentiamine 12 2.6 0.42 chloramphenichol 67 22.0 0.53 griseofulvin 6 14.0 0.26 oxophosphoric acid 7 3.4 0.1 Table 1 shows that the particle size of each micronized compound is less than 1 ~m and that the micronizing process of the invention gives ultrafine parti-cles compared with those obtained by grinding without D-mannitol.
Example 3 Micronization of oxophosphoric acid in the presence of various sugars or sugar alcohols Gxophosphoric acid (1 g), a slightly-soluble pharmaceutical compound, was subjected to the micronizing process as described in Example 1 in the presence of each of various sugars (each 9 g) (60 minutes, mixing ratio of 1:9).
The size distribution of oxophosphoric acid was determined 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 Particle Sizes of Micronized Oxophosphoric Acid Suqars 50% averaqe diameter (~m) None 3-4 glucose 0.22 lactose 0.22 sucrose 0.22 maltose 0.19 xyLitol 0.21 sorbitol 0.22 D-mannitol 0.15 Table 2 shows that all of the listed sugars are effective to give a micronized oxophosphoric acid having a particle size of less than 1 ~m. It can be seen that D-mannitol is the most efficient sugar among others.
Example 4 Isolation of micronized oxophosphoric acid To the micronized product comprising oxophosphoric ~5 acid and D-mannitol (10 g, prepared in Example 3) was added 2~2465 a distilled water (100 ml), and the mixture was stirred in order to disperse the acid and also to dissolve mannitol.
The resultant suspension was charged in an ultrafiltration system ( Model UHP-62* Toyo Paper, Japan, equipped with an ultrafilter UK-50* 50,000-molecular weight cutoff), and ultrafiltered under pressure to remove dissolved D-mannitol.
After the addition of distilled water (lO0 ml), the ultrafiltration was repeated under pressure with stirring.
The solid residue left on the ultrafilter membrane was recovered and dried over phosphorus pentaoxide under reduced pressure for 24 hours at 50 ~C to obtain oxophosphoric acid as an ultrafine powder with high purity (purity > 98%).
Scanning electron microscope observation revealed that it consisted of particles in the form of fine prismatic crys-tals having an average diameter of from about 0.1 to 0.4 ~m.
The above test shows that the micronized oxophosphoric acid can be purified by subjecting the product to dispersing, ultrafiltering, and drying treatments.
ExamPle 5 Micronization of phenytoin A mixture of phenytoin (lO g) and ~-mannitol (90 g) was ground in a ceramic ball mill (yolume: lL; 90 ceramic balls of 20 mm in diameter) at 120 rpm for 48 hours.
Size distribution measurement was carried out in the same manner as in Example 1 and the 50% average diameter was *Trade mark 20~246S
determined. The 50% average diameter of phenytoin before grinding was 3.2 ~m, while it was 0.6 ~m after grinding.
The influence of treating time duration on the particle size was investigated, and it was found that the size was reduced rapidly in the initial stage and almost reached equilibrium within 48 hours. Further grinding up to 200 hours gave no change in the particle size.
The following formulation examples are illustra-tive only and are not intended to limit the scope of the invention.
Formulation 1 Suspension syrups To a micronized product consisting of chloramphenicol (10 g) and sucrose (90 g) prepared according to the procedure described in Example 4 were added methylcellulose and water, and the mixture was homogenized in a homomixer to obtain a suspension syrup of chloramphenicol.
The average diameters of chloramphenicol particles before and after the micronization, and just after formula-tion to the suspension syrup, were determined according to the procedure described in Example 1. Average diameter of the particles was 10 ~m before micronization, and 0.6 ~m after micronization. In suspension syrup, the average diameter of the particles was 0.7 ~m when measured immediately after the preparation, and the size remained unchanged after keeping the syrup at room temperature. The ~ 4,f~
test results show that the formulation procedure giyes no adverse effect to the micronized product, and a stable suspension syrup of chloramphenicol can be obtained while keeping the particle size constant.
~ormulation 2 Tablets To a micronized product consisting of griseofulvin and D-mannitol (prepared in Example 2) were added corn starch as a disintegrator and polyvinylpyrrolidone as a blnder. The m~ure was subjected to a wet granulation process.
Granules so produced were mixed with magnesium stearate, and the mixture was compressed by means of a tablet machine to yield tablets. The tablets were completely disintegrated in water within 10 minutes when subjected to the disintegration test described in the 11th revised edition of Japanese Pharmacopeia. After the disintegration test, size distri-bution of griseofulvin in the solution was measured by a scanning electron micrographic method. The average diameter of griseofulbin in the solution was 0.4 ~m.
Formulation 3 Granules 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 disintegrated in 20~246 5 water within 10 minutes when subjected to the disintegration test described in the 11th revised edition of Japanese Pharmacopeia. After the disintegration test, size distri-bution of oxophosphoric acid in the solution was measured in the manner as in Example 1. The average diameter of oxophosphoric acid in the solution was 0.3 ~m.
REFERENCES
1. H. Sekikawa, et al., Chem.Pharm.Bull., vol.26, 3033 (1978) 2. R. M. Atkinson, et al., Nature, vol.193, 588 (1962) 3. Y. Nakai, Japanese Patent Publication (kokai) No. 51-32728, and K. Takeo, et al., Japanese Patent Publica-tion (kokai) No. 53-9315 4. M. Matsui, et al., Japanese Patent Publication (kokai) No. 60-8220 5. N. Kaneniwa, et al., Chem.Pharm.Bull., vol.23, 2986 (1975) 6. K. Kigasawa, et al., Yakugaku-Zasshi, vol.
101(8), 723 - 732 (1981) ~. ;,
The above countermeasures 1) to 5) are associated with an alteration in the molecular level properties of the drug. These countermeasures, although advantageous in some aspects, have several disadvantages described below.
In the method of item (1) above, it is not always easy to find a suitable nonaqueous solvent. In addition, the capsule size may become too big for oral administration. Furthermore, the production cost may be high.
The second method (disclosed in reference 2), where the drug is converted into a water-soluble salt, is not applicable to all drugs as many drugs may not form such salts. Additionally, formation of a water-soluble salt may often be accompanied by alteration of the pharmaceutical activity of the drug and/or decrease its stability. Therefore, this method is only applicable to 20~2465 certain drugs.
The methods disclosed in references 3 and 4 are not applicable to every drug and the methods require the use of organic solvents which may be harmful to humans and animals. Production costs may also be high in these methods.
In the method disclosed in reference 5, a slightly-soluble drug is mixed with an adduct, e.g.
(1) ~-1,4-glucan, (2) adsorbent, or (3) polyvinylpyrrolidone. The drug is pulverized in the presence of such adduct to obtain the drug in the form of an amorphous powder which may exhibit improved dissolution rate and bioavailability. However, the amorphous form is not physically stable and often converted reversibly to a more stable crystal form. Consequently, the dispersion or dissolution properties of the drug may change as time passes.
The method of item (6) above differs from those of items (1) to (5) which all change the molecular level properties of the drug, in that the former contemplates bioavailability improvement of the drug through micronization. The micronization has the following advantages.
a) Alteration of crystal form of the drug is slight or moderate;
b) Operation is safe because no organic solvent is employed;
c) Production cost is low; and d) The operation is easy.
In general, a milling process (it is also referred to as grinding, pulverization, and the like) is essential in the process of the production of pharmaceutical formula-tions. Examples of mills commonly used involve dry-type mills, e.g. jet, ball, vibration, and hammer mill. These dry-type mills are used to grind a drug alone to afford particles of several ~m in diameter. However, it is difficult to obtain finer particles by conventional means.
Especially, preparation of submicron particles of less than 1 ~m in diameter is almost impossible.
This difficulty is associatedwith the peculiar nature inherent to micronized particles. Micronized ~ticles 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 ~m by conventional milling procedures. Accordingly, a practically applicable process for preparing ultrafine particles of a drug has long been needed.
The present inventors have found that ultrafine particles of a slightly-soluble drug, whose average diameter is less than about 2 to 3 ~m, preferably less than 1 ~m, can be easily obtained by grinding the drug in the presence of a grinding aid selected from a sugar and a sugar alcohol by means of a high-speed stirring mill or impact mill.
2~2465 Accordingly, in one aspect, this invention pro-vides a process for micronizing a slightly-soluble drug characterized by subjecting a mixture of said drug and a sugar or sugar alcohol to high-speed stirring comminution or impact comminution.
This invention also provides a pharmaceutical formulation which comprises, as an active ingredient, a micronized drug produced according to the above process together with suitable excipients or diluents therefor.
The term "slightly-soluble drug" herein used refers to a pharmaceutical compound which dissolves in water, particularly at 20 ~C, at a ratio of 5 mg/ml or less and which is insufficiently absorbed in the gastrointestinal tract when it is administered in the form of conventional solid formulations. Specific examples of the slightly-soluble drugs are coronary vasodilators, e.g.
nifedipine, nicardipine, nimodipine, dipyridamole, disopyramide, prenylamine lactate, and efloxate;
antihypertensives, e.g. dihydroergotoxine and prazosin;
steroidal anti-inflammatory agents, e.g. cortisone, dexamethasone, betamethasone, and fluocinolone acetonide;
non-steroidal anti-inflammatory agents, e.g. indomethacin, naproxen, and ketoprofen; psychoneurotic agents , e.g.
phenytoin, phenacemide, ethylphenacemide, ethotoin, primidone, phensuximide, diazepam, nitrazepam, and 2022 4 ~fi~, clonazepam; cardiacs, e.g. digoxin, digitoxin, and ubidecarenon; diuretics, e.g. spironolactone, triamterene, chlorthalidone, polythiazide, and benzthiazide;
chemotherapeutics, e.g. griseofulvin, nalidixic acid, and S chloramphenicol; skeletal muscle relaxants, e.g.
chlorzoxazone, phenprobamate, and carisoprodol;
anticonvulsants, e.g. etomidoline; antihistaminic agents, e-g- diphenhydramine, promethazine, mequitazine, bisbenthiamine, 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 effects of the 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, thus improving the dissolution rate of the active ingredient. Examples of sug~s and sug~ alcohols suitable for use in the present invention include xylitol, mannitol, sorbitol, 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 preferred sugar is mannitol.
In the process of the invention, one part by weight of an active ingredient is combined with about 2.5 to 2 ~ 6 5 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 example, dry mills capable of grinding a material into ultrafine particles through mechanical impact and/or attrition, which are called high-speed stirring mills and impact mills. Specific examples of the preferred mills are cylinder-type mills, e.g. rotating ball mill, vibrating 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 the 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 impact strength, and it is generally between 5 to 30 minutes under a strong impact, while it is between 8 to 100 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.
Mixtures which have undergone micronizing treatment according to the process of the present invention contain ultrafine particles of the drug having an average diameter of less than 1 ~m. Co-existence 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, thus increasing thedissolution 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 dispers-ing the mixture into water, the resulting suspension can be subjected to ultrafiltration to remove the sugar or sugar alcohol and is subsequently dried to yield a micronized 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, supposi-tories, and the like, with one or more pharmaceutically acceptable excipients and/or diluents.
The following examples further illustrate the present invention. The examples are-not intended to limit the scope of the invention in any respect and should not be so construed.
Example 1 Micronization of naproxene in the presence of D-mannitol Naproxene (1 g), a slightly-soluble pharmaceutical compound, was mixed with D-mannitol (9 g, Katayama Chemi-cals, Ltd.). The mixture was then ground for one hour in a sealed stainless steel vibrational ball mill (Specks, Co., 20~2$i3~
g volume: 50 ml) with the aid of two stainless steel balls of 9 mm in diameter.
The size distribution of naproxene in the resul-tant micronized 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 naproxene powder (untreated raw material) (control 2) were employed in the experiment. The measurement was conducted using a centrifugal particle size analyzer (SA-CP2*, Shimazu Seisakusyo, Japan). The 50% average diame-ter of naproxene was determined on the basis of volume. The results are shown below:
Sample50% average diameter of naproxene Sample 1 0.32 ~m Control 1 -4.4 ~m Control 2 19 ~m The influence of the treating time duration on the particle size was investigated, and it was found that the size was reduced rapidly in the initial stage and almost reached equilibrium within 30 minutes.
Example 2 Micronization of various slightly-soluble drugs in the presence of D-mannitol Slightly-soluble pharmaceutical compounds (each lg) were subjected to the micro-grinding procedure as *Trade Mark .~ . 'h described in Example 1 in the presence of D-mannitol (9 g, Katayama Chemicals, Ltd.) (60 minutes, miX;ng ratio of 1:9).
The size distribution of each compound was determined and the 50% average diameter thereof was obtained in the same manner as above. For comparison, each pharma-ceutical compound was ground alone. Experimental results are shown in Table 1 below.
Table 1 Particle Sizes of Various Compounds Micronized in the Presence of D-mannitol 50% Average Diameter (~m) Before Milling After Milling compound alone mixture indomethacin 9 1.3 0.35 phenytoin 32 2.7 0.27 naproxene 19 4.4 0.32 bisbentiamine 12 2.6 0.42 chloramphenichol 67 22.0 0.53 griseofulvin 6 14.0 0.26 oxophosphoric acid 7 3.4 0.1 Table 1 shows that the particle size of each micronized compound is less than 1 ~m and that the micronizing process of the invention gives ultrafine parti-cles compared with those obtained by grinding without D-mannitol.
Example 3 Micronization of oxophosphoric acid in the presence of various sugars or sugar alcohols Gxophosphoric acid (1 g), a slightly-soluble pharmaceutical compound, was subjected to the micronizing process as described in Example 1 in the presence of each of various sugars (each 9 g) (60 minutes, mixing ratio of 1:9).
The size distribution of oxophosphoric acid was determined 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 Particle Sizes of Micronized Oxophosphoric Acid Suqars 50% averaqe diameter (~m) None 3-4 glucose 0.22 lactose 0.22 sucrose 0.22 maltose 0.19 xyLitol 0.21 sorbitol 0.22 D-mannitol 0.15 Table 2 shows that all of the listed sugars are effective to give a micronized oxophosphoric acid having a particle size of less than 1 ~m. It can be seen that D-mannitol is the most efficient sugar among others.
Example 4 Isolation of micronized oxophosphoric acid To the micronized product comprising oxophosphoric ~5 acid and D-mannitol (10 g, prepared in Example 3) was added 2~2465 a distilled water (100 ml), and the mixture was stirred in order to disperse the acid and also to dissolve mannitol.
The resultant suspension was charged in an ultrafiltration system ( Model UHP-62* Toyo Paper, Japan, equipped with an ultrafilter UK-50* 50,000-molecular weight cutoff), and ultrafiltered under pressure to remove dissolved D-mannitol.
After the addition of distilled water (lO0 ml), the ultrafiltration was repeated under pressure with stirring.
The solid residue left on the ultrafilter membrane was recovered and dried over phosphorus pentaoxide under reduced pressure for 24 hours at 50 ~C to obtain oxophosphoric acid as an ultrafine powder with high purity (purity > 98%).
Scanning electron microscope observation revealed that it consisted of particles in the form of fine prismatic crys-tals having an average diameter of from about 0.1 to 0.4 ~m.
The above test shows that the micronized oxophosphoric acid can be purified by subjecting the product to dispersing, ultrafiltering, and drying treatments.
ExamPle 5 Micronization of phenytoin A mixture of phenytoin (lO g) and ~-mannitol (90 g) was ground in a ceramic ball mill (yolume: lL; 90 ceramic balls of 20 mm in diameter) at 120 rpm for 48 hours.
Size distribution measurement was carried out in the same manner as in Example 1 and the 50% average diameter was *Trade mark 20~246S
determined. The 50% average diameter of phenytoin before grinding was 3.2 ~m, while it was 0.6 ~m after grinding.
The influence of treating time duration on the particle size was investigated, and it was found that the size was reduced rapidly in the initial stage and almost reached equilibrium within 48 hours. Further grinding up to 200 hours gave no change in the particle size.
The following formulation examples are illustra-tive only and are not intended to limit the scope of the invention.
Formulation 1 Suspension syrups To a micronized product consisting of chloramphenicol (10 g) and sucrose (90 g) prepared according to the procedure described in Example 4 were added methylcellulose and water, and the mixture was homogenized in a homomixer to obtain a suspension syrup of chloramphenicol.
The average diameters of chloramphenicol particles before and after the micronization, and just after formula-tion to the suspension syrup, were determined according to the procedure described in Example 1. Average diameter of the particles was 10 ~m before micronization, and 0.6 ~m after micronization. In suspension syrup, the average diameter of the particles was 0.7 ~m when measured immediately after the preparation, and the size remained unchanged after keeping the syrup at room temperature. The ~ 4,f~
test results show that the formulation procedure giyes no adverse effect to the micronized product, and a stable suspension syrup of chloramphenicol can be obtained while keeping the particle size constant.
~ormulation 2 Tablets To a micronized product consisting of griseofulvin and D-mannitol (prepared in Example 2) were added corn starch as a disintegrator and polyvinylpyrrolidone as a blnder. The m~ure was subjected to a wet granulation process.
Granules so produced were mixed with magnesium stearate, and the mixture was compressed by means of a tablet machine to yield tablets. The tablets were completely disintegrated in water within 10 minutes when subjected to the disintegration test described in the 11th revised edition of Japanese Pharmacopeia. After the disintegration test, size distri-bution of griseofulvin in the solution was measured by a scanning electron micrographic method. The average diameter of griseofulbin in the solution was 0.4 ~m.
Formulation 3 Granules 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 disintegrated in 20~246 5 water within 10 minutes when subjected to the disintegration test described in the 11th revised edition of Japanese Pharmacopeia. After the disintegration test, size distri-bution of oxophosphoric acid in the solution was measured in the manner as in Example 1. The average diameter of oxophosphoric acid in the solution was 0.3 ~m.
REFERENCES
1. H. Sekikawa, et al., Chem.Pharm.Bull., vol.26, 3033 (1978) 2. R. M. Atkinson, et al., Nature, vol.193, 588 (1962) 3. Y. Nakai, Japanese Patent Publication (kokai) No. 51-32728, and K. Takeo, et al., Japanese Patent Publica-tion (kokai) No. 53-9315 4. M. Matsui, et al., Japanese Patent Publication (kokai) No. 60-8220 5. N. Kaneniwa, et al., Chem.Pharm.Bull., vol.23, 2986 (1975) 6. K. Kigasawa, et al., Yakugaku-Zasshi, vol.
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Claims (6)
1. A process for micronizing a slightly-soluble drug characterized by subjecting a mixture of said drug and a sugar or sugar alcohol to high-speed stirring comminution or impact comminution, wherein the slightly-soluble drug is a pharmaceutical compound which dissolves in water at a ratio of 5 mg/ml or less, the weight ratio of said sugar or sugar alcohol is 2.5 to 50 parts by weight to one part by weight of the drug, and the micronized drug has an average diameter of less than 1 µm.
2. The process of claim 1, wherein the molecular weight of the sugar or sugar alcohol is less than 500.
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, a pharmaceutically effective amount of a micronized drug according to the process of claim 1, having an average diameter of less than 1 µm together with suitable excipients or diluents therefor.
5. The process of claim 1, wherein the weight ratio of said sugar or sugar alcohol is 2.5 to 20 parts by weight to one part by weight of the drug.
6. The process of claim 1, wherein the weight ratio of said sugar or sugar alcohol is 5 to 10 parts by weight to one part by weight of the drug.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP204132/1989 | 1989-08-04 | ||
| JP1204132A JP2642486B2 (en) | 1989-08-04 | 1989-08-04 | Ultrafine particle method for poorly soluble drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2022465A1 CA2022465A1 (en) | 1991-02-05 |
| CA2022465C true CA2022465C (en) | 1998-04-21 |
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ID=16485367
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002022465A Expired - Fee Related CA2022465C (en) | 1989-08-04 | 1990-08-01 | Process for micronizing slightly-soluble drug |
Country Status (9)
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|---|---|
| US (1) | US5202129A (en) |
| EP (1) | EP0411629B1 (en) |
| JP (1) | JP2642486B2 (en) |
| KR (1) | KR0126465B1 (en) |
| AT (1) | ATE96658T1 (en) |
| CA (1) | CA2022465C (en) |
| DE (1) | DE69004372T2 (en) |
| DK (1) | DK0411629T3 (en) |
| ES (1) | ES2062221T3 (en) |
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| JPH0366613A (en) | 1991-03-22 |
| JP2642486B2 (en) | 1997-08-20 |
| DK0411629T3 (en) | 1993-12-13 |
| EP0411629B1 (en) | 1993-11-03 |
| KR0126465B1 (en) | 1997-12-24 |
| DE69004372D1 (en) | 1993-12-09 |
| ES2062221T3 (en) | 1994-12-16 |
| EP0411629A2 (en) | 1991-02-06 |
| ATE96658T1 (en) | 1993-11-15 |
| EP0411629A3 (en) | 1991-05-08 |
| KR910004183A (en) | 1991-03-28 |
| US5202129A (en) | 1993-04-13 |
| DE69004372T2 (en) | 1994-04-21 |
| CA2022465A1 (en) | 1991-02-05 |
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