🔙 Quay lại trang tải sách pdf ebook Kỹ thuật bào chế và sinh dược học các dạng thuốc - tập 2 Ebooks Nhóm Zalo TRUONG DAI HOC Dl/OC HA NOI ■ ■ ■ • BO MON BAO CHE ■ KY THU A■t BAO CHE VA SINH DLTCJC HOC CAC DANG THUOC TAP II NHA XUAT BAN V HOCm TRlfCfNG DAI HOC DlfOC HA NOI ■ ■ ■ ■ BO MON BAO CHE ■ KY THUAT BAO CHE VA ■ SINH Dime HOC CAC DANG THUOC TAP II (Tai ban Ian thii nhat) NHA XUAT BAN Y HOC HA NOI - 2004 ■ CHU BIEN: VO XUAN MINH n g u y S n VAN LONG THAM GIA BIEN SOAN: • PHAM NGOC BUNG PHAM THI MINH HUE NGUYEN VAN LONG VO XUAN MINH VU VAN THAO LCfl NOI DAU Bao che hoc la mot trong nhflng mon hoc nghiep vu cot loi trong chUdng trinh dao tao dUdc si cua TrUdng dai hoc dUdc Ha Noi. De lam tai lieu hoc tap va tham khao cho sinh vien, trUdc day, Bo mon bao che da bien soan bo giao trinh “Ky thuat bao che cac dang thuoc" gom 2 tap. Sach da dUdc Nha xuat ban y hoc phat hanh va in lai lan thii hai. Cung v6i siJ phat trien cua cac nganh khoa hoc ky thuat khac, trong nhQng nam qua, ky thuat bao che da co nhQng budc tien dang ke. Tii thap ky 70 cua the ky 20, sinh dUOc hoc bao che ra doi da danh dau budc chuyen ve chat tCf “bao che quy U6c” sang “bao che hien dai”. Nhieu ky thuat bao che mdi va dang thuo’c m6i da ra ddi, dap iing nhu cau dung thuoc ngay cang cao cua ngiidi benh. 9 / De giup sinh vien cap nhat dUOc kien thtic, chung toi bien soan lai tai lieu "Ky thuat bao che cac dang thuoc" v6i tieu de "Ky thuat bao che va sinh ditac hoc cac dang thuoc", bu6c dau bo sung nhQng hieu biet ve sinh dUOc hoc bao che, ve mot so" ky thuat m6i va dang thuoc mcii. Sach bao gom 13 chUOng, dUOc s&p xep theo he phan tan cua cac dang thuoc. Mot so" kien thiic chuyen sau se dUOc trinh bay trong cac chuyen de sau dai hoc. Ngoai viec dung lam tai lieu hoc tap cho sinh vien, hy vong cuon sach cung se la tai lieu tham khao bo ich cho cac ban dong nghiep. Do trinh do va thdi gian bien soan co han, chic chin quyen sach khong tranh khoi thieu sot. Tap the tac gia mong nhan duck; y kien dong gop, phe binh cua ngUOi doc de rut kinh nghiem cho nhQng lan in sau. Tap the tac gia C hifdng 6. I. DAI CirdNG THUOC PHUN MU 1. Dinh nghla va vai net ve lich suf phat trien Thuoc phun mu la dang thuoc khi sik dung thuoc dUOc phan tan thanh nhQng tieu phan rat nho the ran hoac the long trong khong kin. DUdc chat co the 6 dang bot, dung dich, nhu tiidng dUdc dong trong do bao goi km va dufdc day t6i noi dieu tri nhd ap suat cua cua khi nen, khi hoa long hoac nhci liic cO hoc do ngiicii dung thuoc tao ra. Thuoc phun mu dtfdc chi dinh dung tai cho tren da, niem mac, dung cho cac hoc cua cd the nhu tai, triic trang, am dao hoac dung xong hit qua dUcing ho hap de thuoc vao phoi, vao xoang mui. Do dac diem thuoc tao ra he phan tan cac tieu phan rat min trong khong khi nen thuoc phun mu co ten goi chung la aerosol (co tai lieu dich la thuoc khi dung). Loai hinh dong goi cac chat thuoc de sii dung trong mot he co ap suat cao co tic trU6c nam 1900. Cho den nam 1942 loai thuoc phun mu dau tien dung de diet sau bo dUdc ling dung trong nong nghiep, cong nghe thuoc phun mu mdi dUdc coi la bit dau va ttf nam 1950 dUdc ap dung trong Nganh dUdc. Thuoc phun mu de (tieu tri bong, vet thUdng nhiem khuan hoac cac benh tren da da dUdc nghien ctiu san xuat trong thcii gian nay. Cho den nam 1955 nidi co loai thuoc phun mu chi dinh dung theo dUdng ho hap v6i dUdc chat la epinephrin. Do thuoc phun mu co nhieu ufu diem, thuan ldi cho ca benh nhan va bac si, nhu cau svL dung thuoc phun mu ngay cang cao. Dang thuoc phun mu da phat trien trd thanh mot dang bao che co gia tri chiem vi tn ngang hang vdi cac dang bao che khac nhu vien nen, nang thuoc, dung dich thuoc... Ngoai viec dung de dieu tri, thuoc phun mu con difdc dung trong chan doan nhiing bat thUdng ve cau tao va chiic nang trong dUdng ho hap dUa tren nghien ciiu sU lang dong va di chuyen cua cac tieu phan min co gan cac nguyen to" phong xa. 5 2. Uu nhtfdc diem cua dang thuoc phun mu Thuoc phun mu la dang bao che sU dung rat thuan tien de dang va nhanh chong tao ra mot lieu thuoc khong can dung mot dung cu nao khac, dam bao ve sinh, khong co sU nhiem ban do dung cu. Thuoc dUdc dong trong binh km, khong co sU xam nhap cua do am, khong khi va vi khuan, vi vay thuoc phun mu co do on dinh cao, tranh dUdc sU phan huy do cac tac nhan hoa hoc cung nhu do sU phat trien cua vi khuan nam moc. Khi can thiet thuoc phun mu co van dinh lieu dam bao sU phan lieu chlnh xac. Thuoc dUdc phun ra phu nhe tren ndi chi dinh, han che toi da cac tac dong gay klch ling ndi dung thuoc. Thuoc phun mu co the dUOc dung thay cho dang thuoc tiem doi v6i mot so loai thuoc nhu hormon, thuoc chong virus... bing cach xong hit hoac phun xit vao mui rat thuan ldi cho benh nhan stf dung. Thuoc phun mu co hieu lUc tac dung dieu tri cao, tranh difdc sU phan huy dUdc chat 0 dUdng tieu hoa va 6 vong tuan hoan qua gan vi thuoc khong di qua dUOng nay. Khi dung tai cho dUdc chat dUdc tiep xuc tot tren da hay niem mac, thuoc co the phat huy tac dung toan than khi dUdc sii dung 6 dang xong hit qua mieng, mui... dUdc chat dUdc hap thu qua mao mach phe nang hay mao mach du6i lUdi vao mau. Noi chung thuoc phun mu sU dung lieu liJdng thap, co the han che dUdc tac dung phu va tac dung khong mong muon. Mot so thuoc can phoi hdp de hiep dong tac dung nhUng co tUdng tac vat ly, hoa hoc khi co mat trong cung dang bao che, co the dUdc dung rieng d dang thuoc phun mu xong hit qua mui hoac mieng de thu6c dUdc hap thu qua dUdng ho hap. Khi dUdc chat 6 dang thuoc uong hoac tiem khong co dUdc nhiing dac tmh dUdc dong hoc thich hdp de co tac dung mong muon, dUdc chat co the dUdc dung du6i dang thuoc phun mu cho phep thuoc co tac dung tot. Thuoc phun mu co nhieu Uu diem nhu tren nhUng cung co mot so nhUdc diem sau day: - Ky thuat san xuat thuoc phun mu noi chung tUdng doi phtic tap. Thuoc phun mu doi hoi do bao goi bao gom binh chtia, he van, dau phun... Qua trinh dong nap chat day dong thdi v6i qua trinh dong goi hoan chinh tao binh thuoc kin doi hoi thiet bi phifc tap. - Thuoc phun mu si dung chat day loai din chat fluocarbon la chat pha huy tang ozon cua khi quyen trai dat. Loai chat day la hydrocarbon khong co nhiidc diem nay nhUng lai la cac chat di gay chay no khi tiep xuc v6i nhiet. 6 - Mot so" thuoc phun mu dung tai cho khi dung nham vao difcJng ho hap co the gay nguy hiem chet ngudi, cac thuoc phun mu tuy ft gay tai bien nhUng doi v6i loai xong hit dUcJng mui hoac mieng, thuoc can phai khong dUdc kich ling dudng ho hap cung nhu niem mac mui, phai tan dUdc trong niem mac mui, hap thu van chuyen dUdc qua dUdng ho hap, dUdc chat phai on dinh va ket hdp dUdc vdi chat din d dUdng mui va co pH tvf 5,5 den 7,5. - Thuoc phun mu dung xong hit vao phoi neu khong co sU phoi hdp hit thd theo dung yeu cau, lieu thuoc se khong dUdc hap thu day du. 3. Phan loai thuoc phun mu - Thuoc phun mu co the phan loai theo dUdng dung: Thuoc phun mu dung tai cho tren da, dung cho tai, trilc trang, am dao, thuoc phun mu dung de xong hit qua mieng, mui vao phoi vao xoang mui, dtfdi lUdi... - Thuoc phun mu co the dUdc phan loai theo trang thai tap hdp cua thuoc va chat day trong binh chiia: Thuoc phun mu hai pha (pha long gom dung dich thuoc tan trong chat day long va pha hdi cua chat day), thuoc phun mu ba pha bao gom hon dich hoac nhu tUdng thuoc va chat day d the khi. - Phan loai theo cau true hoa ly cua he thuoc co the co cac loai: Thuoc phun mu dung dich, hon dich, nhu tUdng, b

v * 9 quyen tan trong mot phan the tich ntf6c ) Cac khi nen con co tfu diem la trd ve mat hoa hoc khong phan ting ttfdng tac vcfi chat thuoc trong he. Khi nitrogen va C 02 con co vai tro day loai khong khi trong he binh thuoc phun mu, trong mot so trtfdng hdp cac khi trd nay gop phan lam tang do on dinh cua thuoc. 2. Binh chtia Binh chtia thuoc phun mu dtfdc lam bang cac vat lieu co kha nang chiu ap suat cao( 12,5 -13,5 atm b 55°C ) Binh chtia thtfdng dtfdc lam bing kim loai hoac bang thuy tinh,it khi lam bang cha't deo. Binh co mieng de lap gin van. Kim loai lam binh co the la nhom, thep khong gi hoac thep ma thie'c 2 be mat bang phtfdng phap dien hoa. Be mat thep co the dtfdc phu mang mong vecni hoac cha't deo. Th£p khong gi co do chiu ap suat cao nhtfng gia thanh dat,thtfdng dung cho loai thuoc phun mu dung de xong hit co dung tich nho khong can phai bit kin be mat. Binh nhom co do day tti 0,25 den 0,4 mm. Cac binh thep thtfdng dtfdc lam day va vai binh rieng sau do han gdn vdi than binh. Binh nhom co the san xua't bang cach due lien khoi nen co tfu diem chiu dtfdc ap suat do khong co moi han. Noi chung cac binh kim loai chiu ap suat tot nhtfng co the bi an mon khi co mat cua ntfdc, ethanol. Dien hinh ve tac hai nay la 14 tracing hdp khi co mat chat day 21 va ethanol, binh nhom se tao ra khi hydrogen, acetyl clorid, nhom clorid va mot so" san pham phan huy khac. Binh chula bang thuy tinh trd ve hoa hoc, khong bi an mon hoa hoc hoac dien hoa nhu binh kim loai nhUng de vd va phai lam day nang hdn. Binh thuy tinh luon dufdc trang boc mot ldp chat deo de bao ve tranh vd, khi vd khong vang bin manh thuy tinh gay nguy hiem. 3. Van Cac van lam nhiem vu bit kin binh chtia va phan phoi thuoc phun ra khoi binh tcti ndi dieu tri nhcJ ap suat cao trong binh. Van dung cho thuoc phun mu doi hoi phai co yeu cau chat lUdng cao. Kim loai va chat deo lam van phai dap ting cac yeu cau dildc dung quy dinh, khong gay tifdng ky v6i che pham thuoc. Van difdc lUa chon tuy thuoc vao cac yeu to": Khi day, che" pham thuoc va cach sii dung. Co nhieu kieu van, dUa tren dac diem tinh nang phun day thuoc cua van co the phan biet 2 loai: Van phun lien tuc va van dinh lieu. 3.1. Van phun lien tuc: Van phun lien tuc la loai khi bam nut me? van thuoc dildc phun ra lien tuc, chi ngifng khi bo tay, nut bam trcJ ve vi tri ban dau dong van lai. Cau tao cua van ditdc mo ta tren hinh 6.1. m B A- Nap van. 9 u B- Cuohg van C- Vong dem D- Than van E- Dai chan A/ F- Ong nhung Hinh 6.1: Cac bo phan cua van phun lien tuc dung cho thuoc phun mil. 15 Van bao gom cac bo phan sau day: - Nap van (hoac vanh chin): Nip van gin vao mieng binh, thtfdng lam bang nhom hoac sit ma thiec. Do mat dtf6i cua nip tiep xuc vdi thuoc va khong khi nen can dtfdc phu mang chat deo epoxy hoac vinyl de tang kha nang chong an mon han gi. Cac nap van dung cho binh thuy tinh hoac ong nhom nho thtfdng dtfdc lam ttf kim loai mem nhtf nhom hoac dong thau. Nap van dtfdc lap vao binh bang cach xoay vao kh6p mep loi d co binh hoac tan dap khoa vao mep co binh. - Cuong van: Lam bang chat deo nylon hoac kim loai mem nhtf dong hoac thep khong gi. Cuong van co mot hoac nhieu lo (1 lo kfch thtfdc 0,33 - 0,73 mm loai 3 lo thtfdng co kfch thtfdc 1mm). - Vong dem: Lam bing cao su Buna N hoac isopren, hai loai vat lieu nay dtfdc dung lam vong dem cho cac thuoc phun mu. - Than van (hay ong van) dtfdc lam bang chat deo nylon co lo he* tai diem tiep xuc v6i ong nhung (kfch thtf6c lo 0,3 - 2,03 mm). Than van co the co hoac khong co ong bat hdi, cau tao bat hdi nay lam cho hdi chat day dtfdc phun xit ra cung vdi chat long thuoc, lam cho cac tieu phan phan tan min hdn tranh cho van khong bi tic do cac tieu phan ran khong tan trong he thuoc, cho phep thuoc dtfdc phun ra khi binh d ttf the quay dau xuong dtfdi. Co them cau tao bat hdi cua van, thuoc phun mu han che dtfdc tac dong lam lanh da cua hdi chat day cung nhtf kha nang bat liia chay cua khf day. - Lb xo lam bang thep khong gi gitf cho vong chan dtfdc co' dinh va ep chat, khi nut bam an vao nha ra van van dtfdc dong chat khft kfn, thuoc chi co the di qua lo hci khe phun khi van mci. V A/ - Ong nhung lam bang polyethylen, polypropylen. Ong polypropylen thtfdng ctfng hdn. Dtfdng kfnh trong cua ong nhung thtfdng khoang 3,0 - 3,2 mm. Co loai ong nhung mao quan dtfdng kfnh 1,25 mm. Ong nhung cho che pham co do nhdt cao dtfdng kfnh trong co the tdi 4,95 mm. Do nhdt cua thuoc va toe do tao ra lieu thuoc co y nghla quan trong khi ltfa chon dtfdng kfnh trong cua ong nhung dam bao do chfnh xac phan lieu va do min cua tieu phan phun ra. 3.2. Van dinh lieu Van dinh lieu la loai van khi bam nut md van, thuoc chi dtfdc phun day ra mot lieu ltfdng xac dinh. Cd sd cua viec tao ra mot lieu thuoc chfnh xac la nhd nguyen tic van co mot khoang trong, kfch thtfdc cua khoang trong nay quyet dinh ltfdng thuoc day ra. Cau tao cua van dtfdc mo ta tren hinh 6.2: 16 Hinh 6.2a. Sd do van dinh lieu sit 9 * dung thang ditng A- Cuong van B- Nip de vong dem dau ra C- Vong dem nap van D- Khoang dinh lieu E- Nip van Hinh 6.2b. Sd do van dinh lieu sit dung quay xuong F- Vong dem dau vao khoang G- Lo xo H- Than van I- Ong nhung Van dinh lieu dtfdc dung cho cac thuoc co hieu ltfc manh, thuoc dung de xong hit can dam bao lieu ltfdng chfnh xac. Cac van thtfdng cho lieu thuoc mot lan khoang 50 - 150 mg ± 10% doi v6i thuoc long. Mot lo thuoc phun mu nho bo tui dung tfch 20ml co the chtfa 100 - 200 lieu thuoc. Van dinh lieu co 2 loai cd ban: Loai van stf dung b the thang dtfng va loai quay dau ngtfdc xuong, loai van dung dtfng thang v6i ong nhung nho thtfdng dung cho thuoc he dung dich. Loai van quay ngtfdc thtfdng khong co ong nhung dung cho he thuoc phun mu chtfa hon dich, nhu ttfdng. Cau tao cua van dinh lieu dtfdc mo ta tren hinh 6.2. Ve cd ban co cac chi tiet nhtf van phun lien tuc nhtfng do co phan khoang dinh lieu nen cuong van dtfdc cau tao 2 doan, can them 2 vong dem bit kfn dau ra va dau vao cua thuoc cho khoang dinh lieu. 6 ttf the nut bam hoat dong, vong dem dau ra tren cuong van cho phep thuoc da chtfa san trong khoang phan tan ra khoi binh qua cuong van va mieng phun, sau do khi khong bam nut vong 17 dem dau vao khoang dUdc ndi ra de bo sung thuoc vao khoang. Nhtf vay khoang dinh lieu luon luon dtfdc nap day thuoc va sin sang cung cap ra mot lieu ltfdng thuoc xac dinh khi bam nut md van lan tiep theo. Cac van nay se gitf dtfdc che do lam viec dinh lieu khi thdi gian gitfa 2 lan bam nut md van khong qua ngan. Tuy nhien thuoc nap trd lai vao khoang co the cham khi binh chtfa (doi vdi loai thuoc co van can sii dung quay dau xuong) de d ttf the dtfng. Mtfc do cham nap thuoc vao khoang dinh lieu xay ra khac nhau tuy cau tao cua van va khoang thdi gian gitfa cac lan bam nut md van. Khi sii dung thuoc binh thtfdng dieu nay khong xay ra. Van dinh lieu can dtfdc ltfa chon sao cho khong co ttfdng tac vdi cac thanh phan trong cong thtfc thuoc, de tranh stf bien dang lam mat do chfnh xac phan lieu hoac phan huy hoat chat. Cung co trtfdng hdp hoat chat bi hap thu vao trong chat deo lam vat lieu van, dan tdi viec giam ham ltfdng hoat chat trong mot lieu thuoc. Cach tien hanh ltfa chpn danh gia se dtfdc neu trong phan kiem tra chat ltfdng. 4. Dau phun Nut bam dong thdi la dau phun, mieng phun lam nhiem vu thuan ldi va nhanh chong giai phong thuoc ra khoi binh chtfa, phun vao ndi can dieu tri. Dau phun dtfdc gin lien vdi he van de khi bam, van se mci ra va cung nhanh chong dong lai khi thoi khong bam nut nhd 16 xo trong van. Kfch thtfdc lo md cung nhtf hinh dang dau phun, mieng phun, ban chat vat ly cua chat day, cach thiet ke cau tao nip phun se quyet dinh dac diem thuoc phun mu tao bot xop hay phun mu phan tan cac tieu phan hdi, long hoac ran... Co mot so loai dau phun cd ban nhtf sau: 4.1. Dau phun mu: Dau phun mu dtfdc stf dung rong rai, co kha nang tao ra cac tieu phan ttfdng doi nho bing cach cho hdi day qua cac lo hd. Dau phun co the co ttf 1 den 3 lo md co dtfdng kfnh ttf 0,4 den 1 mm. Thuoc phun mu dung nut bam loai nay thtfdng chtfa chat day co diem soi thap vdi ty le thanh phan cao nhtf chat day 12 hoac propan. Viec ket hdp stf hoa hdi cua chat day vdi kfch thtfdc lo thoat va cac khe din trung gian co the phun mu vdi cac tieu phan cd kfch thtfdc nhd trong khoang mong muon. Cac khe khuc khuyu khac nhau trong nut bam cd the tao ra stf "dap vd cd hoc" lam cho luong hdi va dap cuon xoay, cac hat phan tan nhd hdn, mat khac han che dtfdc stf thoat hdi cua chat day. Loai dau phun mu va cau tao khe dan dtfdc mo ta tren hinh 6.3. 18 4.2. Dau phun tao bot xop: Dau phun loai nay co lo thoat ttfdng doi rong, ttf 1,78 den 3,81mm va co the rong hdn. Cac lo thoat cho thuoc di vao mot khoang kha rong sau do tiep tuc dtfdc day ra ngoai qua mot mieng phun. 4.3. Dau phun tao cac thuoc the mem: Loai dau phun nay phan tan thuoc ra co the chat mem nhtf thuoc md, bot nhao, cau tao ttfdng ttf loai dau phun tao bot xop. 4.4. Cac dau phun dac biet: Nhieu thuoc phun mu co muc dich s\i dung rieng doi hoi cac dau phun co thiet ke hinh dang cau tao dac biet sao cho thuoc dtfdc dtfa den ndi dieu tri can thiet nhtf b mieng, b yet hau, b mui, mdt, am dao... Cac loai dau phun dtfdc mo ta tren hinh 6.4. Hinh 6.3. A Dau phun thuoc mil loai de xong hit A B - Khe dan tao siC va dap phan chia cd hoc Hinh 6.4. Cac loai dau phun A Dung de xong hit; B. Cho yet hau; C. Cho mui; D. Tao bot xop E. Cho tai; F. Cho khoa rang 19 5. Minh hoa cau tao mot so loai binh thuoc phun mu • • • • Hinh 6.5: Minh hoa thuoc phun mu he 2 pha (dung khi nen) vd 3 pha (dung khi hod long) Hinh 6.6: Minh hoa thuoc phun mu co nap phun dung theo dieting mieng d tit the van quay xuong. 20 Binh chifa Tui chat deo di/ng he thuoc Khi day Hinh 6.7. Thuoc phun mu pitttong tit Thuoc phun mu co tui chat deo do ngan rieng thuoc vd chat day dying thuoc tach rieng khoi chat day Hinh 6.8. Thuoc phun mu co cau tao tach rieng chat day khoi thuoc d tit the van md 21 III. THIET KE CONG THlfC THUOC PHUN MU Thiet ke cong thtfc thuoc phun mu gom 2 noi dung cd ban la xay doing cong thole thuoc va ltfa chon chat day, binh chtfa, van, noit bam. 1. Xay dtfng cong thtfc thuoc Cong thtfc thuoc gom co dtfdc chat hoac hdn hdp cac dtfdc chat va cac chat phu, ta dtfdc, dung moi can thiet nhtf cac chat dien hoat, cac chat on dinh chong oxy hoa... Trtfdc het can ltfa chon he thuoc thuoc cau true he phan tan loai nao: Dung dich, hon dich, hay nhu ttfdng. Viec ltfa chon kieu he phan tan cua thuoc phoi thuoc vao tfnh chat dtfdc ly hoa hpc, vat ly cua dtfdc chat cung nhtf dtfdng dung thuoc, ndi can dieu tri. Sau do la nhtfng van de lien quan den cac dang bao che thong thtfdng can quan tam nhtf do tan, kich thtfdc tieu phan, gia tri HLB (gia tri can bang than dau, than ntfdc)... Trong thtfc te viec xay doing cong thtfc thuoc lien quan chat che vdi viec ltfa chon chat day vi trong hau het cac thuoc phun mu chat day tham gia vao thanh phan cau true he thuoc. Noi dung xay doing cong thtfc dtfdc xem xet coi the cho ttfng kieu he phan tan thuoc nhtf sau: 1.1. Cong thiic thuoc phun mu la dung dich: Dung moi dtfdc ltfa chpn de hoa tan dtfdc chat, ngoai ra con co vai trd lam cham sol hoa hdi coia chat day de ap suat trong binh khong bi giam nhanh trong qua trinh soi doing, dam bao dieu kien phan tan min cac tieu phan khi phun thuoc va do chmh xac phan lieu. Dung moi can phai co kha nang hoa tan chat day. Cac chat day la chat khong phan colc nen rat it co dung moi thich hdp. Ethanol hay dtfdc sit dung lam dung moi cho thuoc phun mu , ngoai ra con dung PEG, propyl glycol, ethyl acetat, hexylen glycol, aceton, glycol ether. Cac chat nay co do doc cao hdn ethanol, can ltfu y xem xet dac biet khi thif dung cho mieng va mui, dung de xong hit... He dung dich thuoc dtfdc ap doing cho thuoc phun mu cac che pham gay me tai cho, tao mang bao ve da, chong viem, thuoc phun mu dung cho mieng, mui. Thuoc phun mu tai cho thtfdng co ty le chat day va thuoc ttf 10:90 den 50:50. Doi vdi thuoc phun mu dung de xong hit cho mieng, mui chat day can nhieu hdn co the ttf 90 - 95% (cd khi tdi 99,5%). Ndi chung ti le chat day cang cao, thuoc phun mu cang tao hat min nhd. Khi md van hdn hdp thuoc, dung moi va chat day dtfdc phun vao khong khf. Cac chat day la khi hoa long se thu nhiet va bay hdi lam cho cac tieu phan thuoc bi vd thanh cac hat nhd hdn va treo Id loing trong khong khi. Cac tieu phan nay nhd ttf 5 - 10 mcm hoac nhd hdn 5 mcm doi vdi cac thuoc phun mu xong hit, va cd loch thtfdc ttf 30 - 50 mcm doi vdi thuoc phun mu tai chd. Cong thtfc thif nghiem cd ban ciia thuoc phun mu he dung dich dung cho mui, mieng va tai chd dtfdc ghi trong bang 6.8, bang 6.9. 22 Bang 6.8: Cdng thitc cho thuoc phun mil xong hit, cho mieng vd mui he dung dich Ten thanh phan Cac chat co the dung trong cong thtfc Hoat chat Tan difdc trong he Dung moi Ethanol Cac glycol Nu6c Chat tang do tan (chat dien hoat) Chat chong oxy hoa Acid ascorbic Chat lam thdm Tinh dau thdm Chat day (hoac hon hdp Chat day 12 chat day) 12/11 12/114 12/11/114 152/142 Bang 6.9: Cong thitc cho thuoc phun mil dung tai cho he dung dich Ten thanh phan Cac chat co the dung trong cong thtic Hoat chat Dung moi Chat chong oxy hoa Chat bao quan Chat day va hon hdp chat day Tan difdc trong he Ethanol va isopropanol Cac glycol Isopropyl ester Cac chat dien hoat Acid ascorbic Methyl va propyl paraben Isobutan Propan/butan Propan/isobutan Chat day 12 Dimethyl ether Chat day 152/142 22/142. 23 Khi thiet ke cong thtfc thuoc phun mu he dung dich can chu y mot so van de sau: - Anh htfcing cua h6n hdp dung moi, chat day den do hoa tan va do on dinh cua dtfdc chat. - Kfch thtfdc tieu phan thuoc phun mu va stfc cang be mat chat long. - Kha nang gay kfch ting cua cac chat phu (chat chong oxy hoa, chat bao quan...) khi dung tai cho va dung cho mieng, mui. - Vdi thuoc phun mu dung cho mieng va mui, chat phu tang do tan can phai de dang dtfdc chuyen hoa khong bi ltfu gitf d mang nhay cua dtfdng ho hap. Ti le thanh phan co the svL dung nhtf cong thtfc sau day khi co hydrocarbon hoat chat ttf 10 - 15 %, dung moi nhtf ethanol hoac propylen glycol ttf 10 -15%, ntfdc cat 10 - 15%, chat day hydrocarbon. Vf du ve cong thtfc thuoc phun mu chi dinh hoat chat chtfa hen dung cho dtfdng ho hap nhu sau: Isoproterenol HC1 0,25 (% trpng ltfdng) Acid ascorbic 0,10 (% trong ltfdng) Ethanol 35,75 (% trong ltfdng) Chat day 12 63,90 (% trpng ltfdng) 1.2. Cong thiic thuoc phun mu he hon dich: Thuoc phun mu he hon dich chtfa cac dtfdc chat khong tan trong chat day hoac trong hon hdp dung moi chat day. Cac dtfdc chat dtfdc phan tan Id lting trong chat day va dung moi. Khi thuoc dtfdc phun ra khoi binh, chat day bay hdi nhanh dtfdc chat dtfdc tach thanh cac tieu phan min nho. He hon dich thtfdng ap dung cho cac che pham chong hen chtfa cac steroid, khang sinh ... He hon dich gay ra kho khan nhtf de tkc van do cac tieu phan tap hdp lai bit lo van (co the dung loai van co cau tao nip bat hdi nhtf da neu d phan van). Mot so yeu to quan trong doi vdi thuoc phun mu he h6n dich can dtfdc xem xet nhtf sau: - Ham dm cua cac thanh phan thuoc: Ham am co the anh htfdng den do phan tan cua cac tieu phan. Dtfdc chat, dung moi, chat day can dtfdc lam khan hoac say kho bang cac phtfdng phap thfch hdp trtf6c khi pha che. Chat day co the dtfdc lam khan bang cach cho di qua chat hut am. - Kich thitdc tieu phan: Kfch thtfdc ban dau cua cac tieu phan can nho cd micromet, noi chung ttf 1 - 5 mcm, khong nen ldn hdn 10 mcm. Bot can dtfdc nghien vdi may nghien bi hoac may nghien sieu min. Doi vdi thuoc phun mu tai cho kfch thtfdc tieu phan chat ran can qua ray 40 - 50 mcm. 24 - Do tan cua dtfdc chat: Dtfdc chat co cac dan chat khac nhau hoac co nhieu loai hinh ket tinh khac nhau, can ltfa chpn loai co do hoa tan thap de tao hon dich nhtfng cung can co kha nang hoa tan trong dich cd the d mot toe do can thiet de co tac dung dieu tri cung nhtf tranh gay kfch ting ndi dung thuoc. - Ti trong cua dtfdc chat vd chat day: Can ltfu y ltfa chon dieu chinh ti trong cua chat day va chat ran khong tan de dam bao do dong nhat, toe do sa lang thap nhat. Co the chon hon hdp cac chat day v6i ti le thfch hdp cung nhtf cho them bot trd de tao hon hdp rkn v6i dtfdc chat. Can ltfu y dam bao yeu cau ve ti trong can phai can doi v6i viec dam bao ap suat hdi cua hon hdp chat day. - Cac chat dien hoat vd gay phan tan: Cac chat dien hoat, gay phan tan can dam bao khong doc va khong kfch ting dtfdng ho hap. Isopropyl miristat (khong phai la chat dien hoat) dtfdc dung vdi dac tfnh lam trdn trong thuoc phun mu, cac dau khoang cung dtfdc stf dung v6i muc dfch nay. - Cac chat dien hoat dung rieng cho thuoc phun mu xong hit, cho mieng, mui, yet hau... gom co cac polisorbat va sorbitan ester dac biet la sorbitan trioleat, mot so khac gom co cac dan chat lecithin, oleyl alcol va ethanol. Cong thtfc thti nghiem cho cac thuoc phun mu he hon dich dtfdc neu trong cac bang sau (bang 6.10, 6.11, 6.12). Bang 6.10: Cong thtic cho thuoc phun mil he hon dich de xong hit Ten thanh phan Cac chat co the dung trong cong thtfc Hoat chat Tac nhan gay phan tan hoac dien hoat Chat day Dtfdc nghien sieu min. Sorbitan trioelat, lecithin va dan chat oleyl alcol, ethanol Chat day 12, 12/114, 12/11, 12/114/11. Bang 6.11: Cong thiic cho thuoc phun mil he hon dich dung tai chd Ten thanh phan Chat co the dung trong cong thtic Hoat chat Chat gay phan tan Chat day Qua ray 40 - 50 mcm Isopropyl myristat; dau khoang; cac ester sorbitan; glycol va cac dan chat. 12/11, 12/114, Hydrocarbon 142,152,22 Dimethyl ether. 25 Bang 6.12: Cong thiic cho thuoc phun mu he hon dich hoac dung dich dung cho mui Ten thanh phan Chat co the dung trong cong thtic Hoat chat Chat chong oxy hoa Chat bao quan Chat tao he dem va dang trtfdng Chat day Vi du minh hoa: Dtfdc tang do tan hoac gay th£fm, tao treo Acid ascorbic Cac bisulfit Benzalkonium clorid. He dem phosphat (pH = 6,5) Natri clorid (dang trtfdng) Ntf6c , Cac chat gay tham hoac dien hoat. 12, 12/11, (cho he khong co ntfdc) 12/114 Nitrogen. - Thuoc phun mu epinephrin dung de xong hit: Epinephrin bitartrat (Kfch thu6c hat 1 - 5 mcm) 0,5% trong ltfdng. Sorbitan trioleat 0,5% trong ltfdng. Chat day 114 49,5% trong ltfdng. Chat day 12 49,5% trong ltfdng. Epinephrin bitartrat co do tan toi thieu trong he chat day nhung tan dtfdc trong dich phoi de co tac dung dieu tri. - Thuoc phun mu isoproterenol sulfat: Isoproterenol sulfat 33,3 mg. Oleyl alcol 33,3 mg. Myristyl alcol 33,4 mg. Chat dayl2 7,0 mg. Chat day 114 7,0 mg. Hon dich nay co do ben cao, isoproterenol dtfdc treo ben vting trong he chat dan, chat day cho phep tao ra cac lieu thuoc thfch hdp. Cong thtfc nay da tfnh toan ltfa chon dam bao do treo cua h6n dich tren cac yeu to: Dieu chinh ti trong, sti dung chat gay phan tan, nghien min dtfdc chat(< 5 mcm), do am va sti dung dan chat thfch hdp la muoi sulfat. 26 Thuoc phun mu xong hit chtia steroid chtia hen: Dtfdc chat 8,4 mg. Acid oleic 0,8 mg. Chat day 11 4,7 mg. Chat day 12 12,2 mg. 6 day acid oleic dong vai trd chat gay phan tan lam cho cac tieu phan dtfdc chat de nghien nho va khong bi tap hdp von ket, mat khac no lam trdn van, chong stf tic van. 1.3. Cong thiic thuoc phun mil he nhu tilting: Thuoc phun mti he nhu ttfdng bao gom cac dtfdc chat, cac chat dan thuoc pha dau khong phai ntf6c va ntf6c, cac chat dien hoat va chat day. Tuy theo stf ltfa chon cac thanh phan trong cong thtfc ma thuoc phun mu tao ra la loai bot xop ben vtfng hoac bot xop vd nhanh trd thanh nhu ttfdng thong thtfdng. Chat day chiem ttf 7% den 10% phoi hdp vdi 93% den 90% thuoc nhu ttfdng. Chat day dong vai trd la mot thanh phan n&m trong pha noi hoac pha ngoai cua nhu ttfdng. Neu chat day nam trong pha noi, thuoc phun mu se tao thanh bot xop dien hinh. Neu chat day nam trong pha ngoai cua nhu ttfdng, thuoc dtfdc phan tan ra khoi binh b dang phun mu thong thtfcfng. Thuoc phun tao bot xop co tfu diem hdn dang phun mu la vi trf ndi dung chfnh xac vcfi dien tfch tiep xuc co the kiem tra dtfdc theo y muon. Cac chat dien hoat thtfdng ft tan trong ca pha dau va pha ntfcic co tac dung lam tham tfdt de dang ca 2 pha tao ra stf phan tan dong nhat. Thuoc phun mu tao bot xop thtfcing dung cac xa phong cua acid beo vdi triethanolamin co them cac chat phu lam am, tham tf6t, lam mem, diu da va niem mac. Noi chung chat day khf hoa long thtfdng dtfdc nhu hoa mot phan nao trong thuoc, khi phan tan thuoc ra khoi binh, chat day bay hdi tao nen khung bot xop ttfdng doi ben vting. Trong cac nhom chat dien hoat, loai chat dien hoat khong ion hoa dtfdc sii dung rong rai cho thuoc phun mu de tao bot xop vi chung khong tfch dien, ft gay ra ttfdng ky v6i thuoc. Cac chat dien hoat pho bien dtfdc dung la cac ester beo cua polyoxyethylen (POE), ester POE sorbitan, alkyl phenoxy ethanol, ester cua cac acid beo, va cac alkanolamid. Loai thuoc phun mu tao bot xop co the an dtfdc chtfa cac chat chtia ho, cung cap calci, vitamin, khang acid va mot so che pham ttfdng ttf khac rat thfch hdp v6i tre em, vdi ngtfdi gia kho nuot cac dang thuoc khac. 27 Bang 6.13: Cong thtic cho thuoc phun mu he nhu titctng dung tai cho Ten thanh phan Chat co the dung trong cong thtfc Hoat chat Chat nhu hoa Cac chat phu trd khac Ch§ft day Dtfdc hoa tan trong acid beo, dau thtfc vat trong glycol. Xa phong hoa cua acid beo (triethanolamin stearat), este polyoxy ethylen sorbitan. Sap nhu hoa. Cac chat dien hoat. Chat lam trdn. Chat bao quan. Chat lam thdm. Chat day 12/114 (chi dung khi dtfdc cho ph£p) Hydrocarbon Chat day 22/152, 22/142, 152/142 Dimethyl ether. Vi du minh hoa thanh phan thuoc phun mu he nhu tiictng: * Thuoc phun mu tao bot xop ben co ntfdc: Hoat chat 2,0% trong ltfdng Nen ta dtfdc nhu ttfdng 90 - 95% trong ltfdng Hydrocarbon A - 48 8 - 5% trpng ltfdng Ta dtfdc nhu ttfdng co thanh phan nhtf sau: Acid myristic 1,33% trong ltfdng Acid stearic 5,33% trong ltfdng Alcol cetylic 0,50% trong ltfdng Lanolin 0,20% trpng ltfdng Isopropyl myristat 1,33% trong ltfdng Triethanol amin 3,34% trpng ltfdng Glycerin 4,70% trong ltfdng Polyvinyl pyrolidon 0,34% trong ltfdng Ntfcic tinh khiet 82,93% trong ltfdng 28 - Ta dtfdc thuoc phun mu tao bot xop ben trong ntfcic: Glycol (vf du PEG) 86% trong ltfdng Chat nhu hoa 4% trong ltfdng Chat day 12/114 (40:60) 10% trong ltfdng - Ta dtfdc thuoc phun mu tao bot xop khong ben: Ethanol 46 - 60% trong ltfdng Chat dien hoat 0,5 - 5% trong ltfdng Ntf6c tinh khiet 28 - 42% trong ltfdng Chat day 3 -1 5 % trong ltfdng 2. Ltfa chon chat day, binh chufa, van, dau phun Trtf6c nam 1978 cac dan chat fluorcarbon v6i dac tfnh trd ve hoa hpc, gan nhtf khong doc hai, khong bat liia dtfdc coi la chat day ly ttfcing dung cho hau het cac thuoc phun mu. Do co tac hai pha huy tang ozon khf quyen nen ngay nay fluorcarbon chi dtfdc gidi han dung cho thuoc phun mu co yeu cau chat ltfdng dac biet cao nhtf de xong hit, dung cho mieng, mui, chtfa cac chat khang sinh, chat sat khuan... Cac fluorcarbon dtfdc de nghi thay bang cac hydrocarbon, cac khf nen N2, C02, cac he bdm day cd hoc cung nhu may nen khf tao ap suat cao. Cac hydrocarbon thfch hdp dung cho thuoc phun mu thanh phan co ntfcic. Cac khf nen co mot so' nhtfdc diem nhtf da neu 6 tren, tao he phan tan tieu phan tho dai nen thtfdng dung cho thuoc phun mu tai cho. Mot so' nguyen tac chtpn chat day va hon hdp cua chung nhtf da neu trong cac phan tren de dam bao ti trong, ap suat hdi va han che kha nang chay no. Noi chung tuy ttfng yeu cau cua tfrng che pham ma ltfa chon vat lieu, cau tao, kfch thtfdc lo van... Nut bam nap phun tuy theo dtfdng dung, ndi dung thuoc ma chon cau tao thfch hdp ve kfch cd va hinh dang.Binh chtfa thuy tinh an toan c) ap suat trong binh thuoc nho hdn 2,7atm va ltfdng chat day nho hdn 15%, ci ap suat cao hdn 3,24 atm can dtfdc phu 2 16p chat deo. Binh thep ma thie'c dtfdc dung rong rai cho thuoc phun mu, an toan v6i he thuoc co ethanol. Vat lieu de tao mang phu bao ve binh chtfa thtfdng dung la nhtf a vinyl hoac epoxy. Nhtfa vinyl tao mang ben ve cd hoc nhtfng lai kem chiu stfc nong cua khf nen va nhiet khi tiet khuan. Nhtfa epoxy co tfu diem chiu nhiet tot dtfdc dung khi co anh htfdng cua nhiet. 29 Bang 6.14: Gidi han dp suat doi vdi cac loai binh chtia thuoc phun mu Loai binh chtfa Ap suat toi da (atm) Nhiet do (°C) Thep ma thiec - Loai dap 6 ap suat thap < 10,5 48,9 - Loai ky hieu 2P 10,5 - 11,8 48,9 - Loai ky hieu 2Q 11,8- 13,2 48,9 Thuy tinh khong bao mang <2,2 21,1 Thuy tinh co bao mang <2,7 21,1 Nhom < 10,5 48,9 Chat deo <2,7 21,1 Thep khong gi < 13,2 48,9 Binh nhom an toan khi dtfng he thuoc chtfa dung moi khong phan ctfc. Can chu y khi dtfng thuoc co ethanol va cac dung moi phan ctfc, ethanol khan ntfdc an mon nhom rat manh theo phan tfng: 6A1 + 6C2H5OH (khan ntfdc) 3H2 + 2(C2H50 )3A1 Hydrogen giai phong ra ttf ttf lam tang ap suat trong binh, cung vdi viec hoa tan nhom co the lam ntft vd binh chtfa. Co the ngan can phan tfng xay ra bang cach them nU6c vao thanh phan thuoc chtfa trong binh. Ti le ntfdc 2 - 3% co the tfc che phan tfng tren. Noi chung can kiem tra ky stf an mon binh nhom va cho them cac chat tfc che. IV. KY THUAT SAN XUAT THUOC PHUN MU Ky thuat san xuat thuoc phun mu chu yeu gom hai giai doan: Dieu che thuoc de dong nap vao binh va dong nap chat day vao binh thuoc (dong thdi hoan chinh dong km binh thuoc). Giai doan dieu che thuoc doi hoi ky thuat va dung cu thiet bi nhtf doi vdi viec san xuat cac dang bao che thong thtfdng thuoc he dung dich, hon dich, nhu ttfdng... Giai doan nap chat day co the thtfc hien b&ng phudng phap dong ap suat hoac dong lanh vdi nguyen t&c cd ban nhtf sau: * PhUdng phap dong dp suat: Thong dung nhat trong congnghiep v6i cac thao tac: - Nap thuoc vao binh chtfa chua gan van (chat long, mem hoac bot). - Dat van va vong dem vao bd mieng binh dong km hoan toan. - Nap khi day qua van vao binh du6i ap suat cao (ngtfdc chieu vdi stf van hanh binh thtfdng cua van). 30 - Dau phun dtfdc dat vao sau cung. Khong khf trong binh dtfdc duoi ra trtf6c khi nap b giai doan da dong van nhd khf nen hoac trtfdc khi dat van ngtfdi ta cho vai giot khi hoa long, khi boc hdi se duoi khong khi ra khoi binh. * PhiicJng phap dong lanh: Thao tac d nhiet do thap, khi hoa long dtfdc nap vao binh, sau do dat van dong kin trtfdc khi nhiet do trd.lai binh thtfdng. Tuy theo quy mo san xuat nho b phong thf nghiem hay quy mo ldn trong cong nghiep can sii dung cac thiet bi may moc thfch hdp. 1. Thiet bi va ky thuat bao che d quy mo nho 1.1. Dung cu dong dp suat: C) quy mo nho trong phong thf nghiem la mot bdm buret co the do dtfdc the tfch nho cua khf long nhd ap suat khf nen dong vao binh chtfa. Chat day dtfdc nen vao binh qua lo van dat b dinh hoac day buret. Khong khf trong binh dtfdc day qua van tren. Khi dat tdi can bang ap suat gitfa binh chtfa va binh khf nen chat day ngtfng chay vao binh. Khf nen nitrogen dtfdc dan vao binh day khong khf ra van tren, sau do dung ap suat cao dtfa chat day qua ong xylanh (buret dinh lieu) qua van dtfdi vao binh. Buret bdm dong thuoc phun mu dtfdc mo ta tren hinh 6.9. 1.2. Thiet bi dong lanh: Thiet bi dong lanh co sd do cau tao mo ta tren hinh 6.10. Khi md van khf day dtfdc di qua he lam lanh theo ong dong xoin co dieu kien tiep xuc lau vdi nguon lanh -40°C. Nguon lanh nay la hon hdp tuyet carbonic (CO2) va aceton, du de hoa long hau het cac chat day. j1000mh> \ 300ml/ ( 500ml | Hinh 6.9: Cac loai buret bctm dong. 31 Hinh 6.10: Sd do thiet bi dong lanh de nap chat day vao binh thuoc phun mil. Thiet bi dong cac khf nen: Chat day la cac khf nen de dang co O cac phong thf nghiem. Khf nen C 02, N2 dilng trong binh thep dildc tfnh theo trong ltfdng. Binh khf co ap suat rat cao nen can dung van co kha nang dieu chinh giam ap suat khi din khf ra. Khf nen dtfdc dong vao binh thuoc phun mu den khi dat ap suat can thiet trong binh chtfa. Nh&m tang ltfdng khf chtia trong binh thuoc can thtfdng xuyen lac de hoa tan toi da khf C 02 hoac N2 vao trong he thuoc khi dong nap khf. 2. San xuat thuoc phun mu of quy mo cong nghiep Qui che ve thtfc hanh san xuat tot (GMP) yeu cau ky thuat dong nap thuoc phun mu phai thtfc hien trong dieu kien ve sinh cao, dam bao khong co sol nhiem tap khuan. Sd do cac giai doan san xuat dUdc trinh bay trong hinh 6.11. 32 Day chuyen lam lanh A- Sd do day chuyen san xuat thuoc phun mu theo phtfdng phap dong lanh B- Sd do day chuyen san xuat thuoc phun mu theo phtfdng phap dong ap suat. Hinh 6.11: Sc? do day chuyen san xuat thuoc phun ?nu. Trong cong nghiep phtfdng phap nap chat day b&ng ap suat dtfdc ap dung rong rai vi tfu diem hdn phtfdng phap dong lanh: It nguy cd nhilm am, khong hao phi chat day, toe do san xuat nhanh. 3. Dung cu tao thuoc phun mu d cac khoa phong dieu tri 6 cac khoa phong dieu tri ngtfdi ta con dung cac dung cu thiet bi co kha nang chuyen hoa cac dang thuoc long thanh thuoc phun mu, phan tan thuoc long thanh cac hat min nho cd vai micromet. Loai nay chu yeu dieu tri dtfdng ho hap tao thuoc phun mu dung de xong hit. Dung cu tao phun mu chii yeu gom mot bo phan de phun va mot bo phan lpc de gitf lai nhtfng hat to. Nguon khong khf nen co the la mot may nen khong khf hoac binh khf nen. May nen co ltfu ltfdng khf 201it/phut dtfcii ap suat nen 600 - 800G/cm2. Bo phan phun chtfa chat long thuoc, chat long se dtfdc hut len mao quan co dau tren dat trtf6c luong khf nen. Dong khf manh tao stf giam ap d T3-KTBC. 33 dau ong mao quan, cuon cac chat long va phan tan no thanh nhtfng hat nho min trong khong khi (hinh 6.12). Bo phan loc co the la mot ong co nhieu bi thuy tinh hoac mau loi co tao khe khuc khuyu lam cho cac hat to bi va dap can lai tren dtfdng di, chi co hat nho dtfdc loi cuon ra ngoai ong loc. Bo phan loc co hieu qua hdn la dung mang loc chan ngang, tuy theo 16 loc co cac tieu phan min cd khac nhau. Stf lam lanh do gian ncJ khf nen anh htfcing khong tot den phoi cua benh nhan, cho nen dung cu tao thuoc phun mu thtfdng dtfdc trang bi them bo phan lam nong. May nen khf Hinh 6.12: Sc/ do dung cu tao thuoc phun mil. Hien nay, cac nha san xuat con dtfa ra loai dung cu tao phun mu gon nho thuan tien cho benh nhan dung tai nha V. KIEM TRA CHAT Ll/ONG THUOC PHUN MU De dam bao chat ltfdng thuoc phun mu, cong tac kiem tra chat ltfdng dtfdc thtfc hien b ttfng cong doan san xuat: Kiem nghiem nguyen phu lieu b giai doan dau, kiem nghiem trong qua trinh san xuat va kiem nghiem thanh pham. 1. Kiem nghiem nguyen phu lieu Chat day: Mot so” chuyen luan chat day fluorcarbon va hydrocarbon dtfdc ghi trong USP. Cac chi tieu chat ltfdng can dtfdc kiem nghiem nhtf dinh tmh ((b&ng sic ky khi), dinh ltfdng ti le chat day, ap suat hdi, ti trong, do tinh khiet (bao gom ham am, halogen, cdn khong bay hdi... ). Van, nut bdm, ong nhung: Co qpy cach rieng cho ttfng loai, can kiem tra ve cac dac tfnh vat ly, hoa hoc, kiem tra do ben chiu ap suat cua van. Doi vdi van dinh lieu co chuyen luan rieng. 34 - Cach kiem tra van dinh lieu: Lay mau 25 van bat ky, trong lo, lap vao binh chtia, dong dung dich thii vao cac binh vdi nut bam co lo thoat chuan. Cho van hoat dong 10 ian. Nhiet do thti 25°C ± 1°C. Can chfnh xac hang 9 * * * * i) 1 /? miligam de xac dinh ltfdng dung dich thik day ra qua van. Tfnh ra the tich (ml) bang cach chia cho ti trong cua dung dich thii. Dung dich thii van dtfdc pha che chon cong thtfc co ty trpng phu hdp v6i thuoc se dong vao binh. Co 3 cong thtfc de pha dung dich thtf van v6i ti trong khac nhau: Dung dich A: Isopropyl myristat 0,1% Diclor difluor methan 49,95% Ti trong 25°C = 1,384 Diclo tetrafluor ethan 49,95% Dung dich B: Isopropyl myristat 0,1% Ethanol 49,9% Diclor difluor methan 25,0% Ti trong 25°C = 1,092 Diclo tetrafluor ethan 25,0% Dung dich C: Isopropyl myristat 0,1% Triclo monofluor methan 24,8% Diclor difluor methan 50,3% Ti trong 25°C = 1,388 Diclo tetrafluor ethan 24,7% - Cac chi tieu quy dinh cho van: Van cho lieu ra < 54 mci gi6i han sai so' ± 15% < 55 - 200mcl gi6i han sai so ± 10% Neu trong 50 lan thii co > 4 lan khong dat gicfi han neu tren, cac van bi loai. Neu 3 lan thii khong dat, thi lam lai v6i 25 van khac (lay miu lan thtf 2). Van bi loai neu co > 4 lan thtf khong dat. Sau 2 lan lay mau thii tren cung mot lo van neu khong dat thi lay m^u thtf 3 (25 van). Neu lan nay khong dat thi lo van bi loai. Binh chtia: Co tieu chuan qui cach rieng ve kfch thtfdc va trong ltfdng. Can kiem tra khuyet tat tren thanh binh va cf ndi han noi (than binh v6i vai, day). 2. Kiem tra trong qua trinh san xuat Trong ttfng cong doan san xuat can kiem tra nhtfng noi dung sau: 35 - Trong ltfdng thuoc, trong ltfdng chat day. - Do km cua binh va van, kiem tra bing cach nhung trong ntfcic co khong che nhiet do. - Stf lip dat cua ong nhung, cuong van kiem tra bang cach thii phun lam ro vi tri lap dat cua ttfng bo phan co dung khong. 3. Kiem nghiem thanh pham thuoc phun mu Thuoc phun mu la che pham dac biet dong trong binh co ap suat cao nen co nhieu phep thvf can thiet de dam bao an toan cho qua trinh bao quan va stf dung. Co mot loat chi tieu ve vat ly, hoa hoc, sinh hpc nhtf sau: - Do bit liia va do chay: Diem nhiet do bat ltfa chay va do dai ngon liia. - Cac dac tinh vat ly: Ap suat hdi, ti trong, ham an, dinh tinh chat day, ti le chat day va thuoc. - Cac chi tieu chlnh cua che pham bao che: Do chlnh xac phan lieu, klch thtfcic tieu phan phun ra... Toe do phun cua van, dien tlch phun, do chlnh xac phan lieu (v6i van dinh lieu), trong ltfdng khong ke bi cua thuoc, do ben cua bot xop, klch thtf6c tieu phan thuoc phun ra, do kin cua binh thuoc. - Cac dac tinh sinh hoc: Cac phep thtf sinh hoc, hoat ltfc dieu tri, doc tinh. Diem bit \vLa (hay nhiet do boc chay): Dtfdc xac dinh bing dung cu chuan. Thuoc phun mu dat ci -25°C, sau do dat vao dung cu thii, chat long trong dung cu dtfdc tang ttf ttf nhiet do den khi hdi phun ra boc chay, nhiet do ltfc nay la diem bat liia. Chi tieu nay thtfc chat la diem chay cua hau het cac chat day. Ap suat hdi: Dtfdc do bing dung cu co ap ke. Ti trong: Dtfdc do bing picnomet hoac hydromet. Do am: Xac dinh bing phtfdng phap Karl Fischer hoac bing sic ky theo quy dinh Dtfdc dien. Dinh tinh va dinh ltfdng ti le cac chat day bing sic ky khi. Dien tlch nen phun: Dtfdc kiem tra nhim danh gia, so sanh stf phun thuoc co dong nhat gitfa cac lo nguyen lieu khac nhau hoac dung van d cac lo me khac nhau. Thuoc phun ra tren bang giay quay co tam chat lieu mau de kiem tra so sanh dien tlch va do dam cua khoi ltfdng cac tieu phan phun ra. Do chlnh xac phan lieu: Nguyen tic la mot lieu thuoc dtfdc phun vao dung moi hoac vat lieu co kha nang hoa tan hay hap thu dtfdc chat, sau do dem dinh ltfdng. 36 Khoi ltfdng trung binh cua lieu thuoc: Nguyen the can binh thuoc trtfdc va sau khi phun mot so' lieu, hieu so khoi ltfdng 2 lan can la khoi ltfdng thuoc ttfdng ting vdi 2 lieu thuoc, ttf do tfnh dtfdc khoi ltfdng trung binh cua lieu thuoc. Cach xac dinh nhtf tren chi cho biet ltfdng thuoc moi lan mci van day ra, ltfdng thuoc nay co the khong dtfdc dan hoan toan vao ndi can tac dung. Ngtfdi ta con che tao cac dung cu ho hap nhan tao de xac dinh lieu thuoc dtfdc hap thu doi vdi benh nhan. Trong ltfdng thuoc khong ke bi: Dtfdc xac dinh trong qua trinh dong nang thuoc vdi cac binh chtfa da can bi san. Doi vdi thanh pham co the kiem tra b^ng cach mci binh thuoc, loai bo het thuoc va chat day. Hieu so trong ltfdng can binh luc chtfa md va bao bi binh thuoc sau khi md la trong ltfdng thuoc khong ke bi. Do ben cua bot xop: Xac dinh bang nhdt ke quay, hoac bang cach do thdi gian nhung sau cua vat nang vao khoi bot, hoac thdi gian de que thtf rdi ra khoi khoi bot. O ✓ a 9 Kich thtfdc tieu phan: Co mot so phtfdng phap xac dinh kfch thtfdc tieu phan nhtf dung kfnh hien vi, dung may dem cho cac dang thuoc nhtf thuoc bot, hon dich... Tuy nhien de ap dung phan tich kich thtfdc tieu phan cua thuoc phun mu, cac phtfdng phap nay co the khong xac dinh dung dtfdc trang thai phan tan ban dau cua cac tieu phan thuoc phun ra khoi binh do co stf tap hdp lai cua cac tieu phan khi phan tich b trang thai tinh. Dung cu phan tfch kfch thtfdc tieu phan theo tang va cham (cascade impactor) thfch hdp dung cho viec danh gia kfch thtfdc khf dong hoc (aerodinamic size) cua cac tieu phan thuoc phun mu. Dung cu co cau tao mo ta tren hinh 6.13, hoat dong theo nguyen tac nhtf sau: Thuoc phun mu dtfdc phun htfdng vao mieng pheu cua dung cu va dtfdc loi cuon qua cac tang pheu nhd ltfc hut chan khong vdi toe do thfch hdp hang dinh. Cac pheu co dtfdng kfnh cuong phlu nho dan theo thtf ttf ttf tang tren xuong tang dtfdi. Gitfa cac tang pheu co cac dia trtfdt quay vdi toe do cao, de tranh stf vang rdi cac tieu phan khi va cham, dia co the dtfdc phu mot ldp dich co do nhdt thfch hdp. Cac tieu phan kfch thtfdc ldn do co momen chuyen dong rdi xuong ldn se va cham vao tang dia dau tien va dtfdc gom gitf lai b day. Cac tieu phan kfch thtfdc nho hdn se theo luong khf di vong qua dia thtf nhat va dtfdc gom lai b dia tiep theo co toe do quay ldn hdn. Ctf tiep tuc nhtf vay, cac tieu phan dtfdc phan tach ra tren cac tang dia vdi kfch thtfdc nho dan. - Tang cuoi cung la mang loc nham gitf lai phan con lai cua cac tieu phan cd trong thuoc phun mu. 37 Cac tieu phan thuoc phun mu 1. Vong dem kin 2. Dia gom gitf tieu phan 3. Tang dau tien 4. Dia gom tang 2 5. Cac tang tiep theo 6. Tang cuo'i cung 7. Dia gom 8. Mang loc Hut chat khong Hinh 6.13: Set do dung cu phan tich kich thtfdc tieu phan theo tang (cascade impactor) Ltfdng thuoc tren m6i dia dtfdc dinh ltfdng bang phtfdng phap quang pho hoac bang phtfdng phap s^c ky thich hdp. Stf phan bo' khoi ltfdng thuoc la mot ham s o 'cua dtfdng kfnh khi dong hoc cua tieu phan, co the dtfdc tinh t* dtfdng chuan cho cac dia. Dtfdng chu£n cho ttfng dia dtfdc lap ttf cac thuoc phun mu ddn phan tan trong dieu kien chuan de biet cd kich thtf6c tieu phan dtfdc gom tren dia. Dung cu thtfdng phan tich cac tieu phan thuoc mu ttf 0,1 mcm den 30 mcm. Chuyen luan "Aerosols" trong USP 23 da co qui dinh mot loat cac chi tieu ky thuat cua thuoc phun mu can danh gia, dung cu va cach tien hanh, cac tinh toan va gi6i han cho phep. Dung cu phan tich kich thtf6c tieu phan co loai nhieu tang va 2 loai ddn tang v6i qui cach cau tao rieng. Doi v6i ttfng che pham thuoc phun mu co qui dinh rieng loai dung cu va cac chi tieu phu hdp v6i yeu cau chat ltfdng cua loai thuoc can stf dung. Cac phep thu: sinh hoc: Cac phep dinh ltfdng sinh hoc, danh gia hieu ltfc dieu tri, xac dinh do doc dtfdc tien hanh nhtf cac che pham thuoc thong thtfdng. 38 VI. MOT SO VI DU CONG THLfC THUOC PHUN MU 1. Dung dich dung de xong hit Bricanyl: (dung thiet bi tao phun mu) Thanh phan: Terbutalin sulfat loai pha tiem 100 mg. Natri clorid 580mg Clorobutol 500mg Dung dich HC1 2M vd pH3 Nif6c pha tiem vd 100ml 2. Thuoc phun mu Salbuvent (dung de xong hit) Thanh phan: Salbutamol (sieu min) 20mg (cho 200 lieu) Soja lecithin 7mg Sorbitan trioleat 5mg Chat day 11 (Tricloromonofluormethan) 4.140mg Chat day 12 (Diclorodifluormethan) 9.660mg 3. Thuoc phun mu Serobid (dung de xong hit) Thanh phan : Salmeterol xinafoat (sieu min) 7mg (cho 100 lieu) Lecithin 0,7mg Chat day 11 3.700mg Chat day 12 lO.OOOmg 4. Thuoc bot Salmeterol (dung de xong hit hop 60 lieu, moi lan sit dung tay bat lilc cd hoc tao phun mu 1 lieu thuoc bot). Thanh phan cho 1 lieu: Salmeterol xinafoat 72,5mcg Fluticasion propionat 500 meg Lactose vd 12,5mg (3 thanh phan deu la bot sieu min) 39 Chifcfng 7. THUOC M0 I. DAI ClTdNG 1. Dinh nghla Theo Dtfdc dien Viet Nam II tap 3: "Thuoc md la dang thuoc co the chat mem, dung de boi len da hay niem mac, nham bao ve da hoac dtfa thuoc tham qua da. Bot nhao boi da la loai thuoc md co chtfa mot ti le 16n dtfdc chat ran khong tan trong ta dtfdc. Kem boi da co the chat mem va min mang do sii dung cac ta dtfdc nhu ttfdng chtfa mot ltfdng chat long dang ke". Tuy nhien, dinh nghia nhtf tren chtfa bao gom het cac loai che" pham dung qua da de dieu tri va phong benh nhtf hien nay. 2. Phan loai 2.1. Theo the chat vd thanh phan cau tao: Thuoc m3 co the dtfdc goi bang nhieu ten khac nhau nhtf: - Thuoc md mem (Unguentum, pomata): La dang chu yeu trtf6c day, co the chat mem. Ta dtfdc thtfdng dung thuoc nhom than dau hoac ta dtfdc khan. Vi du: M3 benzosali (Whitfield), m3 Flucina, m3 tra mdt tetracyclin 1%, m3 tra mkt chlorocid-H ... - Thuoc md dac hay bot nhao boi da (Pasta dermica): La dang thuoc m3 co chtfa mot ltfdng 16n dtfdc chat rin cJ dang bot khong tan trong ta dtfdc (tren 40%). Ta dtfdc co the la than dau nhtf bot nhao Lassar (thanh phan gom tinh bot, k§m oxyd, lanolin khan va vaselin), co the la ta dtfdc than ntfdc, chang han bot nhao Darier (thanh phan gom kem oxyd, calci carbon at, glycerin va ntf3c tinh khiet). - Sap (Cera, unguentum cereum ): La dang thuoc m3 co the chat deo do chtfa mot ty le 16n cac sap, cac alcol beo cao, parafin hoac cac h6n hdp dau thtfc vat va sap. Ngay nay, che pham loai nay It dung, nhtfng lai pho bien trong cong nghe my pham- che tao son moi. - Kem boi da (Creama dermica): La dang thuoc m3 co the chat mem va rat min mang do co chtfa mot ltfdng 16n ta dtfdc long nhtf ntf6c, glycerin, propylen glycol, cac dau thtfc vat, dau khoang, thtfdng co cau true nhu ttfdng 40 kieu N/D hoac D/N. Trong thtfc te hien nay, loai nay dildc dung nhieu hcto ca. Cac loai kem thu6c co the chat long sanh dildc goi la stfa boi da. Tuy nhien, cach phan loai nay khong dap ting mot cach day du cac che pham khac nhut gel, he dieu tri qua da. Mot so tai lieu, Dildc dien tach rieng cac che pham dung qua da thanh ttfng loai cu the, trong do, thuoc md chi la mot dang thuoc dung theo dtfdng qua da. Chang han nhil: Dildc dien My 23 phan loai nhil sau: - Thuoc md (Ointments): La nhtfng che pham co the chat mem, dung boi ngoai da hoac niem mac. - Thuoc md tra mat (Ophthalmic ointments): Dtfdc xep vao nhom cac che pham dung cho nhan khoa (Ophthalmic preparations): La thuoc m3 dung cho mlt, dap tfng du yeu cau cua che pham dung cho nhan khoa, dtfdc san xuat trong dieu kien vo khuan va thanh pham phai bat buoc thtf do vo khuan. - Kem (Creams): La dang thuoc ban ran, co chtfa mot hoac nhieu dtfdc chat dtfdc hoa tan hay phan tan vao ta dtfdc thich hdp. Ngoai cach dung de boi ngoai da, kem con dtfdc dung de boi theo dtfcJng am dao. - Gel (Gels): Dang thuoc co the chat mem, trong do mot hay nhieu dtfdc chat dtfdc hoa tan hay phan tan trong ta dtfdc polymer thien nhien hoac tong hdp. - He tri lieu qua da (Transdermal Therapeutic Systems - TTS) hay con goi la he giai phong thuoc qua da: La dang thuoc dac biet^ dung dan ngoai da (da nguyen lanh), dtfdc thiet ke sao cho dtfdc chat co the giai phong, hap thu qua da vao he mach theo mtfc do va toe do xac dinh. 2.2. Theo quan diem ly hod: Co the coi thuoc md la nhtfng he phan tan dong the hoac di the, trong do chat phan tan la mot hoac hdn hdp dtfdc cha't, con moi trtfdng phan tan la mot hoac hon hdp ta dtfdc. Nhtf vay, co the phan chia ra: - Thuoc md thuoc he phan tan dong the {con goi la thuoc md 1 pha hoac dung dich: Dung dich that hay dung dich keo). Dtfdc chat dtfdc hoa tan trong ta dtfdc than dau hac than ntfde. Vi du: Thuoc md long nao 10 %, cao xoa Sao vang, gel lidocain 3%... - Thuoc md thuoc he phan tan di the (con goi la thuoc md 2 pha), bao gom cac thuoc md co thanh phan gom dtfdc cha't va ta dtfdc khong hoa tan vao nhau.Co the chia thanh 3 nhom: + Thuoc md kieu hon dich: Dtfdc chat ran da nghien, xay min dtfdc phan tan deu trong ta dtfdc, chang han: Cac bot nhao, thuoc md mem (md kem oxyd 10%, md acid crizophanic 5%, md tetracyclin 1%...) + Thuoc m3 kieu nhu ttfdng: Dtfdc chat the long hoac hoa tan trong mot ta dtfdc hoac mot dung moi trung gian, dtfdc nhtf hoa vao mot ta dtfdc khong dong tan. Loai nay chiem ty le 16n hien nay, ca llnh vtfc y hoc va my pham. Chang han nhil: - Thuoc m3 thuy ngan v6i ta dtfdc khan (lanolin + md ldn hoac hon hdp khac). - Thuoc md Dalibour. - Nhieu kem thuoc: Sicorten, Flucinar, Halog, Halog- N, Dermoval... + Thuoc md thuoc nhieu he phan tan con goi la thuoc m3 nhieu pha. Trong cac thuoc m3 nay, ban than ta dildc co the la mot nhu tildng, va dildc chat d dang tieu phan rdn, min dildc phan tan trong ta dildc hoac cung co the dildc chat gom nhieu loai v6i do tan trong ta dildc, dung moi khac nhau hoac do co the xay ra tildng ky neu cung hoa tan trong dung moi...luc do se hinh thanh dang thuoc m3 co cau true phtfc tap hdn, chang han: hon nhu tUdng, dung dich- hon dich, hoac dung dich- hon dich- nhu tildng. Chang han nhil: Voltaren Emugel. 2.3. Theo muc dich su! dung, dieu tri: - Thuoc m3 dung bao ve da va niem mac. - Thuoc m3 gay tac dung dieu tri tai cho: Sat khuan, giam dau... - Thuoc m3 hap thu hoac gay tac dung dieu tri toan than: Thuoc co tac dung phong benh, thuoc m3 chtfa dtfdc chat la cac noi tiet to", dildc chat chong sot ret, chong phan bao, ha huyet ap... 3. He tri lieu qua da (TTS) Do nhtfng tfu diem, trien v Tuy nhien, cac ta dtfdc nay de bi nhiem khuari, vi vay thtfdng cho them cac chat bao quan trong thanh phan. Mat khac, cung can chu y ring dan chat cellulose \co the gay ttfdng ky vdi mot so" dtfdc chat nhtf: Phenol, clocresol, resorcin, tanin, natri clorid, bac nitrat, cac muoi kim loai nang... j Dan chat cellulose co the tao phtic vdi paraben, lam giam hoat tmh cua mot sd" chat khang khuan nhtf natri sulphadimidin, nitrofurazon, mercurocrom, oxiquinolein sulphat, thimerosal..]. Nong do methyl cellulose va CMC thtfdng dung ttf 2 - 5 %, Na CMC ttf 2 -7 % . Con HPMC (Hypromellose) do tao gel cd do trong tot vi vay dtfdc sti dung trong cac che pham dung cho nhan khoa. Vi du: Methyl cellulose 5g Glycerin lOg Dung dich thuy ngan phenylborat 2% 0,5g Ntfdc cat vd 100 ml hoac: Natri carboxy methyl cellulose 6 g Sorbitol 12g Cloreton 0,5g Ntfdc cat vd lOOg 60 - Gel carbomer (carbopol, carboxy poly methylen, carboxy vinyl polymer). Ta dufdc nay la san pham trung hiep cao phan tti cua acid acrylic, co cong thtic chung: -CH2 -CH— " COOH-* n Tinh chat: Bot tr&ng khong tan hoac rat ft tan trong nUdc nhUng trUdng phong trong ntfdc tao gel, co pH acid (dich keo 1 % co pH khoang 3) va do nhdt khong cao. Thtfdng trung hoa gel v6i cac kiem, hay dung hdn ca la mono, di va triethanolamin. Cac gel nay co do nh6t cao hdn, dac hdn, thfch hdp cho ta dtfdc thuoc md. Nong do dung carbopol lam ta dtfdc gel thtfdng tit 0,5 - 5%, tuy theo loai carbopol va thanh phan cau tao cong thtic che pham. USP 23 ghi 6 loai carbopol khac nhau: TT Loai carbopol Do nhdt (cps) 1 910 Gel 1% trong nUdc da trung hoa 3000 - 7000 2 934 Gel 0,5% : 30 500 - 39 400 3 940 Gel 0,5% : 40 000 - 60 000 4 934P Gel 0,5% : 29 400 - 39 400 5 941 Gel 0,5% : 4 000- 11 000 6 1342 Gel 0,5% : 9 500-26 500 Vf du mot cong thtic ta dtfdc carbopol nhu sau: Carbopol 0,5 - 5% Mono, di hoac triethanolamin vd. Glycerin hoac propylen glycol 1 0 - 2 0 % Alcol ethylic hoac isopropylic 1 0 - 2 0 % Chat lam thdm vd. Ntfdc cat vd 1 0 0 %. - Ta dtfdc polyethylen glycol (PEG hoac macrogol, carbowax): Poly ethylen glycol la san pham trung hiep cao phan tti cua ethylen oxyd, co cong thtic chung: OHCH2-(CH2OCH2)n-CH2OH Tuy theo mtic do trung hiep (n), co cac PEG vdi phan tti ltfdng khac nhau, tfnh chat, the chat khac nhau. 61 TT PEG n TLPT Ty trong 1^25 LD50 chuot cong, uong 1 2 0 0 4 190-210 1,124 28,9 ml/kg 2 300 285- 315 1,125 31,7 ml/kg 3 400 8,2 - 9,1 380 - 420 1,125 43,62 ml/kg 4 600 12,5 - 13,9 570 - 630 1,126 38,1 ml/kg 5 1 0 0 0 950 - 1050 1,117 42,0 g/kg 6 1500 2 9 -3 6 1400 - 1600 1 , 2 1 0 44,18 g/kg 7 4000 6 8 -8 4 3500 - 4500 1 , 2 1 2 tren 50 g/kg 8 6000 158-204 6000 - 7500 1 , 2 1 2 tren 50 g/kg Ve the chat: Cac PEG 200, 300 va 400 the long, sanh. PEG 600, 1000 va 1500 giong nhtf sap. PEG ttf 2000 trd len the chat ran. Cac PEG co kha nang hoa tan nhieu dtfdc chat it tan do do cai thien dtfdc do tan va toe do hoa tan cung nhtf kha nang giai phong cua nhieu dtfdc chat it tan. Vi vay, PEG dtfdc svf dung kha rong rai trong ky thuat cac dang thuoc. De lam ta dtfdc thuoc md, thtfdng phoi hdp cac PEG nhtf sau: Loai PEG Ty le % phoi hdp 4000 50 40 - - 35 - 1500 - - 30 50 - 50 1000 - - - 100 - - 400 50 60 70 - 65 50 300 - - - 50 - - * Thanh phan thuoc md PEG ghi trong Dtfdc dien My 23 nhtf sau: PEG 3350 400g. PEG 400 600g. Khi can hut mot ltfdng ntfdc ldn hoac cac chat long phan ctfc, ngtfdi ta phoi hdp PEG vdi alcol beo cao hoac vdi cac chat nhu hoa thfch hdp. Ching han nhtf: * PEG 400 PEG 4000 aa 47,5g Alcol cetylic 5,0g 62 PEG 400 40g PEG 4000 50g Span 40 Ig Ntfdc tinh khiet 9g cd the phoi hdp PEG lam ta dtfdc PEG 4000 2 0 g Alcol stearylic 34g Glycerin 30g Natri laurylsulfat Ig Ntfdc tinh khiet vd 1 0 0 g Khac v6 i mot so" ta dtfdc than ntfdc khac, cac ta dtfdc PEG ben vting, co the bao quan lau, khong bi thuy phan, oxy hoa, oi khet. Ban than cac PEG cung co tac dung sat khuan vi vay it bi vi khuan va nam moc lam hong.| Tuy nhien, PEG co the gay tUdng ky vdi mot so hoat chat\ Chang han nhu PEG lam giam hoat tfnh cua mot so" chat khang khuan nhu cac phenol, cac hdp chat amoni bac bon, paraben. Mat khac, mot so" tap chat co trong PEG, nhat la cac ion kim loai co the lam tang qua trinh oxy hoa khti mot so" dtfdc chat de bi oxy hoa khti, lam giam hoac khong con tac dung cua cac dtfdc chat nay.\ \ Mac du PEG co kha nang giai phong hoat chat nhanh, nhtfng khong co kha nang tham qua da lanh nen ft dung lam ta dtfdc cho thuoc md hap thu, tham sau, ma chi dung lam cac ta dtfdc thuoc md co tac dung tai cho. Ngoai ra, do co tfnh hao am manh, ta dtfdc PEG co the lam cho da bi kho khi boi thuoc trong thdi gian dai. Vi vay, khong dung thuoc md che" vdi ta dtfdc PEG cho nhtfng ngtfdi da kho hoac cac benh cham, vay nen... Tuy nhien, de khic phuc nhtfdc diem nay, ngtfdi ta co the phoi hdp ta dtfdc PEG vdi 10% lanolin, 10% ntfdc hoac 5% alcol cetylic. I 2.3.3. Ta ditdc hap phu (ta ditdc khan, ta ditcJc hut, ta di£dc nhu hod): Nhom ta dtfdc nay cd kha nang hut ntfdc, dung dich ntfdc hoac cac chat long phan ctfc de tao thanh nhu ttfdng kieu N/D. Uj^diem: - Kha ben vtfng, cd the hut ntfdc va cac chat long phan ctfc. - Cd the phoi hdp vdi nhieu loai dtfdc chat ky ntfdc cung nhtf cac dung dich dtfdc chat. - Giai phong hoat chat ttfdng doi nhanh so vdi nhom ta dtfdc than dau. - Cd kha nang tham sau. 63 Nhtfdc diem: - Trdn nhdn, kho rrfa sach, - Co the can trd tdi viec hoat dong sinh ly binh thtfdng cua da. Mot sd" loai dien hinh: + Lanolin khan (xem phan ta dtfdc than dau): La mot ta dtfdc nhu hoa thien nhien, khan, cd kha nang hut ntfdc manh cho nhu ttfdng N/D. + Hdn hdp cua lanolin va cac dan chat cua lanolin vdi vaselin. VI du: Ta dtfdc khan dung cho thuoc md tra mkt dtfdc ghi trong nhieu Dtfdc dien (ching han BP) , cd thanh phan nhtf sau: Dau parafin 10% Lanolin khan 10% Vaselin trung tinh 80% Tuy theo dieu kien thdi tiet, ban chat va nong do cua dtfdc chat, cd the giam ty le dau parafin, tang ltfdng vaselin. Cung cd the thay dau parafin bang mot ltfdng parafin ran d nhtfng vung khi hau nhiet ddi. + Hdn hdp vaselin vdi cholesterol va cac sterol khac: VI du: Vaselin phoi hdp vdi 1 - 5% cholesterol tao thanh hdn hdp ta dtfdc vdi ten goi la Euserin, cd the hut dtfdc 200% ntfdc va cd the dung lam ta dtfdc cho thuoc md tra mat. Vaselin than ntfdc cd thanh phan nhtf sau: Cholesterol 30g Alcol stearylic 30g Sap trang 80g Vaselin 860g hoac hdn hdp ta dtfdc than ntfdc Sap trang 2 0 g Parafin ran 30g Alcol cetostearylic 50g Vaselin 900g Sap nhu hoa (BP93): Alcol cetostearylic 90g Natri laurylsulfat 1 0 g Ntfdc tinh khiet 4 ml Ttf sap nhu hoa cd the che ra thuoc md nhu hoa cd the hut nude va cac chat long phan ctfc de tao ra nhu ttfdng N/D: 64 Sap nhu hoa 30% Dau parafin 2 0 % Vaselin 50% Cung co the tao ra ta dtfdc khan hut ca dau lan ntfdc, vl du: Natri laurylsulfat l,0g PEG 1500 35,Og PEG 4000 40,Og Propylen glycol 24,Og 2.3.4. Ta di/cfc nhu titcfng hoan chinh: Uu diem: + Giai phong hoat chat tUOng doi nhanh. + De bam thanh ldp mong tren da va niem mac, khong can trd hoat dong sinh ly binh thtfdng cua da (loai nhu ttfdng D/N). + Min mang ve the chat, hinh thtfc dep. + Tham sau. 9 Nhtfdc diem: + Do ben nhiet dong kem, de bi tach ldp do anh htf dng cua nhieu yeu to" nhtf: Nhiet do moi trtfdng, do am khong khi, vi khuan va nam moc... + Can phai co chat bao quan vi de bi vi khuan va nam moc phat trien. + Loai nhu ttfdng D/N de rtfa sach bang ntfdc, nhtfng loai N/D kho rtfa sach. De dieu che ta dtfdc nhu ttfdng, can dung cac ta dtfdc dong vai trd ttfdng dau, cac ta dtfdc, ntfdc tinh khiet, dich chiet ntfdc, dung dich ntfdc...lam ttfdng ntfdc va cac chat nhu hoa. Tuy thuoc vao ban chat va sd" ltfdng cac chat nhu hoa, ta dtfdc tao thanh cd cau true kieu nhu ttfdng N/D va D/N. Ttfdng dau thtfdng dung la: - Cac dau, md, sap va cac dan chat dau, md, sap. - Cac acid beo va cac alcol beo cao. - Hydrocarbon no. - Silicon. Ttfdng ntfdc: - Ntfdc tinh khiet. - Propylen glycol. - Glycerin. 65 - PEG 300, 400. - Dich chiet ntfdc ttf dtfdc lieu. - Dung dich ntfdc hac chat long phan ctfc. Chat nhu hoa: + Cho nhu tUdng N/D: - Lanolin va dan chat. - Sap ong, spermaceti. - Alcol beo cao nhu alcol cetylic, alcol cetostearylic... - Chat nhu hoa tong hdp vdi HLB ttf 3-6. - Xa phong da hoa tri. + Cho nhu tUdng D/N: - Cac xa phong kiem nhtf: Kali, natri, amin (thtfdng ket hdp trong thanh phan gom cac acid beo v6i kiem hoa tri mot hoac kiem amin nhtf mono, di hoac triethanolamin de tao ra xa phong kiem). - Cac alcol sulfat (natri laurylsulfat, natri cetylsulfat...) - Cac chat dien hoat cation nhtf: Cetrimit, benzalkonium clorid. - Dien hoat khong ion hoa: Tween 20, 40, 80... Mot so" vl du: - Lanolin ngam ntfdc la ta dtfdc nhu ttfdng N/D. - Cold cream USP XVI co thanh phan nhtf sau: Sap este cetyl (spermaceti tong hdp) 125g Sap trang 120g Dau parafin 560g Natri borat 5g Ntfdc cat 180ml Ta dtfdc nay cung thuoc nhom nhu ttfdng N/D. - Mot vai ta ditUc nhu titcfng N / D khac: Alcol cetylic 15g Lanolin khan 35g Vaselin 30g Ntfdc tinh khiet 20g hoac Acid oleic 5g Dau lac 320g 66 Lanolin Dung dich calci hydroxyd vd hoac Sap ong trang Spermaceti Span 80 Dau lac Dau thau dau Ntfdc tinh khiet - Mot sota dtfdc nhu ttfdng D IN: + Thuoc m3 than nU6c (USP XXIII): Methylparaben Propylparaben Natri laurylsulfat Propylen glycol Alcol stearylic Vaselin Nu3c tinh khiet + Cream nu3c (BP 93) Thuoc m3 nhu hoa Clorocresol Nu3c tinh khiet + Ta dtfdc nhu ttfdng D/N dung chat Acid stearic Dung dich natri hydroxyd 30% Glycerin Ntf6c tinh khiet hoac Acid stearic Triethanolamin Glycerin Ntf6c tinh khiet + Ta dtfdc nhu ttfdng D/N dung chat 80g lOOOg 8g 1 0 g 5g 52g 5g 2 0 g 0,25g 0,15g 1 0 g 1 2 0 g 250g 250g 370ml 30% 0,1 % 69,9% nhu hoa la xa phong kiem: 140g 30g 280g 550ml 24g Ig 13g 62g nhu hoa dien hoat: 67 Alcol cetylic 17g Vaselin 25g Tween 80 7g Glycerin 15g Ntfdc tinh khiet vd 1 0 0 g. hoac Alcol stearylic 15g. Sap ong 8 g Tween 80 3,75g. Span 80 l,25g. Sorbitol 7,5g. Ntfdc tinh khiet vd 1 0 0 g. hoac Cetomacrogol 700 3g Cetomacrogol 1000 2 g Alcol cetostearylic lOg. Vaselin 2 0 g. Dau parafin 5g Ntfdc tinh khiet 60g. Dieu che ta dtfdc nhu ttfdng D/N thtfdng tien hanh tren nguyen tic nhtf sau: Dun chay cac ta dtfdc ttfdng dau, hoa tan chat nhu hoa tan trong dau, dun nong khoang 65-70°C. Dun nong ttfdng ntfdc len cao hdn khoang 3-5°C, hoa tan cac chat nhu hoa, chat bao quan...Sau do phoi hdp, khuay tron cho tdi khi nguoi. III. KY THUAT DIEU CHE- SAN XUAT THUOC MCI 1. Dieu che thuoc md bang phtfdng phap hoa tan 1.1. Dieu kien dp dung: - Dtfdc chat: Hoa tan trong ta dtfdc hoac trong mot dung moi trung gian, cd the tron deu hoac hoa tan vdi ta dtfdc. - Ta dtfdc: Than dau, than ntfdc va ta dtfdc khan. Cau true cua che pham tao thanh thtfdng la kieu dung dich (da phan d dang dung dich keo) va he phan tan thuoc loai he dong the. 68 1.2. Cac giai doqn chinh: 1.2.1. Chuan bi dtfdc chat: Trong mot so" trtfdng hdp, dtfdc chat rin co toe do hoa tan cham, co the lam tang toe do hoa tan bang cach xay, nghien. 1.2.2. Chuan bi ta dtfdc: Neu la hon hdp ta dtfdc, can phai phoi hdp va loc, tiet khuan neu can. Chang han: Ta dtfdc co the la hon hdp ta dtfdc than dau nhom hydrocarbon: vaselin, dau parafin va parafin r&n...luc do can dun chay, loc. Neu la ta dtfdc than ntf6c nhtf PEG cung can phoi hdp, dun chay trtfdc. Neu la.ta dtfdc tao gel, can co thdi gian ngam nguyen lieu tao gel trong moi trtfdng phan tan de gel dong nhat. 1.2.3. Phoi hdp dtfdc chat vdi ta dtfdc: Noi chung co the hoa tan d nhiet do thtfdng hoac dun nong cho giam thdi gian thao tac. Can chu y r&ng co mot so" dtfdc chat de bi bay hdi, thang hoa b nhiet do cao, vi vay, dung cu, thiet bi hoa tan can phai co nip d&y kin. Dien hinh nhat la khi san xuat cao xoa. Dtfdc chat i ' Ta dtfdc ------------► Hoa tan Kiem nghiem ban thanh pham 1 Xtf ly tuyp------ ► Dong tuyp Kiem nghiem thanh pham 1 Dong goi Sd do tom tat dieu che- san xuat thuoc md bang phtfdng phap hod tan 1.2.4. Mot so'vi du: a. Ta dtfdc than dau: - Cao sao vang Cong thtfc: Mentol 12,5g 69 Long nao 1 2 ,5g Tinh dau bac ha 17,0ml Tinh dau long nao 10,5ml Tinh dau khuynh diep 5ml Tinh dau htfdng nhu 2,5ml Tinh dau que vd Ta dtfdc vd lOOg Ta dtfdc gom hon hdp: Vaselin, lanolin, sap ong, cerezin, ozokerit theo ty le thfch hdp. Ngoai ra co the them cac chat on dinh mau, htfdng. Tien hanh: Dun chay hon hdp ta dtfdc, loc qua vat lieu thfch hdp. Tron menthol vdi long nao thanh hon hdp chay long, them cac loai tinh dau vao hoa tan. Phoi hdp vdi ta dtfdc, ham trong dung cu (thiet bi) km, d nhiet do 70-80°C trong thdi gian khoang 2 gid. De nguoi xuong khoang 40-50°C, rot vao hop, de nguoi han, day nap. Hien nay, cac cd sd san xuat da cai tien phtfdng phap san xuat cao xoa nhtf sau: Chuan bi sin ta dtfdc theo phtfdng phap chung. Khi san xuat, can ltfdng ta dtfdc theo cong thtfc, dun nong, hoa tan dtfdc chat, de nguoi xuong nhiet do thfch hdp roi do hop. . Thuoc md methyl salicylat 50% (BP 98) Cong thtic: Methyl salicylat 500g Sap tring 250g Lanolin khan 250g Tien hanh: Dun chay tren cach thuy sap va lanolin, loc neu can thiet, khuay cho tdi khi gan nguoi, them methyl salicylat vao tron deu. b. Ta dtidc than ntfdc: Ta dtfdc gel: Gel Lidocain 3% (BP 98) Thanh phan: Lidocain hydroclorid 3g Ta dtfdc gel vd lOOg Cd the dung cong thtfc gel che ttf CMC, MC hoac HPMC nhtf da ghi trong phan ta dtfdc than ntfdc de dieu che gel lidocain. Hoac sii dung ta dtfdc cd thanh phan nhtf sau: 70 Carboxy methyl cellulose 2-5g Propylen glycol 25g Nipagin 0,lg Ntfdc tinh khiet vd lOOg Profenid gel 2,5% Thanh phan: Ketoprofen 2,5g Ta dtfdc gel vd lOOg Ta dtfdc gel gom: Carbopol, triethanolamin (TEA), alcol ethylic, tinh dau lavande, ntfcic tinh khiet. Niflugel Thanh phan: Acid niflumic 2,5g Ta dtfdc gel vd lOOg Ta dtfdc gel: Carbopol, di-isopropanolamin, alcol ethylic 95%, ntfdc tinh khiet va chat thdm vtia du. Ta ditdc PEG Vf du: Thuoc md clotetracyclin 3% Cong thtic: Clotetracyclin hydroclorid 3g PEG 400 40g PEG 4000 57g Tien hanh: Dun chay PEG 4000, cho PEG 400 vao khuay deu, them clotetracyclin hydroclorid va khuay cho tdi khi tao thanh thuoc m3 dong nhat. Cd tai lieu ghi dung ta dtfdc PEG cho thuoc m3 chtfa levomycetin, lidocain, sulfamit... 2. Dieu che thuoc m 5 bang phtfdng phap tron deu ddn gian 2.1. Dieu kien dp dung: - Dtfdc chat: + Dtfdc*chat ran, khong tan hoac ft tan trong ta dtfdc. + Co the xay ra ttfdng ky giiia cac dtfdc chat neu trong cong thtic cd nhieu dtfdc chat. 71 - Ta dildc: Co the ca 4 nhom (than dau, than ntfdc, ta dtfdc khan va ta dtfdc nhu ttfdng) . 2.2. Cac giai doan chinh■ 2.2.1. Lam bot ddn hoac bot kep dtfdc chat ran co trong cong thtic: De dam bao thuoc m3 dong nhat, dtfdc chat de phan tan deu trong ta dtfdc, nhat la khi nong do dtfdc chat nho, can nghien min dtfdc chat. Trong thtfc te, nhieu dtfdc chat dtfdc lam dtfdi dang bot sieu min hoac sieu sieu min. Neu trong cong thtfc co nhieu dtfdc chat rin, can phai tron bot kep cac dtfdc chat trtfdc khi phoi hdp vdi ta dtfdc. 2.2.2. Chuan bi ta dtfdc: Giong nhtf doi vdi phtfdng phap hoa tan. 2.2.3. Lam md dac: Muc dich cua giai doan nay la: + Lam min them dtfdc chat. + De phoi hdp va tron deu vdi ltfdng ta dtfdc con lai. Tien hanh: Cho dtfdc chat da min vao dung cu thfch hdp (coi stf hoac may) va dong ltfdng ta dtfdc da xii ly, tron ky lam thanh m3 dac. Chuan bi dtfdc chat Chuan bi ta dtfdc . Nghien hoac xay . Phoi hdp hoac dun chay. (neu khong phai la dang microsize) . Tiet khuan neu can thiet. . Ray tron bot kep X Lam thuoc m3 dac .1 Phoi hdp ta dtfdc Can hoac lam dong nhat ---------------► Kiem nghiem ban thanh pham Dong tuyp -------------- ► Kiem nghiem thanh pham Dong goi Scf do tom tat cac giai doan san xuat thuoc md theo phtfdng phap tron deu ddn gian 72 2.2.4. Phoi hcfp md dac vdi ta ditcfc con lai: Theo nguyen the dong ltfdng, neu dieu che vdi ltfdng nhd, cho vao coi, dung chay danh cho tdi khi dong nhat. Neu san xuat ldn, dung cac may lam thuoc md chuyen dung, khuay trong thdi gian xac dinh. 2.2.5. Can hoac lam dong nhdt: Muc dich cua giai doan nay la lam cho che pham dong nhat hdn va min mang. Phtfdng tien stf dung la may can 3 true hoac may lam dong nhat. 2.2.6. Dong goi: Hien nay, thuoc md chu yeu dtfdc dong trong cac tuyp kim loai hoac cac tuyp chat deo vdi cac may dong rieng hoac lien hoan. 2.3. PhitOng tien, thiet bi dung trong san xuat thuoc md: - May xay hoac may nghien bi. - Ray hoac may ray vdi cd ray thfch hdp. - May lam bot sieu min (Micropulverizer). - May tron thuoc md chuyen dung (H.8.4; H.8.5) - May can 3 true hoac may lam dong nhat (H.8 .6 ; H.8.7) Hinh 7.3. May tron thuoc md Hinh 7.4. May tron thuoc md co gan co gan bo phan nhao tron vd bo phan hut chan khong nao vet, qui md nho. 73 Hinh 7.5. Sd do nguyen tac may can thuoc md 3 true. * s £p_ r p ^ -T-irbi., 1 tri Hinh 7.6. Sd do nguyen tac may lam dong nhdt VME - Frima. A. Ctfa cho dtfdc chat rin va ta dtfdc; B. Ctfa cho dtfdc chat long va ta dtfdc. C. Ctfa cho dtfdc chat rin D. San pham hoan chinh. E. Bdm chan khong. . May dong tuyp v6i pittong chuyen dong theo phtfdng thing dtfng hoac theo phtfdng nim ngang (H.8 .8) Hinh 7.7. Sd do nguyen tac may dong thuoc md theo phtfdng nam ngang. 1. Pheu chtia thuoc; 2. True quay; 3. Van dieu chinh; 4. Gia dat tuyp. . Neu dung may lien hoan co the thtfc hien dtfdc cac giai doan ttf tron, dong tuyp, in so" kiem soat. (H.8.9) Hinh 7.8: Sd do mot day chuyen san xuat thuoc md kem oxyd quy m6 cong nghiep 1 . Can 2. Xe van chuyen 3. Noi nung chay vaselin. 4. Binh ap ltfc dun chay ta dtfdc khac 5. May tron ta dtfdc. 6 . Loc 7. May nhao tron kem oxid vdi ta dtfdc. 8 . Xay ray kem oxid. 9. Bdm lam dong nhat 10,11. Dong goi. 75 2.4. Mot so vi du: • « Thuoc md benzosali (Whitfield) - DDVN II,T3 . Cong thtic: Acid salicylic 30g Acid benzoic 60g Ta dtfdc nhu hoa 910g Ta dtfdc nhu hoa theo BP93, da ghi trong phan ta dtfdc khan. Tien hanh: - Chuan bi dtfdc chat: Nghien hoac xay rieng acid benzoic va acid salicylic, ray bot min, tron bot kep. - Chuan bi ta dtfdc: Che sap nhu hoa va thuoc md nhu hoa theo trinh ttf nhtf sau: Dun chay alcol cetostearylic hoac alcol cetylic d nhiet do khoang 95°C. Them natri laurylsulfat, tron deu, them ntfdc tinh khiet, tiep tuc dun tdi nhiet do 115°C va duy tri d nhiet do nay, khuay lien tuc cho tdi khi nguoi han (nen lam lanh nhanh). Dun chay dong thdi sap nhu hoa, vaselin va dau parafin, loc neu can thiet, khuay lien tuc cho tdi khi nguoi. - Lam thuoc md dac: Cho hdn hdp acid benzoic va salicylic vao coi stf hoac may tuy theo ltfdng yeu cau, them dong ltfdng hdn hdp ta dtfdc, khuay, tron, vet ky. - Phoi hdp ta dtfdc con lai vdi thuoc md dac: Tiep tuc cho ta dtfdc, tron vdi md dac theo nguyen t&c dong ltfdng, cho tdi khi dong nhat hoac theo thdi gian da ghi trong quy trinh san xuat. Vdi cac may chuyen dung cd he thong dieu nhiet thi qua trinh tron, dao se thuan ldi hdn. Neu may khuay, tron khong cd he thong dieu nhiet ttf dong, can lip them thiet bi nay de thuoc cd the chat thich hdp trong qua trinh san xuat, nhat la vao mua dong. - Trtfdc khi lay mau kiem nghiem ban thanh pham can thiet phai cho thuoc md qua may can 3 true, nham muc dich lam deu va min them thuoc. - Dong tuyp: Md benzosali thtfdng dtfdc dong trong tuyp nhom trang vecni hoac silicon vdi khoi ltfdng 1 0 -2 0 g. Thuoc md tra mat chlorocid-H C6ng thtic: Cloramphenicol lg Hydrocortison acetat bot sieu min 0,75g Ta dtfdc khan vd lOOg Ta dtfdc khan dung cho thuoc md tra mkt dtfdc ghi trong phan ta dtfdc. 76 Tien hanh: Giong nhil thuoc md benzosali, nhtfng vi la thuoc md tra mat nen can chu y: + Dtfdc chat can phai lam min tdi mtfc do toi da (theo quy dinh cua DDVN II, T3 thi kich thudc tieu phan phai nhd hdn 75 micromet), tot nhat la dung loai bot microsize (sieu min). + Ta dtfdc sau khi loc can phai tiet khuan d 160°C trong 1 gid. + Tien hanh san xuat trong dieu kien vd khuan (quy dinh doi vdi cac che pham vd khuan). Thudc md Gentasone dung tra mat Cong thtic: Gentamycin sulfat (tfnh theo gentamycin base) 0,3g Betamethason natri phosphat (tfng vdi betamethason khan) 0 ,lg Ta dtfdc khan dung cho md tra mit vd lOOg 3. Dieu che thuoc mcf bang phtfdng phap nhu hoa 3.1. Vdi ta dtfdc nhu ttfdng co san: 3.1.1. Dieu kien dp dung: - Dtfdc chat: + Long phan ctfc hoac ban phan ctfc, khong dong tan, kho tron deu vdi ta dtfdc, chang han nhtf: Thuy ngan kim loai, ichtiol, hac in thao moc, bdm Peru, dau cade, dung dich chi acetat kiem, dung dich dong, kem, sulfat... + Dtfdc chat mem hoac ran de hoa tan trong cac dung moi trd phan ctfc (ntfdc, alcol, glycerin, propylen glycol...) chang han nhtf cac cao thuoc, khang sinh dang muoi, muoi ancaloid... + Dtfdc chat ran chi phat huy tac dung dtfdc ly tot nhat khi dtfdc dung dtfdi dang dung dich ntfdc nhtf iod, bac keo (argiron, protacgon, colacgon). - Ta dtfdc: Thuoc nhom ta dtfdc khan. - Thuoc md dieu che theo phtfdng phap nay cd cau true kieu nhu ttfdng N/D, thuoc he phan tan di the. 3.1.2. Cac giai doan: Vdi cac dtfdc chat long: Them dan ttfng ltfdng nhd vao ta dtfdc khan, vtia them vtia khuay nhe nhang trong dung cu thfch hdp. Sau khi da cho het dtfdc chat, tiep tuc khuay tron manh cho tdi khi thu dtfdc thuoc md dong nhat. 77 W du: Thudc md Dalibour Cong thtic: Dong sulfat 0,3g Kem sulfat 0,5g Ntfdc cat 30ml Lanolin khan 50g Vaselin lOOg Tien hanh: Hoa tan dong va kem sulfat vao ntfdc trong mot dung cu thfch hdp, loc. Sau do co the tiep tuc theo 2 cach sau: + Cho ttf ttf dung dich dtfdc chat vao lanolin, khuay tron cho hut het, sau do cho vaselin vao khuay tron t6i khi dong nhat. + Lam hon hdp ta dtfdc khan bing cach dun chay lanolin va vaselin, loc. De nguoi, cho ttf ttf dung dich dtfdc chat vao ta dtfdc, khuay tron trong dung cu, may thfch hdp cho tdi khi tao dtfdc thuoc m3 nhu ttfdng ben, dong nhat. - Vdi cac cao thuoc che ttf dtfdc lieu the chat mem hoac kho: Can hoa tan nong trtfdc vdi glycerin hoac hoa tan trong hdn hdp dung moi gom: Alcol ethylic 1 phan Glycerin 3 phan Ntfdc tinh khiet 6 phan roi phoi hdp vao ta dtfdc khan. Vi du: Thudc md benladon Cong thtic: Cao (mem hoac kho) benladon 10 Glycerin 5g Md ldn canh kien vd lOOg cd the thay md ldn cach kien bang hdn hdp ta dtfdc khan khac. Tien hanh: Hoa tan cao benladon trong glycerin nong, sau do cho vao md ldn hoac ta dtfdc khan khac, khuay tron cho tdi khi dong nhat. Ltfu y rang neu dung md ldn canh kien lam ta dtfdc can cho them mot ty le sap ong thfch hdp (3-5%) de dieu chinh the chat va lam tang kha nang hut ntfdc cua ta dtfdc. - Vdi cac chat long ban phan ctfc, kho tron deu nhtf bdm Peru, dau Cade, can cho ttf ttf, khuay tron nhe nhang vdi ta dtfdc hut, sau do phoi hdp vdi ta dtfdc con lai. 78