CA2245715A1 - 5.alpha.-reductase inhibitory preparation for oral administration, process for producing the same, and use thereof - Google Patents
5.alpha.-reductase inhibitory preparation for oral administration, process for producing the same, and use thereof Download PDFInfo
- Publication number
- CA2245715A1 CA2245715A1 CA 2245715 CA2245715A CA2245715A1 CA 2245715 A1 CA2245715 A1 CA 2245715A1 CA 2245715 CA2245715 CA 2245715 CA 2245715 A CA2245715 A CA 2245715A CA 2245715 A1 CA2245715 A1 CA 2245715A1
- Authority
- CA
- Canada
- Prior art keywords
- alpha
- water
- formulation
- weight
- disintegrant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
A 5.alpha.-reductase inhibitory preparation for oral administration which comprises a composition obtained by pulverizing a mixture comprising an azasteroid, a water-soluble polymer, and a disintegrator.
Description
CA 0224~71~ 1998-08-04 ., , 1 DESCRIPTION
FORMULATION OF A 5a-K~u~LASE INHIBITOR FOR ORAL ADMINISTRATION, AND A PREPARATION PROCESS AND USE THEREOF
Technical Field The present invention relates to a formulation of a Sa-reductase inhibitor for oral A~m; n; stration, and a preparation process and use thereof.
Background Art The azasteroids included as an active ingredient in the formulation of a 5a-reductase inhibitor for oral A~m; n; stration of the present invention, namely, N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carho~Am;de [the compound represented by the formula (I) shown below] and N-(1,1-- dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-carho~Am;de [the compound represented by the formula (II) shown below] are known compounds and exhibit 5a-reductase ; nh; h; tory action. These compounds are therefore useful as a ~-~v~Ltive and/or therapeutic agent for prostatic hypertrophy.
~ IJI ~ ~ OCHJ ~ Jlll CHJ
Do~ ': #28~;868 P76247/FP-9704 (PCT) /t~-~-ig/Engli~h tranolatior~
CA 0224~71~ 1998-08-04 However, the above-described compounds have poor water solubility and it has so far been difficult to prepare a solid formulation cnnt~;n;ng such a compound because of the following reasons.
When a pharmaceutical formulation is prepared from a sparingly-water-soluble compound in a m~nn~r known Per se in the art, the resulting formulation generally has a low dissolution property and therefore does not exhibit sufficient bioavailability. The present inventors practically prepared a pharmaceutical formulation from the above-described azasteroid in a mAnner known per se in the art, but the resulting formulation had a markedly low dissolution property.
In such a case, the method of ~;ng an excess amount of an active ingredient in one dosage unit is thought as a countermeasure for providing sufficient bioavailability for the formulation. Such a method is however inefficient because the preparation of a pharmaceutical formulation contA;n;ng an excess amount of an active ingredient requires an excess amount of the active ingredient. In addition, the A~m;n;stration of such a formulation cont~;n;ng an excess of active ingredient causes fluctuations of the absorption ratio among individual living bodies A~m;n;stered, which heightens the possibility of causing undesirable side effects. The above method cannot therefore be put into practical use.
Conc~rn;ng the formulation of such a sparingly-water-soluble compound, various techniques for i".~-~ving its r~ #285868 P76247/FP-9704(P~T)/tl~a-ig/Engli~h tranE~lation CA 0224~7l~ l998-08-04 dissolution property have so far been reported. Problems such as what is a suitable method for improving the dissolution property of a specific compound and how much the dissolution property can be improved depend on various physical properties (for example, crystal form and particle size) and chemical properties (for example, kind and number of the functional groups). As a matter of fact, these problems will be solved for the first time by preparing various formulations cont~;n;ng the compound in accordance with various processes and evaluating the resulting formulations in practice.
A method of subjecting a compound serving as an active ingredient and a pharmacologically acceptable ingredient to mixed-gr;n~;ng is one technique for improving the dissolution property. Concern;ng this technique, reports have been made as follows:
The ~act that in the case where a m; ~tn~e of phenytoin and casein sodium is ground and in the case where a mixture of phenytoin, casein sodium and oleic acid is ground, the solubility o~ phenytoin increases, while in the case where a mixture of phenytoin, casein sodium and palmitic acid is ground, no change occurs in the solubility is disclosed in UYAKUZAIGAKUn, 50(2), 187-192(1990) N, In "YAKUZAIGAKU", 49(1), 70-77(1989)", it is disclosed that grin~;ng a mixture of 9,3"-diacetylmidecamycin with polyvinylpyrrolidone yields amorphous 9,3 n -diacetylmidecamycin.
In "Japanese Patent Application Kokai No. SHO 60-181030 rc ~: #285868 P76247/FP-s704 (PCT) /tf~a-ig/Engli~h tran~lation CA 0224~7l~ l998-08-04 (Gs-A-2153678)", there is disclosed a pharmaceutical ~ormulation having an i~ ~v~d dissolution property obt~e~ by grinding a mixture o~ a synthesized steroid (Medroxyprogesterone) with cross-linked polyvinylpyrrolidone (crospovidone).
The present inventor there~ore ground a mixture o~ the above aza~teroid with crospovidone in accordance with the process disclosed in the above J~p~n~ e Patent Application Kokai No. SHO 60-181030 in which a compound having a relatively similar structure to the azasteroid of the present invention is disclosed, but a composition having a dissolution property 6u~iciently i",~v~d ~or practical use could not be obtained.
Described speci~ically, the kind o~ ingredient and m; x; ~g ratio thereo~ suitable ~or improving the dissolution property o~
an active ingredient by grinding a mixture thereo~ depends on the physical and chemical properties o~ the active ingredient.
Whether a process according to the prior art will bring about a similar e~ect or not does not depend simply on the similarity or non-similarity o~ the chemical structure o~ the active ingredient.
The present inventors there~ore carried out a further investigation on a process ~or improving the dis~olution property o~ the above-described azasteroid with a view to providing its formulation ~or practical use.
As a result, in the pre~ent invention, it has been found that the constitution o~ the present invention brings about a marked iu~luv~lllent in the dissolution property. In "YAKUGAKU
DQ~ ': #285868 P76247/FP-9704(PCT) /t~-ig/Engli~h LL -lati~n CA 0224~i7l~i l998-08-04 r- 5 ZASSHI~ 109 (12) 1 932-937 (1989) n I there is di~closed a similar composition except for the compound cont~;ne~ therein as the active ingredient. However, the marked improvement in the dissolution property brought about by the present invention cannot be expected from the above prior art. According to the present invention, an orally-dosable solid composition of the above azasteroid, which has so far been unsuitable ~or practical use in an orally-dosable solid composition, can be obtained having a dissolution property which, for the first time, is sufficient for practical use.
Disclo~ure of the Invention The present inventors have carried out an extensive investigation on the formulation of 5a-reductase ;nh;h;tors for oral A~m;n;stration cnntA;n;ng an azasteroid. As a result, it has been found that the dissolution property of the azasteroid can be markedly improved by appropriately selecting pharmacologically acceptable ingredients to be used in combination and carrying out gr;n~;ng of a mixture of these ingredients and the azasteroid, 1~A~; ng to the completion of the present invention.
In one aspect of the present invention;
(1) There is thus provided a formulation of a 5a-reductase inhibitor for oral A~m;n;stration which comprises a composition obtained by gr;n~;ng a m;~tll~e cont~;n;ng one azasteroid selected from the group (A) shown below, a #285868 P76247/PP-9704 (PCI') /t6a-ig/EIlglilsh tr~n-lat~ n CA 0224~7l~ l998-08-04 water-soluble polymer and a disintegrant:
Group (A) N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-ca~bo~d-,-ide; and N-(1,1-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide.
Preferred are:
FORMULATION OF A 5a-K~u~LASE INHIBITOR FOR ORAL ADMINISTRATION, AND A PREPARATION PROCESS AND USE THEREOF
Technical Field The present invention relates to a formulation of a Sa-reductase inhibitor for oral A~m; n; stration, and a preparation process and use thereof.
Background Art The azasteroids included as an active ingredient in the formulation of a 5a-reductase inhibitor for oral A~m; n; stration of the present invention, namely, N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carho~Am;de [the compound represented by the formula (I) shown below] and N-(1,1-- dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-carho~Am;de [the compound represented by the formula (II) shown below] are known compounds and exhibit 5a-reductase ; nh; h; tory action. These compounds are therefore useful as a ~-~v~Ltive and/or therapeutic agent for prostatic hypertrophy.
~ IJI ~ ~ OCHJ ~ Jlll CHJ
Do~ ': #28~;868 P76247/FP-9704 (PCT) /t~-~-ig/Engli~h tranolatior~
CA 0224~71~ 1998-08-04 However, the above-described compounds have poor water solubility and it has so far been difficult to prepare a solid formulation cnnt~;n;ng such a compound because of the following reasons.
When a pharmaceutical formulation is prepared from a sparingly-water-soluble compound in a m~nn~r known Per se in the art, the resulting formulation generally has a low dissolution property and therefore does not exhibit sufficient bioavailability. The present inventors practically prepared a pharmaceutical formulation from the above-described azasteroid in a mAnner known per se in the art, but the resulting formulation had a markedly low dissolution property.
In such a case, the method of ~;ng an excess amount of an active ingredient in one dosage unit is thought as a countermeasure for providing sufficient bioavailability for the formulation. Such a method is however inefficient because the preparation of a pharmaceutical formulation contA;n;ng an excess amount of an active ingredient requires an excess amount of the active ingredient. In addition, the A~m;n;stration of such a formulation cont~;n;ng an excess of active ingredient causes fluctuations of the absorption ratio among individual living bodies A~m;n;stered, which heightens the possibility of causing undesirable side effects. The above method cannot therefore be put into practical use.
Conc~rn;ng the formulation of such a sparingly-water-soluble compound, various techniques for i".~-~ving its r~ #285868 P76247/FP-9704(P~T)/tl~a-ig/Engli~h tranE~lation CA 0224~7l~ l998-08-04 dissolution property have so far been reported. Problems such as what is a suitable method for improving the dissolution property of a specific compound and how much the dissolution property can be improved depend on various physical properties (for example, crystal form and particle size) and chemical properties (for example, kind and number of the functional groups). As a matter of fact, these problems will be solved for the first time by preparing various formulations cont~;n;ng the compound in accordance with various processes and evaluating the resulting formulations in practice.
A method of subjecting a compound serving as an active ingredient and a pharmacologically acceptable ingredient to mixed-gr;n~;ng is one technique for improving the dissolution property. Concern;ng this technique, reports have been made as follows:
The ~act that in the case where a m; ~tn~e of phenytoin and casein sodium is ground and in the case where a mixture of phenytoin, casein sodium and oleic acid is ground, the solubility o~ phenytoin increases, while in the case where a mixture of phenytoin, casein sodium and palmitic acid is ground, no change occurs in the solubility is disclosed in UYAKUZAIGAKUn, 50(2), 187-192(1990) N, In "YAKUZAIGAKU", 49(1), 70-77(1989)", it is disclosed that grin~;ng a mixture of 9,3"-diacetylmidecamycin with polyvinylpyrrolidone yields amorphous 9,3 n -diacetylmidecamycin.
In "Japanese Patent Application Kokai No. SHO 60-181030 rc ~: #285868 P76247/FP-s704 (PCT) /tf~a-ig/Engli~h tran~lation CA 0224~7l~ l998-08-04 (Gs-A-2153678)", there is disclosed a pharmaceutical ~ormulation having an i~ ~v~d dissolution property obt~e~ by grinding a mixture o~ a synthesized steroid (Medroxyprogesterone) with cross-linked polyvinylpyrrolidone (crospovidone).
The present inventor there~ore ground a mixture o~ the above aza~teroid with crospovidone in accordance with the process disclosed in the above J~p~n~ e Patent Application Kokai No. SHO 60-181030 in which a compound having a relatively similar structure to the azasteroid of the present invention is disclosed, but a composition having a dissolution property 6u~iciently i",~v~d ~or practical use could not be obtained.
Described speci~ically, the kind o~ ingredient and m; x; ~g ratio thereo~ suitable ~or improving the dissolution property o~
an active ingredient by grinding a mixture thereo~ depends on the physical and chemical properties o~ the active ingredient.
Whether a process according to the prior art will bring about a similar e~ect or not does not depend simply on the similarity or non-similarity o~ the chemical structure o~ the active ingredient.
The present inventors there~ore carried out a further investigation on a process ~or improving the dis~olution property o~ the above-described azasteroid with a view to providing its formulation ~or practical use.
As a result, in the pre~ent invention, it has been found that the constitution o~ the present invention brings about a marked iu~luv~lllent in the dissolution property. In "YAKUGAKU
DQ~ ': #285868 P76247/FP-9704(PCT) /t~-ig/Engli~h LL -lati~n CA 0224~i7l~i l998-08-04 r- 5 ZASSHI~ 109 (12) 1 932-937 (1989) n I there is di~closed a similar composition except for the compound cont~;ne~ therein as the active ingredient. However, the marked improvement in the dissolution property brought about by the present invention cannot be expected from the above prior art. According to the present invention, an orally-dosable solid composition of the above azasteroid, which has so far been unsuitable ~or practical use in an orally-dosable solid composition, can be obtained having a dissolution property which, for the first time, is sufficient for practical use.
Disclo~ure of the Invention The present inventors have carried out an extensive investigation on the formulation of 5a-reductase ;nh;h;tors for oral A~m;n;stration cnntA;n;ng an azasteroid. As a result, it has been found that the dissolution property of the azasteroid can be markedly improved by appropriately selecting pharmacologically acceptable ingredients to be used in combination and carrying out gr;n~;ng of a mixture of these ingredients and the azasteroid, 1~A~; ng to the completion of the present invention.
In one aspect of the present invention;
(1) There is thus provided a formulation of a 5a-reductase inhibitor for oral A~m;n;stration which comprises a composition obtained by gr;n~;ng a m;~tll~e cont~;n;ng one azasteroid selected from the group (A) shown below, a #285868 P76247/PP-9704 (PCI') /t6a-ig/EIlglilsh tr~n-lat~ n CA 0224~7l~ l998-08-04 water-soluble polymer and a disintegrant:
Group (A) N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-ca~bo~d-,-ide; and N-(1,1-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide.
Preferred are:
(2) a formulation of a 5a-reductase ;nh;h;tor for oral A~m;n;gtration as described above, wherein said one azasteroid selected from the group (A) is N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide;
(3) a formulation of a 5a-reductase inhibitor for oral ~m;n; stration as described above, wherein said water-soluble polymer is a water-soluble cellulose derivative or polyalkenylpyrrolidone derivative;
(4) a ~ormulation of a 5a-reductase inhibitor for oral ~m;n; stration as degcribed above, wherein said water-soluble polymer is hydroxypropylmethylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone;
(5) a formulation of a 5a-reductase inhibitor for oral ~m; n; stration as described above, wherein said disintegrant is sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose or crystalline cellulose;
(6) a ~ormulation of a 5a-reductase inhibitor ~or oral ~m; n; stration as described above, wherein said disintegrant is Dc ': #2as868 P76247/FP-9704(PCT)/tca-ig/Engli~h tr~ncl~tion CA 0224~7l~ l998-08-04 sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium or croscarmellose sodium;
(7) a formulation of a 5a-reductase inhibitor for oral ~m;n;stration as described above, wherein said water-soluble polymer is added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of said azasteroid;
(8) a formulation of a 5a-reductase inhibitor for oral ~m;n;stration as described above, wherein said disintegrant is added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of said azasteroid; and (9) a formulation of a 5a-reductase ;nh;h;tor for oral ~m;n;stration as described above, wherein said disintegrant is added in an amount of 0.5 to 10 parts by weight based on 1 part by weight of said water-soluble polymer.
In another aspect of the present invention, there is also provided:
In another aspect of the present invention, there is also provided:
(10) A process for the preparation of a formulation of a 5a-reductase inhibitor for oral ~m;n;stration, which comprises gr;n~;ng a m;~tll~e cont~;n;ng one azasteroid selected from the group (A) shown below, a water-soluble polymer and a disintegrant:
Group A
N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide; and N-(1,1-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-ca-Lo~d...ide.
Ec : #285868 P76247/FP-9704(PCT)/t~a-ig/Engli~h tr~n~lation CA 0224~7l~ l998-08-04 O , 8 Preferred are:
Group A
N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide; and N-(1,1-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-ca-Lo~d...ide.
Ec : #285868 P76247/FP-9704(PCT)/t~a-ig/Engli~h tr~n~lation CA 0224~7l~ l998-08-04 O , 8 Preferred are:
(11) A process as described above, wherein said one azasteroid selected ~rom the group (A) is N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide;
(12) A process as described above, wherein said water-soluble polymer is a water-soluble cellulose derivative or a polyalkenylpyrrolidone derivative;
(13) A process as described above, wherein said water-soluble polymer is hydroxypropylmethylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone;
(14) A process as described above, wherein said disintegrant is sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose or crystalline cellulose;
(15) A process as described above, wherein said disintegrant is carboxymethyl starch sodium, crospovidone, carmellose, carmellose calcium or croscarmellose sodium;
(16) A process as described above, wherein said water-soluble polymer is added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of said azasteroid;
(17) A process as described above, wherein said disintegrant is added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of said azasteroid; and (18) A process as described above, wherein said di~integrant is added in an ~UIO~lt of 0.5 to 10 parts by weight rc : #z85868 P76247/FP-9704~PCT)/t~a-ig/Engli~h t~ -1 A~i~
CA 0224~71~ 1998-08-04 r based on 1 part by weight of said water-soluble polymer.
In a further aspect of the present invention, there is also provided:
CA 0224~71~ 1998-08-04 r based on 1 part by weight of said water-soluble polymer.
In a further aspect of the present invention, there is also provided:
(19) The use of a formulation of a 5a-reductase inhibitor for oral ~m;~; stration as described above in any one of (1) to (g) as a preventive and/or therapeutic agent for prostatic hypertrophy.
In the "formulation of a 5a-reductase inhibitor ~or oral ~m;~; stration" according to the present invention, the term "azasteroidN means N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide or N-(l,l-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide. Preferred is N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide.
The above compounds happen to absorb water, thereby having adsorbed water or becoming hydrates when allowed to stand in the air or during recrystallization. Such hydrates are also embraced in the "azasteroid".
As the "water-soluble polymer" and "disintegrant"
cont~;ne~ in the ground m;~tll~e for obt~;n;ng the "~ormulation of a 5a-reductase inhibitor for oral ~m; n; ~trationN 0~ the present invention, the following compounds can be given as examples.
Examples of the Uwater-soluble polymern include water-soluble cellulose derivatives such as I~o. : #285868 P76247tEP-9704 (PCT) /t~a-ig/Englif~h tranr~lation CA 0224~71~ 1998-08-04 hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carmellose sodium and methylcellulose;
polyalkenylpyrrolidone derivatives such as polyvinylpyrrolidone;
polyalkenyl alcohol derivatives such as polyvinyl alcohol;
carboxyalkenyl polymer derivatives such as carboxyvinyl polymer;
polyalkenyl organic acid derivatives such as partially-saponified polyvinyl acetate; alkenyl organic acid ester copolymer derivatives such as vinyl acetate copolymer; salts of a polysaccharide such as sodium arginate; ester derivatives of a polysaccharide such as propylene glycol arginate; and polyalkylene glycol derivatives such as polyethylene glycol.
Among them, preferred are water-soluble cellulose derivatives and polyalkenylpyrrolidone derivatives, and hydroxypropylmethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone are more pre~erred. These water-soluble polymers can be used either singly or in combination.
Examples o~ the "disintegrant~ include starch, partially a-converted starch, carboxymethyl starch, hydroxypropyl starch, sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium and low-substituted hydroxypropylcellulose and water-insoluble cellulose derivatives (e.g. cryst~ ne cellulose, ethylcellulose, cellulose acetate, carboxymethylethylcellulose and nitrocellulose). Among them, preferred are sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose and crystalline cellulose, ~ #285868 P76247/FP-9704(PCT)/tDa-ig/Engli~h tran~lation CA 0224~71~ 1998-08-04 and sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium and croscarmellose sodium are more preferred.
The above-exemplified disintegrants can be used either singly or in combination.
The above-described water-soluble polymer can generally be added in an amount of 0.1 to 500 parts by weight based on 1 part by weight o~ the above-described azasteroid. It is preferably added in an amount o~ 0.2 to 300 parts by weight (more preferably 10 parts by weight, particularly preferably 6 parts by weight and most pre~erably 5 parts by weight) based on 1 part by weight of the azasteroid.
The above-described disintegrant can generally be added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of the azasteroid. Preferably, it is added in an amount of 0.25 part by weight (more preferably 0.5 part by weight and most preferably 1 part by weight) to 300 parts by weight (preferably lO parts by weight, particularly preferably 6 parts by weight and most preferably 5 parts by weight) based on 1 part by weight of the azasteroid.
The disintegrant can generally be added in an amount of 0.1 to 100 parts by weight based on 1 part by weight of the above-described water-soluble polymer. It is preferably added in an amount of 0.5 part by weight (more preferably 1 part by weight) to 10 parts by weight (preferably 5 parts by weight) based on 1 part by weight of the water-soluble polymer.
The water-soluble polymer and the disintegrant can D~ ': #285868 P76247/FP-9704(PCT)/t~-ig/Engli~h tran~lation CA 0224~71~ 1998-08-04 generally be added in a total amount o~ 0.2 to 1000 parts by weight based on 1 part by weight o~ the azasteroid.
Preferably,they are added in a total amount o~ 0.5 part by weight (more pre~erably 1 part by weight and particularly pre~erably 2 parts by weight) to 600 parts by weight (more pre~erably 20 parts by weight, particularly pre~erably 10 parts by weight, more particularly pre~erably 6 parts by weight and most pre~erably 5 parts by weight) based on 1 part by weight o~
the azasteroid.
The azasteroids cont~;ned as an active ingredient o~ the ~ormulation o~ 5a-reductase inhibitor ~or oral ~m; n; strationn according to the present invention, that is, N-[1-(4-methoxyphenyl)-l-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide [the compound represented by the above ~ormula (I)]
and N-(l,l-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide [the compound represented by the above formula (II)], are prepared by the processes described in J~p~nese Patent Application Kokai No. HEI 5-32693 and J~p~n~se Patent Application Rokai No. SHO 60-222497 (J~p~nese Patent Application Rokoku No. SHO 63-65080), respectively.
The "composition~ c~nt~;ned by the ~'~ormulation o~ a 5a-reductase ;nh; h; tor ~or oral Zl~m; n; I:tration" o~ the present invention is obt~;ne~ by gr;n~;ng a mixture cont~;n;ng the azasteroid, water-soluble polymer and disintegrant.
The gr;n~;ng can be per~ormed in a known m~nn~r/
pre~erably with a gr;n~;ng machine which allows cont;n~lous ~c ': #285868 P76247/FP-9704(PCT)/tc~-ig/English tr~nslation CA 0224~7l~ l998-08-04 grinding for a long time. Examples of such a gr;n~;ng machine include those using a medium such as a rod mill and a ball mill, and an oscillating ball mill and a medium-agitating type grinding machine are preferred.
Although the time required for gr;n~;ng changes according to the tool or machine to be used for gr;n~;ng, the kind of compound to be ground or the amount of mixture to be ground, gr;n~;ng is generally carried out ~or one minute to 24 hours.
The "compositionN so prepared can be A-lm; n;stered as it is to the human body as a 5a-reductase inhibitor, and also in this case it exhibits a markedly improved dissolution property.
Alternatively, it can be ~lm; n;stered as various dosage forms obt~;n~hle by ~;ng one or more additives to the "composition" and formulating the resulting mixture in a ~nner known E~E se in the art. As the dosage form, solid forms generally known as oral formulations are employed. Examples include powders, granules, tablets and capsules.
For the preparation of powders, for example, the above-described "composition" is used as it is or mixed uniformly with one or more additives described later.
The granules can be prepared, for example, by dry granulation or wet granulation. In this case, it is possible to add, if necessary, one or more of the below-described additives to the "composition" before or after granulation.
The tablets can be prepared, for example, by directly tableting the "composition". Alternatively, they can be r~ #285868 P76247/FP-9704(P~T)/t~-ig/Engli~h tr~nalation CA 0224~7l~ l998-08-04 obt~; n~A by preparing granules from the "composition" and then tableting the resulting granules. In either case, one or more of the below-described additives can be added, if necessary, prior to tableting.
The capsules can be prepared, for example, by filling capsules with the "composition" as it is. Alternatively, they can be obtained by preparing granules as described above in advance and then filling capsules with them. In either case, one or more o~ the below-described additives can be added, if necessary, prior to filling.
Examples of the additive employed for the preparation of a pharmaceutical formulation from the "composition" include excipients, binders, disintegrants, colorants, taste m~#k;ng agents/smell masking agents and lubricants.
As examples of the excipient, there are included kaolin, casein, powdered glycyrrhiza, agar, light anhydrous silicic acid, natural aluminium silicate, synthetic aluminium silicate, synthetic magnesium silicate, silicic anhydride, magnesium silicate, wheat flour, heavy magnesium oxide, aluminium hydroxide, magnesium r~rhon~te co-precipitate, dried aluminium hydroxide gel, gypsum, exsiccated gypsum, gelatin, microcrystalline cellulose, D-~orbitol, calcium carbonate, precipitated calcium carbonate, magnesium carbonate, sodium bicarbonate, talc, dextrin, starch, lactose, calcium lactate, sucrose, glucose, pectin, malt extract, D-mannitol, magnesium metasilicate aluminate, aluminium monostearate, purified Do ': #285868 P76247/FP-9704(PCT)/t~a-ig/Engli~h tr~nn~ ~n CA 0224~7l~ l998-08-04 lanolin, dibasic calcium phosphate and dibasic sodium phosphate.
Preferred are lactose, D-mannitol, sucrose, purified saccharose and crystalline cellulose.
As examples of the h; n~r, there are included sugar syrup, starch syrup, gum arabic, gum arabic powder, ethanol, ethylcellulose, casein sodium, carmellose, carmellose calcium, ErAl~ TK0~ ylycerin, cellulose acetate phth;~l ~te, stearic acid, puri~ied water, gelatin, purified shellAc, white shellac, dextrin, starch, tragacanth, powdered trag~C~nth, honey, microcrystalline cellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropyl starch, hydroxypropylmethyl cellulose, hydroxymethylcellulose, sodium polyphosphate, rice flour, methylcellulose, methylcellulose sodium and polyvinylpyrrolidone.
Examples of the disintegrant include those exemplified above as "disintegrant".
Examples of the colorant include caramel, iron sesquioxide, tar colorants used ~or pharmaceuticals.
Examples o~ the taste masking agent/smell masking agent include ordinarily employed sweeteners, acidifiers and flavors.
As examples o~ the lubricant, there are included c~rn~llh~
wax, light anhydrous silicic acid, synthetic aluminium silicate, natural aluminium silicate, synthetic magnesium silicate, hydrogenated oil, hydrogenated vegetable oil derivatives (for example, Sterotex HM), sesame oil, white beeswax, titanium oxide, dried aluminium hydroxide gel, stearic acid, calcium ~ #285868 P76247/FP-9704(PCT)/t~-ig/Engli~h trdn~lation CA 0224~7l~ l998-08-04 stearate, magnesium stearate, talc, dibasic calcium phosphate and sodium laurylsulfate.
It is also possible to add the above-exemplified additives to the mixture before grinding insofar as they do not adversely affect the grjn~;ng and the dissolution property of the azasteroid and then grind the resulting mixture, thereby preparing the above-described "composition".
Although the dose of a "formulation of a 5a-reductase inhibitor for oral ~m;n;stration of the invention" will change according to the symptoms and age of the patient, it is desired to ~m;n;ster, once or in several portions, the formulation which has been adjusted to c~n~A;n the azasteroid in an amount ranging from 0.1 mg (preferably 0.5 mg) as the lower limit to 100 mg (preferably 50 mg, most preferably 20 mg) as the upper limit per day.
BeRt Mode for performing the In~ention The invention will hereinafter be described more speci~ically by the following examples, cs~rative examples and tests.
Exam~le 1 In a mortar, 1.0 g of N-~1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~ rho~m;de (which will hereinafter be called "Compound I"), 0.5 g of hydroxypropylmethylcellulose (which will hereinafter be D- ': #285868 P76247/FP-9704(PCI)/tl~a-ig/Engli~h Lr -lal~
CA 0224~7l~ l998-08-04 abbreviated as "HPMC") and 2 g of crospovidone ("Kollidon CLn, trade name; product of BASF Japan) were mixed uniformly, followed by gr;n~;ng for 30 minutes in a VIBRATING SAMPLE MILL
model TI-100 (CMT Co., Ltd.) having a rod therein.
Example 2 In a mortar, 1.0 g of Compound I, 0.5 g of HPMC and 2 g of sodium carboxymethyl starch ("Explotab", trade name; product of Kimura Sangyo Co., Ltd.) were mixed uniformly, followed by gr;n~;ng for 30 minutes in a VIBRATING SAMPLE MILL model TI-100 having a rod therein.
Exam~le 3 In a mortar, 1.0 g of Compound I, 0.5 g of HPMC and 2 g of croscarmellose sodium ("Ac-Di-Sol", trade name; product of Asahi Chemical Industry Co., Ltd.) were mixed uniformly, followed by gr;n~;ng for 30 minutes in a VIBRATING SAMPLE MILL model TI-lO0 having a rod therein.
Exam~le 4 Compound I (1170 g), 2B6 g of HPMC, 2B6 g of carmellose calcium and 25B g of crystalline cellulose were mixed. In a DYNAMIC MILL Type lO (Mitsui Miike Engineering Corporation), the resulting mixture was charged and ground at a rate of 60 g/min.
Document: #285B6B P76247/FP-9704(PCT)/t~a-ig/Engli~h tran~lation CA 0224~7l~ l998-08-04 Example 5 Compound I (2 kg), 3.9 kg of carmellose calcium, 0.5 kg of HPMC and 0.4 kg of cry6talline cellulose were mixed. In a DYNAMIC MILL Type lO (Mitsui Miike Engineering Corporation), the resulting mixture was charged and ground at a rate of 120 g/min.
ExamPle 6 In a mortar, 1 g of N-(l,l-dimethylethyl)-3-oxo-4-aza-5a-androst-l-ene-17~-carboxamide (which will hereinafter be called "Compound II~), 3 g of HPMC and 2 g of Kollidon CL were mixed uni~ormly, ~ollowed by gr;n~;ng for 30 minute6 in a VIBRATING
SAMPLE MILL model TI-lOO having a rod therein.
Com~arative Exam~le 1 In a VIBRATING SAMPLE MILL model TI-100 having a rod therein, 5 g of Compound I in the form of crystals were charged, followed by gr~ n~; ng for 30 minutes.
Com~arative Exam~le 2 1170 g of Compound I, 286 g of HPMC, 286 g of carmellose calcium and 258 g of cryst~ll;n~ cellulo6e were mixed.
Cnm~ rative Exam~le 3 10 mg of Compound I were dis601ved in 20 ml of polyethylene glycol 400.
r~ : #285868 P76247/FP-9704~PCI)/tsa-ig/Engli~h tram31ation CA 0224~7l~ l998-08-04 ~ I 1 19 Test 1: Dissolution test Amounts of the compositions obt~;n~ in Examples 1 to 4, the powders obtained in Comp~ative Example 1 and the mixture obtained in Comr~ative Example 2, each corresponding to 10 mg of Compound I were weighed. They were subjected to a dissolution test in accordance with the method 2 (paddle method) described in the Dissolution Test defined in the Pharmacopoeia of Japan (the 12th edition).
In the case of the compositions obtA;n~ in Examples l to 3 and the powders obt~;ne~ in Comparative Example l, 900 ml of the second test fluid as described in the Disintegration Test de~ined in the Pharmacopoeia of Japan (the 12th edition) were used as the solution ~or dissolution. The test was con~l~cted at a paddle rotational ~requency of 200 rpm. In the case of the composition obt~;ne~ in Example 4 and the mixture obtained in Comp~ative Example 2, water was used as a solution for di6solution and the test was con~l~cted at a paddle rotational rate of 200 rpm. Results are shown in Table~ 1 and 2.
Table 1: Results of Dissolution Test 1 Example 1 Example 2 Example 3 ro~r~ative Example 1 D(~) 30 min 94 91 9O 5 D(~) 30 min: Dissolution ratio 30 minutes after the beg;nn;ng O~
r~ : #285868 P76247/FP-9704(PCT)/tua-ig/EIlgli~h tr~n~l.t~
CA 0224~71~ 1998-08-04 r I ~ 20 the dissolution test.
Test 2: Results of Dissolution Test 2 Example 4 Comparative Example 2 D(~) 30 min 92 7 D(~) 30 min: Dissolution ratio 30 minutes after the beg;nn;ng of the dissolution test.
As is apparent from Tables 1 and 2, the dissolution property of Compound I was improved enough for practical use by grinding a mixture of Compound I, a water-soluble polymer and a disintegrant. Thus, the formulation o~ a 5~-reductase ; nh; hitor ~or oral ~m;n; stration of the invention is markedly useful, because it is not necessary to incorporate an excess amount o~
an active ingredient in one dosage unit and because, in addition, fluctuations in the absorption ratio among individual living bodies ~m;n; stered can be suppressed to the m;n;~-lm Test 2: Change o~ concentration of Compound I in blood An amount of the composition obt~;ne~ in Example 5 correspsn~; ng to 10 mg of Compound I was suspended in 20 ml of water to prepare a suspension. The resulting suspension and the solution obt~; ne~ in Comparative Example 3 were respectively Document: #285868 P76247/FP-9704(PCT) /t~-ig/Engli~h L~ t j ~n CA 0224~7l~ l998-08-04 orally ~m;n; stered to beagles. Blood samples were obtA;ne~
~rom the upper portion o~ its ~orearm with the lapse o~ time and concentration (ng/ml) of Compound I in the blood was measured.
Results are shown in Table 3.
Table 3: Change o~ concentration (ng/ml) of Compound I in blood Suspension o~ the Solution o~
Time compositionComparative Ex. 2 (hr) obtained in Ex. 5 O O O
0.25 391 369 0.5 589 635 1.5 873 743 From Table 3, it has been found that the formulation Of a 5a-reductase inhibitor for oral ~m;n; stration of the present invention has a bioavA;l~h;lity equivalent to the solution of Compound I.
rc~: #285a68 P76247/FP-9704(PCT)/t6a-ig/Engli~h tr~nclation CA 0224~7l~ l998-08-04 ~~ ~ 22 Test 3: Improvement in dissolution property by grinding An amount of the composition obt~-n~ in Example 6 correspon~ing to 100 mg of Compound II was weighed and a dissolution test for it was conducted in accordance with the method 2 (paddle method) described in the Dissolution Test of the Pharmacopoeia of Japan (the 12th edition). In the test, 900 ml of the second test fluid as described in the Disintegration Test of the Pharmacopoeia of Japan (the 12th edition) were used as the solution for dissolution and the test was conducted at a paddle rotational rate of 200 rpm.
Table 4: Improvement in dissolution property by grinding Before grinding A~ter gr;n~ng D(~) min 36 78 As is apparent from Table 4, the dissolution property of Compound II was markedly improved by gr;nAlng the mixture.
~ #2B586B P76247/FP-9704(PCT)/ts~-ig/E~gli~h tr~n~latio~
In the "formulation of a 5a-reductase inhibitor ~or oral ~m;~; stration" according to the present invention, the term "azasteroidN means N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide or N-(l,l-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide. Preferred is N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide.
The above compounds happen to absorb water, thereby having adsorbed water or becoming hydrates when allowed to stand in the air or during recrystallization. Such hydrates are also embraced in the "azasteroid".
As the "water-soluble polymer" and "disintegrant"
cont~;ne~ in the ground m;~tll~e for obt~;n;ng the "~ormulation of a 5a-reductase inhibitor for oral ~m; n; ~trationN 0~ the present invention, the following compounds can be given as examples.
Examples of the Uwater-soluble polymern include water-soluble cellulose derivatives such as I~o. : #285868 P76247tEP-9704 (PCT) /t~a-ig/Englif~h tranr~lation CA 0224~71~ 1998-08-04 hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carmellose sodium and methylcellulose;
polyalkenylpyrrolidone derivatives such as polyvinylpyrrolidone;
polyalkenyl alcohol derivatives such as polyvinyl alcohol;
carboxyalkenyl polymer derivatives such as carboxyvinyl polymer;
polyalkenyl organic acid derivatives such as partially-saponified polyvinyl acetate; alkenyl organic acid ester copolymer derivatives such as vinyl acetate copolymer; salts of a polysaccharide such as sodium arginate; ester derivatives of a polysaccharide such as propylene glycol arginate; and polyalkylene glycol derivatives such as polyethylene glycol.
Among them, preferred are water-soluble cellulose derivatives and polyalkenylpyrrolidone derivatives, and hydroxypropylmethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone are more pre~erred. These water-soluble polymers can be used either singly or in combination.
Examples o~ the "disintegrant~ include starch, partially a-converted starch, carboxymethyl starch, hydroxypropyl starch, sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium and low-substituted hydroxypropylcellulose and water-insoluble cellulose derivatives (e.g. cryst~ ne cellulose, ethylcellulose, cellulose acetate, carboxymethylethylcellulose and nitrocellulose). Among them, preferred are sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose and crystalline cellulose, ~ #285868 P76247/FP-9704(PCT)/tDa-ig/Engli~h tran~lation CA 0224~71~ 1998-08-04 and sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium and croscarmellose sodium are more preferred.
The above-exemplified disintegrants can be used either singly or in combination.
The above-described water-soluble polymer can generally be added in an amount of 0.1 to 500 parts by weight based on 1 part by weight o~ the above-described azasteroid. It is preferably added in an amount o~ 0.2 to 300 parts by weight (more preferably 10 parts by weight, particularly preferably 6 parts by weight and most pre~erably 5 parts by weight) based on 1 part by weight of the azasteroid.
The above-described disintegrant can generally be added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of the azasteroid. Preferably, it is added in an amount of 0.25 part by weight (more preferably 0.5 part by weight and most preferably 1 part by weight) to 300 parts by weight (preferably lO parts by weight, particularly preferably 6 parts by weight and most preferably 5 parts by weight) based on 1 part by weight of the azasteroid.
The disintegrant can generally be added in an amount of 0.1 to 100 parts by weight based on 1 part by weight of the above-described water-soluble polymer. It is preferably added in an amount of 0.5 part by weight (more preferably 1 part by weight) to 10 parts by weight (preferably 5 parts by weight) based on 1 part by weight of the water-soluble polymer.
The water-soluble polymer and the disintegrant can D~ ': #285868 P76247/FP-9704(PCT)/t~-ig/Engli~h tran~lation CA 0224~71~ 1998-08-04 generally be added in a total amount o~ 0.2 to 1000 parts by weight based on 1 part by weight o~ the azasteroid.
Preferably,they are added in a total amount o~ 0.5 part by weight (more pre~erably 1 part by weight and particularly pre~erably 2 parts by weight) to 600 parts by weight (more pre~erably 20 parts by weight, particularly pre~erably 10 parts by weight, more particularly pre~erably 6 parts by weight and most pre~erably 5 parts by weight) based on 1 part by weight o~
the azasteroid.
The azasteroids cont~;ned as an active ingredient o~ the ~ormulation o~ 5a-reductase inhibitor ~or oral ~m; n; strationn according to the present invention, that is, N-[1-(4-methoxyphenyl)-l-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide [the compound represented by the above ~ormula (I)]
and N-(l,l-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17~-carboxamide [the compound represented by the above formula (II)], are prepared by the processes described in J~p~nese Patent Application Kokai No. HEI 5-32693 and J~p~n~se Patent Application Rokai No. SHO 60-222497 (J~p~nese Patent Application Rokoku No. SHO 63-65080), respectively.
The "composition~ c~nt~;ned by the ~'~ormulation o~ a 5a-reductase ;nh; h; tor ~or oral Zl~m; n; I:tration" o~ the present invention is obt~;ne~ by gr;n~;ng a mixture cont~;n;ng the azasteroid, water-soluble polymer and disintegrant.
The gr;n~;ng can be per~ormed in a known m~nn~r/
pre~erably with a gr;n~;ng machine which allows cont;n~lous ~c ': #285868 P76247/FP-9704(PCT)/tc~-ig/English tr~nslation CA 0224~7l~ l998-08-04 grinding for a long time. Examples of such a gr;n~;ng machine include those using a medium such as a rod mill and a ball mill, and an oscillating ball mill and a medium-agitating type grinding machine are preferred.
Although the time required for gr;n~;ng changes according to the tool or machine to be used for gr;n~;ng, the kind of compound to be ground or the amount of mixture to be ground, gr;n~;ng is generally carried out ~or one minute to 24 hours.
The "compositionN so prepared can be A-lm; n;stered as it is to the human body as a 5a-reductase inhibitor, and also in this case it exhibits a markedly improved dissolution property.
Alternatively, it can be ~lm; n;stered as various dosage forms obt~;n~hle by ~;ng one or more additives to the "composition" and formulating the resulting mixture in a ~nner known E~E se in the art. As the dosage form, solid forms generally known as oral formulations are employed. Examples include powders, granules, tablets and capsules.
For the preparation of powders, for example, the above-described "composition" is used as it is or mixed uniformly with one or more additives described later.
The granules can be prepared, for example, by dry granulation or wet granulation. In this case, it is possible to add, if necessary, one or more of the below-described additives to the "composition" before or after granulation.
The tablets can be prepared, for example, by directly tableting the "composition". Alternatively, they can be r~ #285868 P76247/FP-9704(P~T)/t~-ig/Engli~h tr~nalation CA 0224~7l~ l998-08-04 obt~; n~A by preparing granules from the "composition" and then tableting the resulting granules. In either case, one or more of the below-described additives can be added, if necessary, prior to tableting.
The capsules can be prepared, for example, by filling capsules with the "composition" as it is. Alternatively, they can be obtained by preparing granules as described above in advance and then filling capsules with them. In either case, one or more o~ the below-described additives can be added, if necessary, prior to filling.
Examples of the additive employed for the preparation of a pharmaceutical formulation from the "composition" include excipients, binders, disintegrants, colorants, taste m~#k;ng agents/smell masking agents and lubricants.
As examples of the excipient, there are included kaolin, casein, powdered glycyrrhiza, agar, light anhydrous silicic acid, natural aluminium silicate, synthetic aluminium silicate, synthetic magnesium silicate, silicic anhydride, magnesium silicate, wheat flour, heavy magnesium oxide, aluminium hydroxide, magnesium r~rhon~te co-precipitate, dried aluminium hydroxide gel, gypsum, exsiccated gypsum, gelatin, microcrystalline cellulose, D-~orbitol, calcium carbonate, precipitated calcium carbonate, magnesium carbonate, sodium bicarbonate, talc, dextrin, starch, lactose, calcium lactate, sucrose, glucose, pectin, malt extract, D-mannitol, magnesium metasilicate aluminate, aluminium monostearate, purified Do ': #285868 P76247/FP-9704(PCT)/t~a-ig/Engli~h tr~nn~ ~n CA 0224~7l~ l998-08-04 lanolin, dibasic calcium phosphate and dibasic sodium phosphate.
Preferred are lactose, D-mannitol, sucrose, purified saccharose and crystalline cellulose.
As examples of the h; n~r, there are included sugar syrup, starch syrup, gum arabic, gum arabic powder, ethanol, ethylcellulose, casein sodium, carmellose, carmellose calcium, ErAl~ TK0~ ylycerin, cellulose acetate phth;~l ~te, stearic acid, puri~ied water, gelatin, purified shellAc, white shellac, dextrin, starch, tragacanth, powdered trag~C~nth, honey, microcrystalline cellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropyl starch, hydroxypropylmethyl cellulose, hydroxymethylcellulose, sodium polyphosphate, rice flour, methylcellulose, methylcellulose sodium and polyvinylpyrrolidone.
Examples of the disintegrant include those exemplified above as "disintegrant".
Examples of the colorant include caramel, iron sesquioxide, tar colorants used ~or pharmaceuticals.
Examples o~ the taste masking agent/smell masking agent include ordinarily employed sweeteners, acidifiers and flavors.
As examples o~ the lubricant, there are included c~rn~llh~
wax, light anhydrous silicic acid, synthetic aluminium silicate, natural aluminium silicate, synthetic magnesium silicate, hydrogenated oil, hydrogenated vegetable oil derivatives (for example, Sterotex HM), sesame oil, white beeswax, titanium oxide, dried aluminium hydroxide gel, stearic acid, calcium ~ #285868 P76247/FP-9704(PCT)/t~-ig/Engli~h trdn~lation CA 0224~7l~ l998-08-04 stearate, magnesium stearate, talc, dibasic calcium phosphate and sodium laurylsulfate.
It is also possible to add the above-exemplified additives to the mixture before grinding insofar as they do not adversely affect the grjn~;ng and the dissolution property of the azasteroid and then grind the resulting mixture, thereby preparing the above-described "composition".
Although the dose of a "formulation of a 5a-reductase inhibitor for oral ~m;n;stration of the invention" will change according to the symptoms and age of the patient, it is desired to ~m;n;ster, once or in several portions, the formulation which has been adjusted to c~n~A;n the azasteroid in an amount ranging from 0.1 mg (preferably 0.5 mg) as the lower limit to 100 mg (preferably 50 mg, most preferably 20 mg) as the upper limit per day.
BeRt Mode for performing the In~ention The invention will hereinafter be described more speci~ically by the following examples, cs~rative examples and tests.
Exam~le 1 In a mortar, 1.0 g of N-~1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17~ rho~m;de (which will hereinafter be called "Compound I"), 0.5 g of hydroxypropylmethylcellulose (which will hereinafter be D- ': #285868 P76247/FP-9704(PCI)/tl~a-ig/Engli~h Lr -lal~
CA 0224~7l~ l998-08-04 abbreviated as "HPMC") and 2 g of crospovidone ("Kollidon CLn, trade name; product of BASF Japan) were mixed uniformly, followed by gr;n~;ng for 30 minutes in a VIBRATING SAMPLE MILL
model TI-100 (CMT Co., Ltd.) having a rod therein.
Example 2 In a mortar, 1.0 g of Compound I, 0.5 g of HPMC and 2 g of sodium carboxymethyl starch ("Explotab", trade name; product of Kimura Sangyo Co., Ltd.) were mixed uniformly, followed by gr;n~;ng for 30 minutes in a VIBRATING SAMPLE MILL model TI-100 having a rod therein.
Exam~le 3 In a mortar, 1.0 g of Compound I, 0.5 g of HPMC and 2 g of croscarmellose sodium ("Ac-Di-Sol", trade name; product of Asahi Chemical Industry Co., Ltd.) were mixed uniformly, followed by gr;n~;ng for 30 minutes in a VIBRATING SAMPLE MILL model TI-lO0 having a rod therein.
Exam~le 4 Compound I (1170 g), 2B6 g of HPMC, 2B6 g of carmellose calcium and 25B g of crystalline cellulose were mixed. In a DYNAMIC MILL Type lO (Mitsui Miike Engineering Corporation), the resulting mixture was charged and ground at a rate of 60 g/min.
Document: #285B6B P76247/FP-9704(PCT)/t~a-ig/Engli~h tran~lation CA 0224~7l~ l998-08-04 Example 5 Compound I (2 kg), 3.9 kg of carmellose calcium, 0.5 kg of HPMC and 0.4 kg of cry6talline cellulose were mixed. In a DYNAMIC MILL Type lO (Mitsui Miike Engineering Corporation), the resulting mixture was charged and ground at a rate of 120 g/min.
ExamPle 6 In a mortar, 1 g of N-(l,l-dimethylethyl)-3-oxo-4-aza-5a-androst-l-ene-17~-carboxamide (which will hereinafter be called "Compound II~), 3 g of HPMC and 2 g of Kollidon CL were mixed uni~ormly, ~ollowed by gr;n~;ng for 30 minute6 in a VIBRATING
SAMPLE MILL model TI-lOO having a rod therein.
Com~arative Exam~le 1 In a VIBRATING SAMPLE MILL model TI-100 having a rod therein, 5 g of Compound I in the form of crystals were charged, followed by gr~ n~; ng for 30 minutes.
Com~arative Exam~le 2 1170 g of Compound I, 286 g of HPMC, 286 g of carmellose calcium and 258 g of cryst~ll;n~ cellulo6e were mixed.
Cnm~ rative Exam~le 3 10 mg of Compound I were dis601ved in 20 ml of polyethylene glycol 400.
r~ : #285868 P76247/FP-9704~PCI)/tsa-ig/Engli~h tram31ation CA 0224~7l~ l998-08-04 ~ I 1 19 Test 1: Dissolution test Amounts of the compositions obt~;n~ in Examples 1 to 4, the powders obtained in Comp~ative Example 1 and the mixture obtained in Comr~ative Example 2, each corresponding to 10 mg of Compound I were weighed. They were subjected to a dissolution test in accordance with the method 2 (paddle method) described in the Dissolution Test defined in the Pharmacopoeia of Japan (the 12th edition).
In the case of the compositions obtA;n~ in Examples l to 3 and the powders obt~;ne~ in Comparative Example l, 900 ml of the second test fluid as described in the Disintegration Test de~ined in the Pharmacopoeia of Japan (the 12th edition) were used as the solution ~or dissolution. The test was con~l~cted at a paddle rotational ~requency of 200 rpm. In the case of the composition obt~;ne~ in Example 4 and the mixture obtained in Comp~ative Example 2, water was used as a solution for di6solution and the test was con~l~cted at a paddle rotational rate of 200 rpm. Results are shown in Table~ 1 and 2.
Table 1: Results of Dissolution Test 1 Example 1 Example 2 Example 3 ro~r~ative Example 1 D(~) 30 min 94 91 9O 5 D(~) 30 min: Dissolution ratio 30 minutes after the beg;nn;ng O~
r~ : #285868 P76247/FP-9704(PCT)/tua-ig/EIlgli~h tr~n~l.t~
CA 0224~71~ 1998-08-04 r I ~ 20 the dissolution test.
Test 2: Results of Dissolution Test 2 Example 4 Comparative Example 2 D(~) 30 min 92 7 D(~) 30 min: Dissolution ratio 30 minutes after the beg;nn;ng of the dissolution test.
As is apparent from Tables 1 and 2, the dissolution property of Compound I was improved enough for practical use by grinding a mixture of Compound I, a water-soluble polymer and a disintegrant. Thus, the formulation o~ a 5~-reductase ; nh; hitor ~or oral ~m;n; stration of the invention is markedly useful, because it is not necessary to incorporate an excess amount o~
an active ingredient in one dosage unit and because, in addition, fluctuations in the absorption ratio among individual living bodies ~m;n; stered can be suppressed to the m;n;~-lm Test 2: Change o~ concentration of Compound I in blood An amount of the composition obt~;ne~ in Example 5 correspsn~; ng to 10 mg of Compound I was suspended in 20 ml of water to prepare a suspension. The resulting suspension and the solution obt~; ne~ in Comparative Example 3 were respectively Document: #285868 P76247/FP-9704(PCT) /t~-ig/Engli~h L~ t j ~n CA 0224~7l~ l998-08-04 orally ~m;n; stered to beagles. Blood samples were obtA;ne~
~rom the upper portion o~ its ~orearm with the lapse o~ time and concentration (ng/ml) of Compound I in the blood was measured.
Results are shown in Table 3.
Table 3: Change o~ concentration (ng/ml) of Compound I in blood Suspension o~ the Solution o~
Time compositionComparative Ex. 2 (hr) obtained in Ex. 5 O O O
0.25 391 369 0.5 589 635 1.5 873 743 From Table 3, it has been found that the formulation Of a 5a-reductase inhibitor for oral ~m;n; stration of the present invention has a bioavA;l~h;lity equivalent to the solution of Compound I.
rc~: #285a68 P76247/FP-9704(PCT)/t6a-ig/Engli~h tr~nclation CA 0224~7l~ l998-08-04 ~~ ~ 22 Test 3: Improvement in dissolution property by grinding An amount of the composition obt~-n~ in Example 6 correspon~ing to 100 mg of Compound II was weighed and a dissolution test for it was conducted in accordance with the method 2 (paddle method) described in the Dissolution Test of the Pharmacopoeia of Japan (the 12th edition). In the test, 900 ml of the second test fluid as described in the Disintegration Test of the Pharmacopoeia of Japan (the 12th edition) were used as the solution for dissolution and the test was conducted at a paddle rotational rate of 200 rpm.
Table 4: Improvement in dissolution property by grinding Before grinding A~ter gr;n~ng D(~) min 36 78 As is apparent from Table 4, the dissolution property of Compound II was markedly improved by gr;nAlng the mixture.
~ #2B586B P76247/FP-9704(PCT)/ts~-ig/E~gli~h tr~n~latio~
Claims (18)
1. A formulation of a 5.alpha.-reductase inhibitor for oral administration which comprises a composition obtained by grinding a mixture containing one azasteroid selected from the group (A) shown below, a water-soluble polymer and a disintegrant:
Group (A) N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide; and N-(1,1-dimethylethyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide.
Group (A) N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide; and N-(1,1-dimethylethyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide.
2. A formulation of a 5.alpha.-reductase inhibitor for oral administration according to claim 1, wherein said one azasteroid selected from the group (A) is N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide.
3. A formulation of a 5.alpha.-reductase inhibitor for oral administration according to claim 1 or 2, wherein said water-soluble polymer is a water-soluble cellulose derivative or polyalkenyl pyrrolidone derivative.
4. A formulation of a 5.alpha.-reductase inhibitor for oral administration according to claim 1 or 2, wherein said water-soluble polymer is hydroxypropylmethyl cellulose, hydroxypropylcellulose or polyvinylpyrrolidone.
5. A formulation of a 5.alpha.-reductase inhibitor for oral administration according to any one of claims 1 to 4, wherein said disintegrant is sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose or crystalline cellulose.
6. A formulation of a 5.alpha.-reductase inhibitor for oral administration according to any one of claims 1 to 4, wherein said disintegrant is sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium or croscarmellose sodium.
7. A formulation of a 5.alpha.-reductase inhibitor for oral administration according to any one of claims 1 to 6, wherein said water soluble polymer is added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of said azasteroid.
8. A formulation of a 5.alpha.-reductase inhibitor for oral administration according to any one of claims 1 to 7, wherein said disintegrant is added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of said azasteroid.
9. A formulation of a 5.alpha.-reductase inhibitor for oral administration according to any one of claims 1 to 8, wherein said disintegrant is added in an amount of 0.5 to 10 parts by weight based on 1 part by weight of said water-soluble polymer.
10. A process for the preparation of a formulation of a 5.alpha.-reductase inhibitor for oral administration, which comprises grinding a mixture containing one azasteroid selected from the group (A) shown below, a water-soluble polymer and a disintegrant:
Group A
N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide; and N-(1,1-dimethylethyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide.
Group A
N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide; and N-(1,1-dimethylethyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide.
11. A process according to claim 10, wherein said one azasteroid selected from the group (A) is N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide.
12. A process according to claim 10 or 11, wherein said water-soluble polymer is a water-soluble cellulose derivative or a poly(alkenylpyrrolidone) derivative.
13. A process according to claim 10 or 11, wherein said water-soluble polymer is hydroxypropylmethyl cellulose, hydroxypropylcellulose or poly (vinylpyrrolidone).
14. A process according to any one of claims 10 to 13, wherein said disintegrant is sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose or crystalline cellulose.
15. A process according to any one of claims 10 to 13, wherein said disintegrant is sodium carboxymethyl starch, crospovidone, carmellose, carmellose calcium or croscarmellose sodium.
16. A process according to any one of claims 10 to 15, wherein said water soluble polymer is added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of said azasteroid.
17. A process according to any one of claims 10 to 16, wherein said disintegrant is added in an amount of 0.1 to 500 parts by weight based on 1 part by weight of said azasteroid.
18. A process according to any one of claims 10 to 17, wherein said disintegrant is added in an amount of 0.5 to 10 parts by weight based on 1 part by weight of said water-soluble polymer.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8/18718 | 1996-02-05 | ||
| JP1871896 | 1996-02-05 | ||
| PCT/JP1997/000273 WO1997027875A1 (en) | 1996-02-05 | 1997-02-04 | 5α-REDUCTASE INHIBITORY PREPARATION FOR ORAL ADMINISTRATION, PROCESS FOR PRODUCING THE SAME, AND USE THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2245715A1 true CA2245715A1 (en) | 1997-08-07 |
Family
ID=29422265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2245715 Abandoned CA2245715A1 (en) | 1996-02-05 | 1997-02-04 | 5.alpha.-reductase inhibitory preparation for oral administration, process for producing the same, and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2245715A1 (en) |
-
1997
- 1997-02-04 CA CA 2245715 patent/CA2245715A1/en not_active Abandoned
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4562069A (en) | Two-phase formulation | |
| US6645526B2 (en) | Storage stable thyroxine active drug formulations and methods for their production | |
| US6764997B2 (en) | Stabilized azithromycin compositions | |
| US5972381A (en) | Solid solution of an antifungal agent with enhanced bioavailability | |
| US4101651A (en) | Process for preparing preparations for oral administration | |
| HU192407B (en) | Process for producing antidiabetic pharmaceutical compositions for oral application | |
| JP2014507424A (en) | Solid dispersion formulation and method of use thereof | |
| JP2008540644A (en) | New granulation method and granulated material produced therefrom | |
| US6245352B1 (en) | Pharmaceutical formulation | |
| US20070014864A1 (en) | Novel pharmaceutical granulate | |
| US7052717B2 (en) | Storage stable thyroxine active drug formulations and methods for their production | |
| EP0954288B1 (en) | Solid solution of an antifungal agent with enhanced bioavailability | |
| KR100525275B1 (en) | Solid Dispersion Containing Sialic Acid Derivative | |
| PL201388B1 (en) | Pharmaceutical agent comprising a benzamide derivative as active ingredient | |
| JP2009506085A (en) | Pharmaceutical composition comprising perindopril or a salt thereof | |
| EP0923942B1 (en) | 5alpha-REDUCTASE INHIBITORY PREPARATION FOR ORAL ADMINISTRATION, PROCESS FOR PRODUCING THE SAME, AND USE THEREOF | |
| CA2245715A1 (en) | 5.alpha.-reductase inhibitory preparation for oral administration, process for producing the same, and use thereof | |
| EP1292303B1 (en) | A stable pharmaceutical formulation comprising torsemide modification ii | |
| EP0563697B1 (en) | Cytarabine ocfosfate hard capsule | |
| JPH09278656A (en) | Oral 5-alpha-reductase-inhibitory preparation and its production | |
| EP0724886A1 (en) | Base for sustained-release preparation, sustained-release preparation, and process for producing the preparation | |
| CZ299018B6 (en) | Quick-dissolving pharmaceutical preparation | |
| JP2002003377A (en) | Laxative formulated with picosulfate sodium | |
| EP1541134A2 (en) | Stabilized azithromycin compositions | |
| KR20000011013A (en) | Pharmaceutical compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |