JP2021143208A - シクロベンザプリン塩酸塩およびアミトリプチリン塩酸塩の共融製剤 - Google Patents
シクロベンザプリン塩酸塩およびアミトリプチリン塩酸塩の共融製剤 Download PDFInfo
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- JP2021143208A JP2021143208A JP2021105582A JP2021105582A JP2021143208A JP 2021143208 A JP2021143208 A JP 2021143208A JP 2021105582 A JP2021105582 A JP 2021105582A JP 2021105582 A JP2021105582 A JP 2021105582A JP 2021143208 A JP2021143208 A JP 2021143208A
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- mannitol
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- hcl
- eutectic
- cyclobenzaprine hcl
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Abstract
Description
本出願は、2013年3月15日に出願された米国仮特許出願第61/792,757号に対する優先権を主張し、その内容および開示はその全体が参考として本明細書に援用される。
シクロベンザプリン、すなわち3−(5H−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−N,N−ジメチル−1−プロパンアミンは、局所起始の急性筋痙攣の処置について1977年に米国食品医薬品局により初めて承認された。(Katz,W.ら、Clinical Therapeutics 10:216−228(1988))。アミトリプチリン、または3−(10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−N,N−ジメチル−1−プロパンアミンは、うつ病の処置について米国食品医薬品局により初めて承認された。
後続の研究は、シクロベンザプリンが、線維筋痛症候群、心的外傷後ストレス障害(PTSD)、外傷性脳損傷(TBI)、全般性不安障害およびうつ病の処置にも有効であることを示している。さらに、眠りを深める薬剤として、睡眠の質を改善するため、または睡眠妨害状態を処置するための薬剤としてのシクロベンザプリンの有用性も研究されてきた。しかしながら、FDAが承認した治療薬は疼痛および気分に働きかけるもので、線維筋痛症候群に伴う妨害された睡眠および疲労に働きかけるFDA承認の処置法は現在のところ無い。シクロベンザプリンによる処置は、線維筋痛症候群、長期的疲労、慢性疲労、慢性疲労症候群、睡眠障害、心因性疼痛障害、慢性疼痛症候群(II型)、薬物の投与、自己免疫疾患、ストレスまたは不安により誘発されるか、増悪されるかまたはこれらに関連する睡眠妨害状態を処置する場合に、または睡眠妨害状態により誘発されるかまたは増悪される病気およびかかる病気の症状を処置するのに特に有用であり得る。例えば、米国特許第6,395,788号および6,358,944号参照、これらについては参照により本明細書に援用する。
本発明は、例えば以下の項目を提供する。
(項目1)
マンニトールおよびシクロベンザプリンHClの共融物を含む薬学的組成物。
(項目2)
60重量%〜90重量%のシクロベンザプリンHClおよび40重量%〜10重量%のマンニトールを含む、項目1に記載の薬学的組成物。
(項目3)
60重量%±2重量%シクロベンザプリンHClおよび40重量%±2重量%マンニトール、65重量%±2重量%シクロベンザプリンHClおよび35重量%±2重量%マンニトール、70重量%±2重量%シクロベンザプリンHClおよび30重量%±2重量%マンニトール、75重量%±2重量%シクロベンザプリンHClおよび25重量%±2重量%マンニトール、80重量%±2重量%シクロベンザプリンHClおよび20重量%±2重量%マンニトール、85重量%±2重量%シクロベンザプリンHClおよび15重量%±2重量%マンニトール、および90重量%±2重量%シクロベンザプリンHClおよび10重量%±2重量%マンニトールから選択された量のシクロベンザプリンHClおよびマンニトールを含む、項目2に記載の薬学的組成物。
(項目4)
75重量%±2重量%のシクロベンザプリンHClおよび25重量%±2重量%のマンニトールを含む、項目3に記載の薬学的組成物。
(項目5)
前記シクロベンザプリンHCl:マンニトールのモル比が1.76±0.1である、項目1〜4のいずれか1項に記載の薬学的組成物。
(項目6)
前記シクロベンザプリンHClが、微細化されたシクロベンザプリンHClである、項目1〜5のいずれか1項に記載の薬学的組成物。
(項目7)
さらに塩基性化剤を含む、項目1〜6のいずれか1項に記載の薬学的組成物。
(項目8)
前記塩基性化剤がK2HPO4である、項目7に記載の薬学的組成物。
(項目9)
前記塩基性化剤がNa2HPO4である、項目7に記載の薬学的組成物。
(項目10)
前記塩基性化剤がクエン酸三ナトリウムの無水物である、項目7に記載の薬学的組成物。(項目11)
シクロベンザプリンHClおよびマンニトールを混合するかまたはシクロベンザプリンHClおよびマンニトールを粉砕することを含む、項目1〜10のいずれか1項に記載の共融組成物の製造方法。
(項目12)
シクロベンザプリンHClおよびマンニトールを粉砕することを含む、項目11に記載の方法。
(項目13)
前記シクロベンザプリンHClおよびマンニトールを、高せん断造粒機で粉砕する、項目12に記載の方法。
(項目14)
シクロベンザプリンHClおよびマンニトールを混合することを含む、項目11に記載の方法。
(項目15)
前記シクロベンザプリンHClおよびマンニトールを、加圧により混合する、項目14に記載の方法。
(項目16)
前記シクロベンザプリンHClおよびマンニトールを、ローラー圧縮により加圧する、項目15に記載の方法。
(項目17)
シクロベンザプリンHClおよびマンニトールを噴霧乾燥することを含む、項目1〜10のいずれか1項に記載の共融組成物の製造方法。
(項目18)
前記シクロベンザプリンHClが、微細化されたシクロベンザプリンHClである、項目11〜17のいずれか1項に記載の方法。
(項目19)
前記薬学的組成物が塩基性化剤を含む、項目11〜18のいずれか1項に記載の方法。
(項目20)
前記塩基性化剤がK2HPO4である、項目19に記載の方法。
(項目21)
前記塩基性化剤がNa2HPO4である、項目19に記載の方法。
(項目22)
前記塩基性化剤がクエン酸三ナトリウムの無水物である、項目19に記載の方法。
(項目23)
マンニトールおよびアミトリプチリンHClの共融物を含む薬学的組成物。
(項目24)
前記共融混合物が133±3℃で融解する、項目23に記載の薬学的組成物。
(項目25)
60重量%〜90重量%のアミトリプチリンHClおよび40重量%〜10重量%のマンニトールを含む、項目23に記載の薬学的組成物。
(項目26)
40重量%±2重量%アミトリプチリンHClおよび60重量%±2重量%マンニトール、45重量%±2重量%アミトリプチリンHClおよび55重量%±2重量%マンニトール、50重量%±2重量%アミトリプチリンHClおよび50重量%±2重量%マンニトール、55重量%±2重量%アミトリプチリンHClおよび45重量%±2重量%マンニトール、60重量%±2重量%アミトリプチリンHClおよび40重量%±2重量%マンニトール、65重量%±2重量%アミトリプチリンHClおよび35重量%±2重量%マンニトール、70重量%±2重量%アミトリプチリンHClおよび30重量%±2重量%マンニトール、75重量%±2重量%アミトリプチリンHClおよび25重量%±2重量%マンニトール、80重量%±2重量%アミトリプチリンHClおよび20重量%±2重量%マンニトール、85重量%±2重量%アミトリプチリンHClおよび15重量%±2重量%マンニトール、および90重量%±2重量%アミトリプチリンHClおよび10重量%±2重量%マンニトールから選択される量のアミトリプチリンHClおよびマンニトールを含む、項目25に記載の薬学的組成物。
(項目27)
75重量%±2重量%のアミトリプチリンHClおよび25重量%±2重量%のマンニトールを含む、項目26に記載の薬学的組成物。
(項目28)
50重量%±2重量%のアミトリプチリンHClおよび50重量%±2重量%のマンニトールを含む、項目26に記載の薬学的組成物。
(項目29)
前記アミトリプチリンHClが、微細化されたアミトリプチリンHClである、項目23〜28のいずれか1項に記載の薬学的組成物。
(項目30)
さらに塩基性化剤を含む、項目23〜29のいずれか1項に記載の薬学的組成物。
(項目31)
前記塩基性化剤がK2HPO4である、項目30に記載の薬学的組成物。
(項目32)
前記塩基性化剤がNa2HPO4である、項目30に記載の薬学的組成物。
(項目33)
前記塩基性化剤がクエン酸三ナトリウムの無水物である、項目30に記載の薬学的組成物。
(項目34)
前記マンニトールがβマンニトールである、項目1〜10および23〜33のいずれか1項に記載の薬学的組成物。
(項目35)
前記組成物がシクロベンザプリンHClを含み、前記共融物が143.6±3℃で融解する、項目34に記載の薬学的組成物。
(項目36)
前記マンニトールがδマンニトールである、項目1〜10および23〜33のいずれか1項に記載の薬学的組成物。
(項目37)
前記組成物がシクロベンザプリンHClを含み、前記共融物が134℃±3℃で融解する、項目36に記載の薬学的組成物。
(項目38)
アミトリプチリンHClおよびマンニトールを混合するかまたはアミトリプチリンHClおよびマンニトールを粉砕することを含む、項目23〜35のいずれか1項に記載の共融組成物の製造方法。
(項目39)
アミトリプチリンHClおよびマンニトールを粉砕することを含む、項目38に記載の方法。
(項目40)
前記アミトリプチリンHClおよびマンニトールを、高せん断造粒機で粉砕する、項目39に記載の方法。
(項目41)
アミトリプチリンHClおよびマンニトールを混合することを含む、項目38に記載の方法。
(項目42)
前記アミトリプチリンHClおよびマンニトールを、加圧により混合する、項目41に記載の方法。
(項目43)
前記アミトリプチリンHClおよびマンニトールを、ローラー圧縮により加圧する、項目42に記載の方法。
(項目44)
アミトリプチリンHClおよびマンニトールを噴霧乾燥することを含む、項目23〜34および36のいずれか1項に記載の共融組成物の製造方法。
(項目45)
前記アミトリプチリンHClが、微細化されたアミトリプチリンHClである、項目38〜44のいずれか1項に記載の方法。
(項目46)
前記薬学的組成物が塩基性化剤を含む、項目38〜45のいずれか1項に記載の方法。
(項目47)
前記塩基性化剤がK2HPO4である、項目46に記載の方法。
(項目48)
前記塩基性化剤がNa2HPO4である、項目46に記載の方法。
(項目49)
前記塩基性化剤がクエン酸三ナトリウムの無水物である、項目46に記載の方法。
(項目50)
前記共融組成物がβマンニトールを含む、項目11〜22および38〜49のいずれか1項に記載の方法。
(項目51)
前記組成物がシクロベンザプリンHClを含み、前記共融物が143.6±3℃で融解する、項目50に記載の方法。
(項目52)
前記共融組成物がδマンニトールを含む、項目11〜22および38〜49のいずれか1項に記載の方法。
(項目53)
前記組成物がシクロベンザプリンHClを含み、前記共融物が134℃±3℃で融解する、項目52に記載の方法。
(発明の要旨)
1.マンニトールおよびシクロベンザプリンHClの共融物を含む薬学的組成物。
2.60重量%〜90重量%のシクロベンザプリンHClおよび40重量%〜10重量%のマンニトールを含む、実施形態1記載の薬学的組成物。
3.60重量%±2重量%シクロベンザプリンHClおよび40重量%±2重量%マンニトール、65重量%±2重量%シクロベンザプリンHClおよび35重量%±2重量%マンニトール、70重量%±2重量%シクロベンザプリンHClおよび30重量%±2重量%マンニトール、75重量%±2重量%シクロベンザプリンHClおよび25重量%±2重量%マンニトール、80重量%±2重量%シクロベンザプリンHClおよび20重量%±2重量%マンニトール、85重量%±2重量%シクロベンザプリンHClおよび15重量%±2重量%マンニトール、および90重量%±2重量%シクロベンザプリンHClおよび10重量%±2重量%マンニトールから選択される量のシクロベンザプリンHClおよびマンニトールを含む、実施形態2記載の薬学的組成物。
4.75重量%±2重量%のシクロベンザプリンHClおよび25重量%±2重量%のマンニトールを含む、実施形態3記載の薬学的組成物。
5.前記シクロベンザプリンHCl:マンニトールのモル比が1.76±0.1である、実施形態1〜4のいずれか1つに記載の薬学的組成物。
6.前記シクロベンザプリンHClが、微細化されたシクロベンザプリンHClである、実施形態1〜5のいずれか1つに記載の薬学的組成物。
7.さらに塩基性化剤を含む、実施形態1〜6のいずれか1つに記載の薬学的組成物。
8.前記塩基性化剤がK2HPO4である、実施形態7記載の薬学的組成物。
9.前記塩基性化剤がNa2HPO4である、実施形態7記載の薬学的組成物。
10.前記塩基性化剤がクエン酸三ナトリウムの無水物である、実施形態7記載の薬学的組成物。
11.シクロベンザプリンHClおよびマンニトールを混合するかまたはシクロベンザプリンHClおよびマンニトールを粉砕することを含む、実施形態1〜10のいずれか1つに記載の共融組成物の製造方法。
12.シクロベンザプリンHClおよびマンニトールを粉砕することを含む、実施形態11に記載の方法。
13.前記シクロベンザプリンHClおよびマンニトールを、高せん断造粒機で粉砕する、実施形態12記載の方法。
14.シクロベンザプリンHClおよびマンニトールを混合することを含む、実施形態11記載の方法。
15.前記シクロベンザプリンHClおよびマンニトールを、加圧により混合する、実施形態14記載の方法。
16.前記シクロベンザプリンHClおよびマンニトールを、ローラー圧縮により加圧する、実施形態15記載の方法。
17.シクロベンザプリンHClおよびマンニトールを噴霧乾燥することを含む、実施形態1〜10のいずれか1つに記載の共融組成物の製造方法。
18.前記シクロベンザプリンHClが、微細化されたシクロベンザプリンHClである、実施形態11〜17のいずれか1つに記載の方法。
19.前記薬学的組成物が塩基性化剤を含む、実施形態11〜18のいずれか1つに記載の方法。
20.前記塩基性化剤がK2HPO4である、実施形態19記載の方法。
21.前記塩基性化剤がNa2HPO4である、実施形態19記載の方法。
22.前記塩基性化剤がクエン酸三ナトリウムの無水物である、実施形態19記載の方法。
23.マンニトールおよびアミトリプチリンHClの共融物を含む薬学的組成物。
24.前記共融混合物が133±3℃で融解する、実施形態23記載の薬学的組成物。
25.60重量%〜90重量%のアミトリプチリンHClおよび40重量%〜10重量%のマンニトールを含む、実施形態23記載の薬学的組成物。
26.40重量%±2重量%アミトリプチリンHClおよび60重量%±2重量%マンニトール、45重量%±2重量%アミトリプチリンHClおよび55重量%±2重量%マンニトール、50重量%±2重量%アミトリプチリンHClおよび50重量%±2重量%マンニトール、55重量%±2重量%アミトリプチリンHClおよび45重量%±2重量%マンニトール、60重量%±2重量%アミトリプチリンHClおよび40重量%±2重量%マンニトール、65重量%±2重量%アミトリプチリンHClおよび35重量%±2重量%マンニトール、70重量%±2重量%アミトリプチリンHClおよび30重量%±2重量%マンニトール、75重量%±2重量%アミトリプチリンHClおよび25重量%±2重量%マンニトール、80重量%±2重量%アミトリプチリンHClおよび20重量%±2重量%マンニトール、85重量%±2重量%アミトリプチリンHClおよび15重量%±2重量%マンニトール、および90重量%±2重量%アミトリプチリンHClおよび10重量%±2重量%マンニトールから選択される量のアミトリプチリンHClおよびマンニトールを含む、実施形態25記載の薬学的組成物。
27.75重量%±2重量%のアミトリプチリンHClおよび25重量%±2重量%のマンニトールを含む、実施形態26記載の薬学的組成物。
28.50重量%±2重量%のアミトリプチリンHClおよび50重量%±2重量%のマンニトールを含む、実施形態26記載の薬学的組成物。
29.前記アミトリプチリンHClが、微細化されたアミトリプチリンHClである、実施形態23〜28のいずれか1つに記載の薬学的組成物。
30.さらに塩基性化剤を含む、実施形態23〜29のいずれか1つに記載の薬学的組成物。
31.前記塩基性化剤がK2HPO4である、実施形態30記載の薬学的組成物。
32.前記塩基性化剤がNa2HPO4である、実施形態30記載の薬学的組成物。
33.前記塩基性化剤がクエン酸三ナトリウムの無水物である、実施形態30記載の薬学的組成物。
34.前記マンニトールがβマンニトールである、実施形態1〜10および23〜33のいずれか1つに記載の薬学的組成物。
35.前記組成物がシクロベンザプリンHClを含み、前記共融物が143.6±3℃で融解する、実施形態34記載の薬学的組成物。
36.前記マンニトールがδマンニトールである、実施形態1〜10および23〜33のいずれか1つに記載の薬学的組成物。
37.前記組成物がシクロベンザプリンHClを含み、前記共融物が134℃±3℃で融解する、実施形態36記載の薬学的組成物。
38.アミトリプチリンHClおよびマンニトールを混合するかまたはアミトリプチリンHClおよびマンニトールを粉砕することを含む、実施形態23〜35のいずれか1つに記載の共融組成物の製造方法。
39.アミトリプチリンHClおよびマンニトールを粉砕することを含む、実施形態38記載の方法。
40.前記アミトリプチリンHClおよびマンニトールを、高せん断造粒機で粉砕する、実施形態39記載の方法。
41.アミトリプチリンHClおよびマンニトールを混合することを含む、実施形態38記載の方法。
42.前記アミトリプチリンHClおよびマンニトールを、加圧により混合する、実施形態41記載の方法。
43.前記アミトリプチリンHClおよびマンニトールを、ローラー圧縮により加圧する、実施形態42記載の方法。
44.アミトリプチリンHClおよびマンニトールを噴霧乾燥することを含む、実施形態23〜34および36のいずれか1つに記載の共融組成物の製造方法。
45.前記アミトリプチリンHClが、微細化されたアミトリプチリンHClである、実施形態38〜44のいずれか1つに記載の方法。
46.前記薬学的組成物が塩基性化剤を含む、実施形態38〜45のいずれか1つに記載の方法。
47.前記塩基性化剤がK2HPO4である、実施形態46記載の方法。
48.前記塩基性化剤がNa2HPO4である、実施形態46記載の方法。
49.前記塩基性化剤がクエン酸三ナトリウムの無水物である、実施形態46記載の方法。
50.前記共融組成物がβマンニトールを含む、実施形態11〜22および38〜49のいずれか1つに記載の方法。
51.前記組成物がシクロベンザプリンHClを含み、前記共融物が143.6±3℃で融解する、実施形態50記載の方法。
52.前記共融組成物がδマンニトールを含む、実施形態11〜22および38〜49のいずれか1つに記載の方法。
53.前記組成物がシクロベンザプリンHClを含み、前記共融物が134℃±3℃で融解する、実施形態52記載の方法。
特に断らなければ、本願で使用されている科学的および技術的用語は、当業者が普通に理解している意味を有するものとする。一般的に、本明細書で記載されている、薬理学、細胞および組織培養、分子生物学、細胞および癌生物学、神経生物学、神経化学、ウイルス学、免疫学、微生物学、遺伝子およびタンパク質および核酸化学の技術に関連して使用されている命名法および技術は、当業界で周知の慣用的なものである。
(化合物)
(共融組成物)
(共融組成物の製造方法)
T入口(℃):120
T出口(℃):73〜76
フィード速度(ml/分):4
流速(L/時):600
吸引(100%):100
デルタ圧力(mbar):2〜10
また、これらの条件を率に応じて増大させることにより、より高度のハイスループット製造が達成され得る。
(共融組成物の検出方法)
(共融組成物の投与方法)
本発明の薬学的組成物は、結合組織炎としても知られる線維筋痛症候群の発現を処置または予防するのに使用され得る(例、Moldofskyら、J Rheumatol 38(12):2653−2663(2011)およびThomas、J Rheumatol 38(12):2499−2500(2011)参照)。線維筋痛症は、慢性の非炎症性リウマチ障害である。米国リウマチ学会(The American College of Rheumatology、ACR)は、1990年に線維筋痛症についての分類基準を公表した(Wolfe,F.ら、Arthritis and Rheumatism 33:160−172(1990))。それに続いて、ACR基準に修正を加えたことを公表した(Wolfeら、J Rheumatol 38(6):1113−22(2011))。診断基準はまた、“Outcome Measures in
Rheumatology” clinical trialsまたはOMERACTと呼ばれる研究グループの国際ネットワークによっても公表された(Mease Pら、J Rheumatol.2009;36(10):2318−29)。線維筋痛症は、従来、硬直または放散性疼痛、うずく痛み、筋肉痛、睡眠妨害状態または疲労を特徴とする。疼痛は、概して広汎性であり、一般的に特定の「圧痛点」に局在し、これが触れられた時に広汎性疼痛および筋肉痙攣を引き起こし得る。他の症状としては、集中力低下および過敏性などの精神障害および情緒障害およびうつ病および不安などの神経精神症状、関節腫脹、頭痛、無感覚がある。線維筋痛症は、爽快感のない睡眠、倦怠感、睡気、逆流、並行作業が困難となる場合を含むメンタル・フォグおよび認知障害と関連している。線維筋痛症はまた、睡眠障害、疲労、非回復性睡眠、不安およびうつ病と併存していることが多い。本発明の組成物および方法は、上記で示した状態のいずれか1つ、およびそれらの任意の組み合わせを処置するのに使用され得る。
(塩基性化剤)
(賦形剤)
(増量剤)
(崩壊剤)
(滑剤)
(滑沢剤)
(甘味剤)
(着香料)
(着色剤)
(併用療法)
熱分析技術を使用することにより、シクロベンザプリンHCl(API)を含有する製剤(錠剤)の適合性を評価した。適合性評価を、1:1比率でAPIおよび幾つかの可能な賦形剤間において実施した。各成分について、および混合物について記録された熱事象に基づいて、APIおよび賦形剤間の混合物における示差走査熱量測定(DSC)により記録されたピークを調べることにより、分析を実施した。単一化合物およびめのう乳鉢での生成物の粉砕後に得られた関連混合物の間の熱プロフィールの差異を評価した。安定性および適合性についても、1か月間40℃および50℃でのストレス条件後の最終製剤に基づいて評価した。
シクロベンザプリンHCl
フマル酸ステアリルナトリウム
二塩基性リン酸カリウム
クロスポビドン(Kollidon CL)
コロイド状ケイ素
Pearlitol flash
Opadry 03F190003 Clear
Opadryll 85F19000 Clear
(示差走査熱量測定(DSC))
加熱速度:10℃/分
雰囲気:窒素30mL/分
試料ホルダー:通常の蓋なしアルミニウムパン
温度範囲:25℃〜250℃
計器校正:インジウム試料純度99.999%
実施例2
シクロベンザプリンHCl
リン酸二ナトリウム無水物
リン酸二ナトリウム二水和物
リン酸二ナトリウム七水和物
クエン酸三ナトリウム二水和物
Effersoda(登録商標)
ソルビトール
マンニトール
ミックスのAPI+リン酸二ナトリウム無水物
ミックスのAPI+リン酸二ナトリウム二水和物
ミックスのAPI+リン酸二ナトリウム七水和物
ミックスのAPI+クエン酸三ナトリウム二水和物
ミックスのAPI+Effersoda(登録商標)
ミックスのAPI+ソルビトール
ミックスのAPI+マンニトール
クエン酸三ナトリウム無水物
炭酸グリシン二ナトリウム
ミックスのAPI+クエン酸三ナトリウム無水物
ミックスのAPI+炭酸グリシン二ナトリウム
(示差走査熱量測定(DSC))
加熱速度:10℃/分
雰囲気:窒素30mL/分
試料ホルダー:通常の蓋なしアルミニウムパン
温度範囲:25℃〜250℃
計器校正:インジウム試料純度99.999%
減衰全反射を用いたフーリエ変換赤外分光法(FT−IR/ATR)
X線粉末回折(XRPD)
FT−IR/ATR
実施例3
ゾーンA:過剰のマンニトール(液体共融物+固体マンニトール)
ゾーンB:過剰のシクロベンザプリンHCl(液体共融物+固体シクロベンザプリンHCl)
ゾーンC:マンニトールを伴う固体共融物
ゾーンD:シクロベンザプリンHClを伴う固体共融物
ゾーンE:マンニトールおよびシクロベンザプリンHClを伴う液体相
XRPD
実施例4
アミトリプチリンHCl
フマル酸ステアリルナトリウム
ステアリン酸
グリセロールジベヘネート
ステアリン酸マグネシウム
Pearlitol flash
Pearlitol200SO/マンニトール
UnipureDW/アルファ化コーンスターチ
クロスポビドン−Kollidon CL
コロイド状ケイ素/Aerosil 200
リン酸ナトリウム二塩基性
重炭酸ナトリウム
炭酸ナトリウム
リン酸ナトリウム12水和物
リン酸ナトリウム無水物。
実施例4
加熱速度:10℃/分
雰囲気:窒素30mL/分
試料ホルダー(older):通常の蓋なしアルミニウムパン
温度範囲:25℃〜250℃
計器校正:インジウム試料純度99.999%
ULTIMA IV(Rigaku)装置を用いて、試料を据え付けの試料ホルダー上に載せ、X線粉末回折(XRPD)試験を実施した。X線結像スリットは、θ値でインターロックされた可変幅を有した。X線管は銅ターゲットを有し、電流強度は40mAおよび電圧は50kVであった。Cockcroft−Walton方法により発生させた放射線は、Kα1(1.540562オングストローム)およびKα2(1.544398オングストローム)という構成である。分析条件は次のとおりであった:
固定時間
サンプリング幅:0.02度
走査速度:1.0秒/ステップ
2θ範囲:3÷50度
試料ホルダー:非晶質ガラス−等角9200/2G、0.2mm深さであった。試料をガラスプレートでプレスした。
実施例5
Pharmacy 35(6):712−718(2009)参照。理論に拘束されることを望むものではないが、マンニトールの多形状態の変化は、噴霧乾燥とシクロベンザプリンの添加の組み合わせに起因すると思われる。これは、湿式または乾式混合とは異なり、噴霧乾燥は、成分を溶解し、次いでそれらを一緒に共結晶化させることを含むためであり得る。DSCにより試験された混合物は、25%シクロベンザプリン:75%マンニトール(重量による)(図102)、50%シクロベンザプリン:50%マンニトール(重量による)(図103)、75%シクロベンザプリン:25%マンニトール(重量による)(図104)、および90%シクロベンザプリン:10%マンニトール(重量による)(図105)であった。これらの測定結果を使用して、134℃の融点を算出し、共融組成物についての相図を作製した(図106)。噴霧乾燥後に得られた相図(δ多形)を、混合後の相図(β多形、図65)と比較したとき、融点間の差異が明白に観察され得る。β多形についての融点は143℃であり、δ多形についての融点は134℃である。この低い方の融点は、下記のように、そのことが溶解を助けるため有益である。また、純粋なマンニトールおよびシクロベンザプリンHClのXRPD(図107)を、噴霧乾燥後に形成された共融物のXRPD(図108)と比較することにより、噴霧乾燥がδマンニトールの形成をもたらすことが確認される。事実、XRPDパターンは、10%マンニトールでさえ、マンニトールの全部がδ多形で存在することを示している。
装置:USP Paddle
RPM:50
媒質:ピロリン酸緩衝液0.5% pH=4.5±0.05
添加剤:メトセル0.3%
容器容量:300mL
温度37±0.5℃
サンプリング時間:1、2、5、10、20、30、および60分、次いで6時間まで1時間毎。
サンプリング溶液を1〜50mLに希釈し、次いで媒質で1〜50mLとして、下記条件のもとUV(GBC Cintral 10e)でUV分析にかけた:
λmax:224nm
キュベット:石英1cm
ブランク:媒質
図117は、異なるpHでのシクロベンザプリンのイオン化を示す。特に、pH4.5では、遊離塩基が依然として存在している。遊離塩基は溶解しないため、シクロベンザプリン溶解は100%に到達しない。湿式造粒混合物(図118)および噴霧乾燥混合物(図119および120)で溶解試験を実施することにより、δマンニトール共融物が、βマンニトール溶解生成物とは異なる溶解特性を有するか否かを試験した。図119は、6時間にわたる、湿式造粒(WG)混合物、乾式混合(MIX)混合物および噴霧乾燥(SD)混合物、ならびにシクロベンザプリンHCl単独(API)間の比較を示す。これらの実験は、特に最初の1時間の間(図120)、噴霧乾燥組成物が、湿式造粒および乾式混合の両組成物よりも速く溶解することを示しており、δマンニトール共融物の利点が立証されている。この高い溶解性は、経口製剤および舌下製剤の両方においてシクロベンザプリンの吸収速度を増加させるため、有益である。δマンニトール共融物はまた、オーブン中50℃で貯蔵した場合の加速的安定性試験の3週間後でさえ安定している。これらの試験において、δ形態は未変化のままであり、β形態への形態変換は観察されなかった(データは示さず)。
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