ZA200207221B - Alprazolam inclusion complexes and pharmaceutical compositions thereof. - Google Patents
Alprazolam inclusion complexes and pharmaceutical compositions thereof. Download PDFInfo
- Publication number
- ZA200207221B ZA200207221B ZA200207221A ZA200207221A ZA200207221B ZA 200207221 B ZA200207221 B ZA 200207221B ZA 200207221 A ZA200207221 A ZA 200207221A ZA 200207221 A ZA200207221 A ZA 200207221A ZA 200207221 B ZA200207221 B ZA 200207221B
- Authority
- ZA
- South Africa
- Prior art keywords
- cyclodextrin
- beta
- mol
- inclusion complex
- alprazolam
- Prior art date
Links
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 title claims description 61
- 229960004538 alprazolam Drugs 0.000 title claims description 61
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 21
- 229920000858 Cyclodextrin Polymers 0.000 claims description 90
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 36
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 34
- 229960004853 betadex Drugs 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000001116 FEMA 4028 Substances 0.000 claims description 17
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 13
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 11
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- -1 hydroxypropyl groups Chemical group 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 8
- 239000000443 aerosol Substances 0.000 claims description 7
- 208000019906 panic disease Diseases 0.000 claims description 7
- 239000006190 sub-lingual tablet Substances 0.000 claims description 7
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000007921 spray Substances 0.000 claims description 6
- 238000007726 management method Methods 0.000 claims description 5
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical group OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 claims description 4
- 239000006189 buccal tablet Substances 0.000 claims description 4
- 239000000829 suppository Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 description 22
- 239000000243 solution Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 15
- 229940097362 cyclodextrins Drugs 0.000 description 12
- 239000003623 enhancer Substances 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 9
- 230000035515 penetration Effects 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004898 kneading Methods 0.000 description 5
- 210000004379 membrane Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000006069 physical mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 208000019901 Anxiety disease Diseases 0.000 description 4
- 230000036506 anxiety Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 210000000214 mouth Anatomy 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 229920003169 water-soluble polymer Polymers 0.000 description 4
- YZOUYRAONFXZSI-SBHWVFSVSA-N (1S,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-37,39,40,41,42,43,44,45,46,47,48,49-dodecamethoxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38-diol Chemical compound O([C@@H]([C@H]([C@@H]1OC)OC)O[C@H]2[C@@H](O)[C@@H]([C@@H](O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3O)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O3)O[C@@H]2CO)OC)[C@H](CO)[C@H]1O[C@@H]1[C@@H](OC)[C@H](OC)[C@H]3[C@@H](CO)O1 YZOUYRAONFXZSI-SBHWVFSVSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010033664 Panic attack Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003232 mucoadhesive effect Effects 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940098466 sublingual tablet Drugs 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 206010002869 Anxiety symptoms Diseases 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000014749 Mentha crispa Nutrition 0.000 description 1
- 244000024873 Mentha crispa Species 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- DCQLZTSRKLWEAB-UHFFFAOYSA-N ac1ndudu Chemical compound O1C(C(C2OCC(C)O)OCC(C)O)C(COCC(C)O)OC2OC(C(C2OCC(C)O)OCC(C)O)C(COCC(C)O)OC2OC(C(C2OCC(C)O)OCC(C)O)C(COCC(C)O)OC2OC(C(C2OCC(C)O)OCC(C)O)C(COCC(C)O)OC2OC(C(OCC(C)O)C2OCC(C)O)C(COCC(O)C)OC2OC(C(C2OCC(C)O)OCC(C)O)C(COCC(C)O)OC2OC2C(OCC(C)O)C(OCC(C)O)C1OC2COCC(C)O DCQLZTSRKLWEAB-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000004479 aerosol dispenser Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000004955 epithelial membrane Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000013563 matrix tablet Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960005480 sodium caprylate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- VMSNAUAEKXEYGP-YEUHZSMFSA-M sodium glycodeoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 VMSNAUAEKXEYGP-YEUHZSMFSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 238000003836 solid-state method Methods 0.000 description 1
- 238000010671 solid-state reaction Methods 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000004964 sulfoalkyl group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Description
of va \ ALPRAZOLAM INCLUSION COMPLEXES AND PHARMACEUTICAL
COMPOSITIONS THEREOF
This invention relates to an inclusion complex of alprazolam and an unsubstituted or substituted beta- or gamma-cyclodextrin, and to pharmaceutical compositions containing such a complex, particularly for oral, nasal or rectal mucosal delivery, for the treatment of anxiety and panic attack.
Alprazolam is also known as 8-chloro-1-methyl-6-phenyl-4H-[1,2 4]triazolo[4,3- a|[1,4]benzodiazepine.
Alprazolam is indicated for the short term treatment of Generalised Anxiety
Disorder (GAD) and has particular utility as an agent for the management of panic disorders (with or without agoraphobia).
A In an acute state such as a panic attack, a rapid onset of action is desirable. ‘ Although alprazolam is well absorbed from a tablet formulation after conventional orogastric administration, maximum plasma levels occur between
CONFIRMATION COPY i) . a4 : ’
A 0,7 to 1,8 hours post-dose. The onset of anxiolysis correlates with attainment - of maximum plasma levels. The absorption rate is therefore often not ‘ sufficiently rapid to provide immediate symptomatic relief in an anxiety crisis.
Absorption of alprazolam from the stomach is further adversely affected by the presence of food and antacids, the use of the latter being frequently associated with stress related syndromes. Rapid absorption of alprazolam in a manner which would avoid these complications and avoid the need for administration of the dosage form with a liquid would have distinct advantages.
The mucosal route of drug delivery, in particular the sublingual or nasal mucosal routes, offer a useful alternative to parenteral delivery where a rapid therapeutic effect is desired. Sublingual use of the commercially available oral tablet dosage forms of alprazolam offers no significant benefit over conventional orogastric administration in terms of speed of onset [see J.M.
Scavone et al, J. Clin. Psychopharmacol., 1987, 7, 332-335). Formulation of alprazolam in a manner which permits rapid uptake from the sublingual, nasal or rectal mucosa would have distinct utility in the emergency relief of anxiety symptoms.
The oral, nasal and rectal cavities have several advantages as sites for systemic drug delivery, particularly avoidance of pre-systemic metabolism.
However, the low permeability of the membranes that line the oral and nasal cavities result in a low flux of drug. There is therefore a need to enhance drug solubility and penetration to improve bioavailability following oral or nasal mucosal drug delivery.
There are several methods known in the art to deliver drugs to the oral, nasal . and rectal mucosae. These include buccal and sublingual tablets or lozenges, . adhesive patches, gels, solutions or sprays (powder, liquid or aerosol) for the . oral cavity and solutions or sprays (powder, liquid or aerosol) for the nasal cavity and suppositories for rectal administration.
: The absorption of drugs from mucosal membranes may be enhanced by (i) . increasing drug solubility, (i) pH modification to favour the unionised form of the drug, (iii) addition of mucoadhesive agents to improve contact between the delivery system and the membrane and (iv) incorporation of so-called penetration enhancers.
There are a number of penetration enhancers known to influence the permeability of drugs across epithelial membranes (for a recent review see
Walker, R.B. and Smith, EW. Advanced Drug Delivery Reviews 1996, 18, 295 - 301).
Cyclodextrins and their derivatives have found extensive application as solubilizers and stabilizers due to their ability to form inclusion compiexes with a wide variety of compounds (see J. Szejtli, Cyclodextrin Technology, Kluwer
Academic Press) and (J. Szejtli & K-H Fromming, Cyclodextrins in Pharmacy,
Kluwer Academic Press). Cyclodextrins have been used to enhance intenstinal absorption of drugs primarily through increasing solubility. Recently, cyclodextrins have been shown to have positive and negative effects on transdermal penetration of drugs (see Loftsson, T. et al International Journal of
Pharmaceutics 1995, 115, 255 - 258), (Vollmer, U. et al. International Journal of Pharmaceutics 1993, 99, 51 - 58), (Legendre, J.Y. et al. European Journal of Pharmaceutics 1995, 3, 311 - 322) and (Vollmer, U. et al Journal of
Pharmacy and Pharmacology 1994, 46, 19 - 22). Cyclodextrins may improve nasal absorption of drugs (see Merkus, F.W. et al. Pharmaceutical Research 1992, 9, 1157 - 1163) and enhance absorption from sublingual administration of drug / cyclodextrin complexes. Cyclodextrins also protect nasal mucosal damage by penetration enhancers (see Jabbal.Gill, I. et al. European Journal . of Pharmaceutical Sciences 1994, 1 (5), 229 - 236). a : Cyclodextrins are water soluble cone-shaped cyclic oligosaccharides containing 6, 7 or 8 glucopyranose units. The interior or “cavity” of the cone is
. a hydrophobic whilst the exterior is hydrophilic. The size of the cavity increases
LE with increasing number of glucose units. Several cyclodextrin derivatives such as alkyl, hydroxyalkyl and sulfoalkyl ethers have been prepared with improved solubility (see J. Szeijtli & K-H Fromming, Cyclodextrins in Pharmacy, Kluwer
Academic Press) and (Stella, V.J. et al. Pharmaceutical Research 1995, 12 (9)
S205). Suitably sized hydrophobic “guest” molecules may enter the “host” cavity to form a classical host-guest “inclusion compound” or “inclusion complex” with either the entire guest molecule included or only a portion thereof. The driving mechanism for cyclodextrin inclusion complexation is the affinity of the hydrophobic guest molecule for the cavity of the cyclodextrin host molecule with displacement of cavity water molecules to a thermodynamically more stable state. The term “complex stability” or stability of a given inclusion complex refers to the association / dissociation equilibrium of host and guest in solution. Complex stability depends on the number of intermolecular bonding interactions between the host and guest. Van der Waals forces and hydrophobic interactions are the main interactions stabilising inclusion complexes (Bergeron, R.J. et al. Journal of the American Chemical Society 1977, 99, 5146). Depending on the nature and position of hydrogen bonding functionalities on a given guest, there may be hydrogen bonding between the guest and hydroxyl groups of the cyclodextrin or other hydrogen bonding groups in the case of cyclodextrin derivatives. lonic interactions between the host and guest are also possible in the case of ionic cyclodextrins such as sulfobutyl ethers (Stella, V.J. et al. Pharmaceutical Research 1995, 12 (9),
S205).
Cyclodextrin inclusion complexes may be prepared on the basis of liquid state, solid state or semi-solid state reaction between the components (J. Szeijtli, - Cyclodextrin Technology, Kluwer Academic Press). The first is accomplished ~ by dissolving the cyclodextrin and guest in a suitable solvent or mixture of . solvents and subsequently isolating the solid state complex by crystallisation, evaporation, spray drying or freeze drying. In the solid state method, the two
Ea | fe a components may be screened to uniform particle size and thoroughly mixed whereafter they are ground in a high energy mill with optional heating, screened and homogenised. In the semi-solid state, the two components are kneaded in the presence of small amounts of a suitable solvent, and the complex so-formed, is dried, screened and homogenised.
The liquid state reaction generally provides optimum conditions for completeness of reaction. Depending on solvent conditions, the dissolved inclusion complex exists in equilibrium between uncomplexed host and guest and complexed host / guest.
The use of cyclodextrins to increase the solubility of alprazolam has been described. In an article in Acta Pharm. Nord. 3(4), 1991, 215-217, Loftsson et al describe the effect of the cyclodextrin derivative, 2-hydroxypropyl-i3- cyclodextrin, on the aqueous solubility of 13 different drugs, including alprazolam. A 16-fold solubility enhancement for alprazolam in a 20% solution of 2-hydroxypropyl-f3-cyclodextrin is reported. No solid complex is described.
In a subsequent article published in Int. J. Pharm,1994, 110, 169-177, Loftsson et al describe the effect of 2-hydroxypropyl-3-cyclodextrin on the water solubility of alprazolam in the presence and absence of water soluble polymers. Enhanced solubility of alprazolam is obtained following heating of a solution of 2-hydroxypropyl-B-cyclodextrin and a water soluble polymer in a sealed container at 120°C for 20 minutes. No solid complex is described.
JP 07165616 to Hisamitsu Pharmaceutical Company, Japan similarly claims the formation of inclusion complexes of drugs with cyclodextrin in the presence of water soluble polymers to improve solubility and stability.
Loftsson et al [see Int. J. Pharm,1998, 162(2), 115-121] have also reported an enhancement in the solubility and have demonstrated improved complexing
[I , fa ’ ability for R-cyclodextrin in solutions of drugs containing water soluble polymers, including the drug alprazolam. No solid complex is described.
DE 44 28 986 A1 to KRKA, Slovenia teaches the formulation of rapidly dissolving solid dosage forms for orogastric administration of alprazolam containing alpha-, beta-, or gamma cyclodextrin when employed as water soluble carriers. Alprazolam is deposited on the carrier by spray drying prior to incorporation into a tablet.
US Patents Nos 5 288 497 and 5 785 989 to Stanley, T.H.et al (The University of Utah) entitled “Compositions of Oral Dissolvable Medicaments” and “Compositions and Methods of Manufacturing of Oral Dissolvable
Medicaments”, respectively, recite in their claims a drug-containing dosage form (where the drug is a benzodiazepine) which permits absorption through the mucosal tissues of the mouth. The dosage form is referred to as an “appliance or holder” containing drug dispersed into a carbohydrate, fat, protein, wax or other dissolvable matrix.
According to a first aspect of the invention there is provided a pharmaceutical composition for transmucosal delivery comprising an inclusion’ complex of (a) alprazolam and (b) a water soluble unsubstituted or substituted beta- or gamma-cyclodextrin, and a pharmaceutically acceptable carrier therefor.
The pharmaceutically acceptable carrier must be suitable for transmucosal
A delivery of the alprazolam inclusion complex.
) The cyclodextrin is preferably a water soluble unsubstituted or substituted beta-cyclodextrin, more preferably an alkylated beta-cyclodextrin, a hydroxyalkylated beta-cyclodextrin, or a sulfoalkylated beta-cyclodextrin.
The inclusion complex is preferably an inclusion complex of alprazolam and 2- hydroxypropyi-beta-cycodextrin, of alprazolam and a randomly methylated- beta-cyclodextrin, or of alprazolam and sulfobuty! ether beta-cyclodextrin.
The inclusion complex preferably has a stoichiometry of (a) to (b) from 1 : 1 mol / mol to 1 : 10 mol / mol inclusive and more preferably 1:7 mol / mol inclusive.
According to a second aspect of the invention there is provided an inclusion complex of (a) alprazolam and (b) a water soluble unsubstituted or substituted beta- or gamma- cyclodextrin.
The pharmaceutical composition is preferably for use in the treatment of
Generalised Anxiety Disorder (GAD) and has particular utility as an agent for the management of panic disorders.
The pharmaceutical composition is preferably adapted for oral, nasal or rectal mucosal delivery.
BRIEF DECRIPTION OF THE DRAWINGS
Figure 1 represents the effect of varying concentrations of beta- cyclodextrin (BCD) on the aqueous solubility of alprazolam at \ 25°C.
Figure 2 represents the effect of methyl-beta cyclodextrin (squares) and . 2-hydroxypropyl-beta-cyclodextrin (triangles) on the aqueous solubility of alprazolam at 25°C.
vo La ) Figure 3 represents the dissolution rate of alprazolam from a physical mixture (solid squares) of alprazolam and 2-hydroxypropyl- beta-cyclodextrin and the corresponding complex (open diamonds) obtained from Example 3 and performed according to Example 5.
Figure 4 represents the dissolution rate of alprazolam from a physical mixture (solid squares) of alprazolam and methyl-beta- cyclodextrin and the corresponding complex (open diamonds) obtained from Example 4 and performed according to Example 5. The powder samples were compressed into disks using a single punch and die.
- The crux of the invention is an inclusion complex of (a) alprazolam and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin, and pharmaceutical compositions containing the inclusion complex for transmucosal delivery.
The second component of the inclusion complex is an unsubstituted or substituted beta- or gamma-cyclodextrin.
Highly water soluble cyclodextrins such as 2-hydroxypropylated or randomly methylated or sulfoalkylated derivatives of beta-cyclodextrin are the preferred cyclodextrins of the invention. Gamma-cyclodextrin or 2-hydroxypropylated or randomly methylated or sulfoalkylated derivatives of gamma-cyclodextrin may . also be used in the same manner as the corresponding preferred beta- cyclodextrin derivatives. The degree of substitution of the cyclodextrin . derivatives may vary between 1 to 20 substituents per cyclodextrin molecule, but more preferably between 3 to 15 substituents per cyclodextrin molecule.
: When the cyclodextrin is 2-hydroxypropyl-beta-cyclodextrin, the preferred degree of substitution is between 3,9 and 5,1 hydroxypropyl groups per ’ cyclodextrin molecule. When the cyclodextrin is a randomly methylated-beta- cyclodextrin, the preferred degree of substitution is between 1,8 and 2 methyl groups per glucose unit. When the cyclodextrin is sulfobutyl ether-beta- cyclodextrin, the preferred degree of substitution is between 1 and 7 sulfobutyl ether groups per cyclodextrin molecule.
The inclusion complex of the invention may be prepared from aqueous solutions, slurries or pastes of alprazolam and cyclodextrin according to : conventional methods. The molar ratio of alprazolam to cyclodextrin may vary between 1 : 1 to 1: 10 inclusive, but more preferably between 1 : 1 to 1:7 inclusive. Solutions are prepared by dissolving the cyclodextrin in a sufficient quantity of purified deionised water. Alprazolam is added to the solution with stirring until dissolved. The solution may be used in the preparation of liquid delivery systems such as drops, sprays or aerosols. Where a solid inclusion complex is desired, the solution or slurry may be dried by spray drying or freeze drying.
Alternatively, alprazolam and cyclodextrin are mixed. The powder mixture is wetted with water while mixing vigorously until a paste is formed. The paste is mixed for 0,25 to 2 hours and dried in an oven or in vacuo at elevated temperature. The dried complex is crushed and sieved to the desired particle size.
The particle size of the complex is preferably 95% less than 100 microns and most preferably 95% less than 50 microns, to facilitate wetting of a solid - formulation.
The second aspect of the invention is a pharmaceutical composition which comprises as an active ingredient an inclusion complex as described above.
The pharmaceutical composition of the invention is of particular application in the treatment of GAD and for the management of panic disorders.
Further, the pharmaceutical composition of the invention is preferably adapted for oral, nasal, or rectal mucosal delivery.
The administration of an anxiolytic drug through the mucosal tissue of the nose, mouth or rectum avoids the problems associated with oral administration of alprazolam (i.e. slow onset of action, low bio-availability and associated poor compliance).
Absorption of the drug from the pharmaceutical composition of the invention is rapid such that the drug reaches the systemic circulation almost as fast as through injection and appreciably faster than oral administration, which is highly advantageous for the rapid relief of anxiety.
Further, the unpleasant taste and irritant properties of the active principle are reduced by presenting the drug to the nasal or rectal oral mucosal membranes in the form of a cyclodextrin inclusion complex.
The present invention achieves these advantages by molecular encapsulation of the drug in a cyclodextrin, so forming a molecular inclusion complex which may be used in the solid form for the preparation of sublingual or buccal tablets, buccal patches, nasal inhalation powders (insufflations), suppositories, - or powder aerosols for nasal or pulmonary application. The inclusion complex may be used in the liquid state for the preparation of metered dose sprays, . drops or pressurised aerosols for nasal or oral administration. The complex according to the invention may be incorporated into a shearform matrix .
] designed for immediate release as described in Fuisz Technolgies Ltd. patents (Eur. Pat. Appl. EP 95-650038 and PCT Int. Appl. WO 95/34293).
The water soluble complexes of alprazolam according to the invention may be incorporated into controlled release matrices for sustained release following oral administration of a matrix tablet. The matrix may be composed of any suitable erodible matrix such as substituted celluloses and the like.
Alternatively the complexes may be applied to non-pareil spheres by coating methods known in the art. The coated spheres may be optionally coated with controlled release polymers such as polyacrylates and the like.
According to the invention, alprazolam has been found to be included in the cavity of beta- and gamma-cyclodextrins to form molecular inclusion complexes. Inclusion complexes of alprazolam may therefore be prepared according to methods known in the art such as spray drying, freeze drying and kneading, as described above. The complexes according to the invention may also be incorporated into microspheres by methods appreciated in the art. The complexes according to the invention are stable and highly water soluble.
Penetration enhancers may be used to promote the passage of alprazolam across the mucosal membranes. Typical permeation enhancers include fatty acids and their salts such as sodium caprate, sodium caprylate and sodium cleate, sodium laurate, and bile salts such as sodium glycodeoxycholate, sodium glycocholate, sodium cholate and sodium laurodeoxychoiate. Other penetration enhancers may include tensides, ionic surfactants such as sodium lauryl sulphate, or non-ionic surfactants such as polyethylene glycol 660 hydroxystearate or polyoxyethylene lauryl ethers, fusidates such as sodium “ taurodihydrofusidate. Other specific enhancers include azone and chitosan.
Combinations of permeation enhancers such as polyoxyethylene 8 lauryl ether and sodium glycocholate or mixed micelles such as sodium caprate and sodium glycocholate may also be used. The penetration enhancers may also be used in combination with sulfoalkyl derivatives. Typical concentrations of permeation enhancers are between 0,1 % to 5 %, more preferably between 0,25 % to 3 % by weight of the composition.
Liquid compositions suitable for nasal or oral administration may contain a suitable -quantity of viscosity modifying agents such as hypromellose or carbopol 934P and preservative agents such as benzalkonium chloride, chlorhexidine gluconate or thiomersal.
Oral compositions may contain suitable flavouring and sweetening agents such as cherry, mint, spearmint, vanilla, aspartame, sucrose, xylitol, saccharin and the like.
Typical sublingual or buccal tablets may include lubricants such as magnesium stearate, calcium stearate and sodium stearyl fumarate to facilitate tablet compression, diluents such as lactose, microcrystalline cellulose, maize starch and the like and mucoadhesive agents such as chitosan, carbopol 934P, and hydroxypropylcellulose and the like.
Typical disintegrants to enhance sublingual tablet disintegration may include sodium carboxymethylcellulose, sodium starch glycolate, polyplasdone XL, and dried starch.
Typical suppositories may be formulated according to methods known in the art described in the Pharmaceutical Codex 12" Edition, the Pharmaceutical
Press, pp 170 - 176 or Remington's Pharmaceutical Sciences 18" Edition,
Mack Publishing Company, pp 1609 - 1614.
The following examples illustrate the present invention.
EXAMPLE 1
An excess of alprazolam is added to aqueous solutions of varying concentrations of beta-cyclodextrin. The mixtures are shaken for 24 hours and filtered. The filtrate is analysed by Ultraviolet spectrophotometry for alprazolam concentration. The concentration of alprazolam is plotted as a function of beta- cyclodextrin concentration in Figure 1.
EXAMPLE 2
An excess of alprazolam is added to aqueous solutions of varying concentrations of methyi-beta-cyclodextrin and 2-hydroxypropyl-beta- cyclodextrin. The mixtures are shaken for 24 hours and filtered. The filtrate is analysed by Ultraviolet spectrophotometry for alprazolam concentration. The concentration of alprazolam is plotted as a function of cyclodextrin concentration in Figure 2.
EXAMPLE 3
Alprazolam (6,53 g) and 2-hydroxypropyl-beta-cyclodextrin (200,4 g) are mixed. Purified deionised water (70 ml) is added with vigorous kneading to form a uniform paste with optional heating. Kneading is continued for 5 hours and the paste is dried in vacuo at 80°C. The dried complex is crushed and passed through a 250 micron sieve.
EXAMPLE 4
Alprazolam (6,0g) and methyl-beta-cyclodextrin (198 g) are mixed. Purified deionised water (70 ml) is added with vigorous kneading to form a uniform paste with optional heating. Kneading is continued for 5 hours and the paste is dried in vacuo at 80°C. The dried complex is crushed and passed through a oo 250 micron sieve.
EXAMPLE 5
Dissolution behaviour of the inclusion complexes prepared in Examples 3 and 4 and their corresponding physical mixtures were evaluated in phosphate buffer pH 6,8 using USP Apparatus | (basket, 100rpm, 500ml, 37°C).
Compressed disks (200mg) containing an amount of inclusion complex or physical mixture equivalent to 1 mg alprazolam were prepared using a single punch and die. The dissolution rate of alprazolam from the systems is shown in
Figures 3 and 4.
The complexes of Examples 3 and 5 result in a significantly faster dissolution rate within the first 20 minutes compared with the physical mixture.
EXAMPLE 6
The unit composition of a sublingual tablet containing the equivalent of 1,0 mg alprazolam is as follows:
Alprazolam / 2-hydroxypropyl-beta-cyclodextrin complex (from Example 3) 32,7 mg
Lactose NF 19 mg
Sodium stearyl fumarate 0.6 mg
The complex is blended with lactose and the lubricant. The mixture is formed into sublingual tablets by compression at 10 — 30 N.
EXAMPLE 7
The powdered inclusion complexes prepared according to Examples 3 and 4 were stored in an oven at 60°C. Chromatographic analysis showed the
SE complexes to be chemically stable after one months storage at 60°C.
; EXAMPLE 8
Methylated beta-cyclodextrin D.S.1.8 (200 g) is dissolved in 90 ml purified ’ deionised water. Alprazolam (2.5 g) is added to the solution with stirring until a clear solution is obtained. Benzalkonium chloride (0.01%) is added as a preservative. The volume is adjusted to 1000 mi by addition of purified . deionised water. The tonicity of the final solution is adjusted by addition of sodium chloride. The solution is filtered through a 0.45 um filter. Each 0.1 milliliter of solution contains 0.25 mg alprazolam. The solution is well tolerated after intranasal administration by drops or spray.
EXAMPLE 9
The solution obtained from Example 8 is packaged in a suitable metered dose aerosol dispenser adapted for intranasal application. The concentration of the solution provides convenient dispensing of 0.25 mg alprazolam per 0.1 mi.
Claims (4)
- ) CLAIMS1 A pharmaceutical composition for transmucosal delivery comprising an inclusion complex of (a) alprazolam and (b) a water soluble unsubstituted or substituted beta-or gamma-cyciodextrin, and a pharmaceutically acceptable carrier therefor.
- 2 A pharmaceutical composition according to claim 1 wherein the cyclodextrin is a water soluble unsubstituted or substituted beta- cyclodextrin.
- 3 A pharmaceutical composition according to claim 2 wherein the water soluble beta-cyclodextrin is selected from the group consisting of an alkylated beta-cyclodextrin, a hydroxyalkylated beta-cyclodextrin, and a sulfoakylated beta-cyclodextrin.
- 4 A pharmaceutical composition according to claim 1 wherein the cyclodextrin is selected from the group consisting of 2-hydroxypropyl- beta-cyclodextrin with a degree of substitution between 3,9 and 5,1 hydroxypropyl groups per cyclodextrin molecule, a randomly methylated beta-cyclodextrin with a degree of substitution between 1,8 and 2 methyl groups per glucose unit, and sulfobutyl ether-beta-cyclodextrin with a degree of substitution between 1 and 7 sulfobutyl ether groups per cyclodextrin molecule.A pharmaceutical composition according to any one of claims 1 to 4 wherein the inclusion complex has a stoichiometry of (a) to (b) of from: 1:1 mol/mol to 1:10 mol/mol inclusive.h 6 A pharmaceutical composition according to claim 5 wherein the inclusion complex has a stoichiometry of (a) to (b) of from 1:1 mol/mol to 1:7 mol/mol inclusive.7 A pharmaceutical composition according to any one of claims 1 to 6 wherein the pharmaceutical composition comprises a solution of the inclusion complex of alprazolam and the cyclodextrin in a pharmaceutically acceptable liquid carrier.8 A pharmaceutical composition according to claim 7 formulated for administration as drops, a spray or an aerosol.9 A pharmaceutical composition according to any one of claims 1 to 6 wherein the inclusion complex of alprazolam and the beta-cyclodextrin is a solid mixed with or incorporated into a pharmaceutically acceptable solid carrier.A pharmaceutical composition according to claim 9 formulated as sublingual tablets, buccal tablets, buccal patches, nasal inhalation powders, suppositories, and powder aerosols.11 An inclusion complex of alprazolam and a water soluble unsutstituted or substituted beta- or gamma-cyclodextrin.12 An inclusion complex according to claim 11 wherein the cyclodextrin is a water soluble unsubstituted or substituted beta-cyclodextrin., 13 An inclusion complex according to claim 12 wherein the water soluble beta-cyclodextrin is selected from the group consisting of an alkylated n beta-cyclodextrin, a hydroxyalkylated beta-cyclodextrin, and a sulfoakylated beta-cyclodextrin.14 An inclusion complex according to claim 11 wherein the cyclodextrin is selected from the group consisting of 2-hydroxypropyl-beta-cyclodextrin with a degree of substitution between 3,9 and 5,1 hydroxypropyl groups per cyclodextrin molecule, a randomly methylated beta-cyclodextrin with a degree of substitution between 1,8 and 2 methyl groups per glucose. unit, and sulfobutyl ether-beta-cyclodextrin with a degree of substitution between 1 and 7 sulfobutyl ether groups per cyclodextrin molecule. An inclusion complex according to any one of claims 11 to 14 wherein the inclusion complex has a stoichiometry of (a) to (b) of from 1:1 mol/mol to 1:10 mol/mol inclusive. 16 An inclusion complex according to claim 15 wherein the inclusion complex has a stoichiometry of (a) to (b) of from 1:1 mol/mol to 1.7 mol/mol inclusive. 17 The use of an inclusion complex of alprazolam and a water soluble unsubstituted or substituted beta- or gamma-cyclodextrin in the manufacture of a medicament for use in the treatment of generalised anxiety disorder or for the management of panic disorders. 18 A method of treating a patient suffering from generalised anxiety disorder or of management of a patient suffering from a panic disorder comprising transmucosal administration of an inclusion complex of alprazolam and a water soluble unsubstituted or substituted beta- or gamma-cyclodextrin.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ZA200207221A ZA200207221B (en) | 2000-03-28 | 2002-09-09 | Alprazolam inclusion complexes and pharmaceutical compositions thereof. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ZA200001567 | 2000-03-28 | ||
ZA200207221A ZA200207221B (en) | 2000-03-28 | 2002-09-09 | Alprazolam inclusion complexes and pharmaceutical compositions thereof. |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200207221B true ZA200207221B (en) | 2003-09-09 |
Family
ID=32853680
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200207221A ZA200207221B (en) | 2000-03-28 | 2002-09-09 | Alprazolam inclusion complexes and pharmaceutical compositions thereof. |
Country Status (1)
Country | Link |
---|---|
ZA (1) | ZA200207221B (en) |
-
2002
- 2002-09-09 ZA ZA200207221A patent/ZA200207221B/en unknown
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2401424C (en) | Alprazolam inclusion complexes and pharmaceutical compositions thereof | |
AU712546B2 (en) | Inclusion complex containing indole selective serotonin agonist | |
Jansook et al. | Cyclodextrins: structure, physicochemical properties and pharmaceutical applications | |
US7683040B2 (en) | Intranasal formulation of rotigotine | |
AU565966B2 (en) | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation | |
US6407079B1 (en) | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation | |
EP0814844B1 (en) | Thyroxine/cyclodextrin complexes and pharmaceutical compositions containing the same | |
EP0579435B1 (en) | Cyclodextrin complexation | |
US10363316B2 (en) | Pharmaceutical formulation comprising NSAID and cyclodextrin | |
US20050153931A1 (en) | Novel natural cyclodextrin complexes | |
US20050090468A1 (en) | Novel methylated cyclodextrin complexes | |
WO2011064474A1 (en) | Pharmaceutical composition containing strontium salt, vitamin d, and cyclodextrin | |
US20160206641A1 (en) | Rapidly-dissolving thin film formulation of water soluble digitalis glycoside for the treatment of congestive heart disease | |
WO1998018827A1 (en) | Inclusion complexes of beta-2-andrenergics for oral mucosal delivery | |
US5231089A (en) | Method of improving oral bioavailability of carbamazepine | |
JP2000507258A (en) | Diclofenac / gamma-cyclodextrin inclusion compound | |
ZA200207221B (en) | Alprazolam inclusion complexes and pharmaceutical compositions thereof. | |
JPH07165616A (en) | Complex composition of cyclodextrin and method for making complex | |
WO2004084883A1 (en) | Complexes of isotretinoin with natural beta or gamma-cyclodextrin | |
WO2004082589A2 (en) | Nasally administrable, bioavailable pharmaceutical composition of loratadine | |
Magnúsdóttir et al. | The conventional model of drug/cyclodextrin complex formation (salicylic acid/β-cyclodextrin inclusion complex). | |
JP2005527615A (en) | A novel formulation for parenteral application of sodium channel blockers |