SE447447B - ADJUVANCING COMPOSITION TO PROMOTE ABSORPTION OF PHARMACOLOGICALLY ACTIVE SUBSTANCES CONTAINING NON-TOXIC SALTS OF FAT ACIDS WITH 8-12 COLATOMES AND NON-TOXIC SALTS OF LEUCIC ACID - Google Patents
ADJUVANCING COMPOSITION TO PROMOTE ABSORPTION OF PHARMACOLOGICALLY ACTIVE SUBSTANCES CONTAINING NON-TOXIC SALTS OF FAT ACIDS WITH 8-12 COLATOMES AND NON-TOXIC SALTS OF LEUCIC ACIDInfo
- Publication number
- SE447447B SE447447B SE8007820A SE8007820A SE447447B SE 447447 B SE447447 B SE 447447B SE 8007820 A SE8007820 A SE 8007820A SE 8007820 A SE8007820 A SE 8007820A SE 447447 B SE447447 B SE 447447B
- Authority
- SE
- Sweden
- Prior art keywords
- acid
- toxic salts
- toxic
- pharmacologically active
- base
- Prior art date
Links
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- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229960004244 cyclacillin Drugs 0.000 description 1
- HGBLNBBNRORJKI-WCABBAIRSA-N cyclacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C1(N)CCCCC1 HGBLNBBNRORJKI-WCABBAIRSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 229950004791 pirbenicillin Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
Description
447”447 2 ningar av dessa läkemedel har försökts så har dessa försök 7hittills inte visat sig helt lyckosamma. 447 ”447 2 nings of these drugs have been tried, so these attempts 7 so far have not proved completely successful.
Föreliggande uppfinnare anförde en intensiv forskning under ovanstående omständigheter. Forskningen ledde till upptäckten att (1) icke-tokiskatsalter av fettsyror med 8-12 kolatomer och icke-toxiska salter av leucinsyra kan'befrämja absorption, från rektum in i blodbananI av en lång rad farmakologiskt aktiva substanser, i synnerhet/5-laktamföreningar såsom peni- cilliner och cefalosporiner och till och med peptider med hög molekylvikt, såsom insulin, och även att (2) den absorptions- Il 'befrämjande verkan hos dessa icke-toxiska salter åstadkommes, när de införlivas i beredningarna-i höga koncentrationer. Ovan- stående'upptäckt följdes av_ytterligare forskning, som har lett fram till föreliggande'uppfinning.The present inventors conducted intensive research under the above circumstances. The research led to the discovery that (1) non-toxic fatty salts of 8-12 carbon atoms and non-toxic salts of leucic acid can promote absorption, from the rectum into the bloodstream of a wide range of pharmacologically active substances, in particular β-lactam compounds such as penicillins and cephalosporins and even high molecular weight peptides such as insulin, and also that (2) the absorption-promoting effect of these non-toxic salts is achieved when incorporated into the preparations in high concentrations. The above discovery was followed by further research which has led to the present invention.
Denna“uppfinning avser därför en absorptionsbefrämjande adju- vanskomposition (för att befrämja absorptionen av farmakolo- giskt aktiva 'substanser från rektuxn) , som innehåller 0,5-20 vikts-% av minst ett icke-toxiskt salt av en fettsyra med 8-12 kolatomer och/eller ett icke-toxiskt salt av leucinsyra och en lämplig mängd av en bas för rektala beredningar och en farmaceutisk komposition innehållande 0,5-20 vikt-% av minst ett av nämnda icke-toxiska salter, en lämplig mängd av en 'farmakologiskt aktiv substans och en lämplig mängd av en bas för rektala beredningar.This invention therefore relates to an absorption-promoting adjuvant composition (to promote the absorption of pharmacologically active substances from rectoxin), which contains 0.5-20% by weight of at least one non-toxic salt of a fatty acid having 8-12 carbon atoms and / or a non-toxic salt of leucic acid and a suitable amount of a base for rectal preparations and a pharmaceutical composition containing 0.5-20% by weight of at least one of said non-toxic salts, a suitable amount of a pharmacologically active substance and an appropriate amount of a base for rectal preparations.
Det är därför ett ändamål med denna uppfinning att åstadkomma ett adduvans, som befrämjar absorptionen av en farmakologiskt aktiv substans genom rektumÄ Ytterligare ett ändamål med'uppfinningen är att åstadkomma en É farmaceutisk komposition för rektal administration, vilken kom- fposition är fördelaktig'i det att den farmakologiskt aktiva substans som finns däri med.lätthet absorberas in i blodom- loppet genom rektum även när nämnda aktiva substans vanligen är endast med avsevärd svårighet absorberbar genom rektum. 10 15 20 25 30 -35 3- 447 447 Andra ändamâlfkommer att framgå av följande beskrivning och krav.It is therefore an object of this invention to provide an adduct which promotes the absorption of a pharmacologically active substance through the rectum. A further object of the invention is to provide a pharmaceutical composition for rectal administration, which composition is advantageous in that the pharmacologically active substance contained therein is readily absorbed into the bloodstream through the rectum even when said active substance is usually only with considerable difficulty absorbable through the rectum. 10 15 20 25 30 -35 3- 447 447 Other objects will appear from the following description and claims.
De fettsyror med 8-12 kolatomer, vihææ sflrer ænümdsi.emUghetvæd denna uppfinning kan vara naturligt förekommande syror eller 'syntetiska syror} fastän naturligt förekommande-syror i all- mänhet föredrages. Sådana fettsyror kan ha rak eller grenad kedja{ fastän sådana med rak kedja är föredragna.The fatty acids having 8 to 12 carbon atoms, which are extremely useful in this invention, may be naturally occurring acids or 'synthetic acids', although naturally occurring acids are generally preferred. Such fatty acids may be straight or branched chain, although straight chain ones are preferred.
Antalet kolatomer i fettsyrorna är såsom nämnts 8-12 (t.ex. kaprylsyra, akprinsyra, laurinsyra; etc.) men är företrädes- vis 10 (såsom kaprinsyra).The number of carbon atoms in the fatty acids is as mentioned 8-12 (eg caprylic acid, acpric acid, lauric acid; etc.) but is preferably 10 (such as capric acid).
De icke-toxiska salterna att användas i föreliggande uppfin- ning kan vara'vilket salt som helst som är farmakologiskt acceptabelt. Exempel på nämnda salter är alkalimetallsalter (t.ex. natriumsalt, kaliumsalt), salter med organiska baser (t.ex. salter med basiska aminosyror såsom argininsalt, lysin- salt, etx.) etc.The non-toxic salts to be used in the present invention may be any salt which is pharmacologically acceptable. Examples of said salts are alkali metal salts (eg sodium salt, potassium salt), salts with organic bases (eg salts with basic amino acids such as arginine salt, lysine salt, etc.), etc.
Som fettsyror, leucinsyra och icke-toxiska salter därav kan 'som exempel.nämnas kaprinsyra, dess natrium-, kalium-, lysin- och argininsalterj pelargonsyra, dess natrium-, lysin- och argininsalter; kaprylsyra} dess natrium-, kalium-; lysin- och argininsalter; undekylsyra och dess argininsalter; laurinsyra, dess natrium-} kalium-, lysin- och argininsalter; dodekylsyra och dess lysinsalt och leucinsyra; dess natrium-, kalium-, lysin- och arginínsalter, företrädesvis kaprinsyra och dess salter; laurinsyra och dess salter och kaprylsyra och dess salter; speciellt föredrages kaprylsyra och dess salter.Examples of fatty acids, leucic acid and non-toxic salts thereof are capric acid, its sodium, potassium, lysine and arginine salts, geranium acid, its sodium, lysine and arginine salts; caprylic acid} its sodium, potassium; lysine and arginine salts; undecylic acid and its arginine salts; lauric acid, its sodium, potassium, lysine and arginine salts; dodecylic acid and its lysine salt and leucic acid; its sodium, potassium, lysine and arginine salts, preferably capric acid and its salts; lauric acid and its salts and caprylic acid and its salts; especially preferred is caprylic acid and its salts.
De icke-toxiska salterna av syrorna kan användas antingen en- samma eller i kombination.The non-toxic salts of the acids can be used either alone or in combination.
UL rycket "farmakologiskt aktiva substanser" såsom det användes '1 Vala denna beskrivning betyder vilka som helst och alla ar som uppvisar farmakologisk effekt efter absorption Híodcmloppet. Eftersom till och med sådana substanser w- ...~-_.._.._._-_.~._._._-.... v U1 10 15 20 25 30 35' 447 447 4 som annars inte kan absorberas, när de administreras oralt, och hittills endast har administrerats parènteralt med lätt- het absorberas från rektüm, när adjuvanset enligt denna upp- "finning används, ligger vikten för adjuvanset enligt uppfin- '-ningen i dess tillämfining på sâdana.svârabsorberbara farmako- 'logiskt aktiva substanser. Som specifika exempel på sådana "farmakologiskt aktiva substanser kan nämnasFš-laktamantibio- 'tika (såsom penicilliner och cefalosporiner), peptider, poly- sackarider och aminoglykosidantibiotika etc.The UL term "pharmacologically active substances" as used herein means that any and all arrays exhibit a pharmacological effect after absorption. Since even such substances w- ... ~ -_.._.._._-_. ~ ._._._-.... v U1 10 15 20 25 30 35 '447 447 4 as otherwise can not be absorbed when administered orally, and has hitherto only been administered parenterally with ease absorbed from the rectum, when the adjuvant of this invention is used, the weight of the adjuvant of the invention in its application is such. specific absorbable pharmacologically active substances. Specific examples of such pharmacologically active substances are β-lactam antibiotics (such as penicillins and cephalosporins), peptides, polysaccharides and aminoglycoside antibiotics, etc.
Penicillinerna innefattar ampicillin, ciklacillin, kloxacillin, bensylpenicillin, karbenicillin, piperacillin, mezlocillin, pirbenicillin, tikarcillin, (2S, 5R, GR)-6- [(R)-2-(4-hydroxy-1,5-naftylidin-3-karboxamid)-2-fenylacet- amid]-3,3~dimetyl-7-oxo-4-tia~1-azabicyk1o[3.2.0] heptan-2- -karboxylsyra och åeras salter såsom natriumsalter, etc.The penicillins include ampicillin, ciclacillin, cloxacillin, benzylpenicillin, carbenicillin, piperacillin, mezlocillin, pirbenicillin, ticarcillin, (2S, 5R, GR) -6 - [(R) -2- (4-hydroxy-1,5-naphthylidine-3- carboxamide) -2-phenylacetamide] -3,3-dimethyl-7-oxo-4-thiaz-1-azabicyclo [3.2.0] heptane-2-carboxylic acid and its salts such as sodium salts, etc.
Cefalosporinerna innefattar cefalotin, cefokitin, ce- fazolin, cefaloridin, cefacetril, cefctiam, ceforanid, ce- fäH0fl, C@fäkl0I¶ cefàöroxil, cefatrizin, cefradin, cefalo- glycin, 7- CD(-)~IX-(4-etyl~2,3-dioxo-1~piperazinkarboxamid)- OL-(4-hydroxyfenyl)acetamid] -3-[(1-metyl-1H-tetrazol-5-yl) tiometyll-3-cefam-4-karboxylsyra (nedan betecknad T-1551), (sn, vn)-[(z)-2-metoxyim1no-2-(2-imino-4-tíazolin-4-y1) acet- amid]-8-oxo-5-tia-1-azabicyklo E 4.2.0 1 okt-2-en-2-karboxyl~ syra (FK-749), (6R, 7R)-7- [2-karboxy-2-(4-hydroxyfenyl) acet- amid] -7-metoxy-3- l:(1-metyl-1H-tetrazol-S-yl-tio) metyl] -8- oxo-5~oxa~1-azabicyklo [4.2.0] okt~2-en-2-karboxylsyra, 7 -}Å-[2-(2fiaminotiazol-4-yD~(Z)-2~metoxyiminoacetamid] -3- - E(1-metyl-1H-tetrazol-5-yl) tiometyl]-cef-§-en-4-karboxyl- syra, 7-(2-amino-2-fenylacetamid)-3~metoxy-8-oxo~5-tia-1- azabicyklo- [4.2.0] Okt-2-en-2-karboxylsyra och salter därav såsom natriumsalter etc.The cephalosporins include cephalothin, cefokitin, cefazoline, cephaloridine, cefacetril, cefctiam, cephoranide, cefaH0 fl, C @ fecl0I¶ ceferaoxil, cefatrizine, cefradine, cephaloglycine, 7-CD (-) 2,3-dioxo-1-piperazinecarboxamide) - OL- (4-hydroxyphenyl) acetamide] -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepham-4-carboxylic acid (hereinafter referred to as T -1551), (sn, nn) - [(z) -2-methoxyimino-2- (2-imino-4-thiazolin-4-yl) acetamide] -8-oxo-5-thia-1-azabicyclo E 4.2.0 1 Oct-2-ene-2-carboxylic acid (FK-749), (6R, 7R) -7- [2-carboxy-2- (4-hydroxyphenyl) acetamide] -7-methoxy -3-1: (1-methyl-1H-tetrazol-5-yl-thio) methyl] -8-oxo-5-oxa-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 7 -} Å- [2- (2-Aminothiazol-4-yl] - (Z) -2-methoxyiminoacetamide] -3- - E (1-methyl-1H-tetrazol-5-yl) thiomethyl] -ceph-§-en-4 -carboxylic acid, 7- (2-amino-2-phenylacetamide) -3-methoxy-8-oxo-5-thia-1-azabicyclo [4.2.0] Oct-2-ene-2-carboxylic acid and its salts such as sodium salts etc.
Peptiderna innefattar insulin, ACTH, enkefalin, TRH, LH-RH, polymyxin, kolistin; gramiéidin, nacitracin, iseltsaktiverande protein från Brodetella pertussis och inhibitor av angiotensin I-omvandlande enzym E (t.ex. Glu-Trp-Pro-Arg-Pro-G1u-Ileu-Pro-Pro (nedan be- tgcknat sa 20881) ] etc. 10 15 20 35 s 447 447 Polysackariderna innefattar heparin etc.The peptides include insulin, ACTH, enkephalin, TRH, LH-RH, polymyxin, colistin; gramamide, nacitracin, islet activating protein from Brodetella pertussis and inhibitor of angiotensin I-converting enzyme E (eg Glu-Trp-Pro-Arg-Pro-G1u-Ileu-Pro-Pro (hereinafter referred to as 20881)] etc The polysaccharides include heparin, etc.
Aminoglykosidantibiotika innefattar gentamicin, dibeka- cin, streptomycin, kanamycin, tobramycin, sisomycin och amikacin etc.Aminoglycoside antibiotics include gentamicin, dibecacin, streptomycin, kanamycin, tobramycin, sisomycin and amikacin, etc.
Den farmaceutiska kompositionen för rektal administra- tion i enlighet med denna uppfinning används vanligen som ett rektalt suppositorium eller en beredning framställd genom att fördela en farmakologiskt aktiv substans, ett adjuvans och andra beståndsdelar i en flytande oljaktig bas för att framställa en suspension eller salva och genom att fylla suspensionen eller salvan.LuÜdkä gelatinkapslar eller rör.The pharmaceutical composition for rectal administration in accordance with this invention is commonly used as a rectal suppository or preparation prepared by dispersing a pharmacologically active substance, an adjuvant and other ingredients in a liquid oily base to prepare a suspension or ointment. to fill the suspension or ointment.LuÜdkä gelatin capsules or tubes.
Dessa beredningar kan tillverkas genom i och för sig hävd- vunna farmaceutiska åtgärder. Basen för rektala beredningar i enlighet med denna uppfinning är en som vanligen används 1 så- dana beredningar och i synnerhet är oljaktiga och vattenlösliga baser önskvärda för uppfinningens syfte.These preparations can be manufactured by customary pharmaceutical measures per se. The base for rectal formulations in accordance with this invention is one commonly used in such formulations and in particular oily and water-soluble bases are desirable for the purpose of the invention.
Den oljaktiga basen innefattar bland annat sådana vegeta- biliska oljor såsom jordnötsolja, olivolja, majsolja, fett- syraglycerid [t.ex. Witepsol (Dynamite Nobel Chemicals), SB-Base (Kanegafuchi Chemical Co., Ltd), 0.D.0š§) (Nisshin Oil K.K.) etcß] och sådana mineraloljor som paraffin och vase- lin.The oily base includes, but is not limited to, vegetable oils such as peanut oil, olive oil, corn oil, fatty acid glyceride [e.g. Witepsol (Dynamite Nobel Chemicals), SB-Base (Kanegafuchi Chemical Co., Ltd), 0.D.0š§) (Nisshin Oil K.K.) etcß] and such mineral oils as paraffin and Vaseline.
Den vattenlösliga basen innefattar polyetylenglykol, propyleñglykol, glycerol, etc.The water-soluble base includes polyethylene glycol, propylene glycol, glycerol, etc.
Den farmaceutiska kompositionen för rektal administration 'enligt uppfinningen kan tillverkas på följande sätt. Först sätts nämnda salt till en bas och sedan tillsätts och fördelas en far- makologiskt aktiv substans. Ordningsföljden för tillsatsen be- höver inte vara begränsad till den som beskrivs ovan utan kan vara omvänd. Det är även möjligt att införliva ett antioxidations- medel, ett konserveringsmedel, en volymgivare, etc.The pharmaceutical composition for rectal administration according to the invention can be manufactured in the following manner. First the said salt is added to a base and then a pharmacologically active substance is added and distributed. The order of the additive need not be limited to that described above but may be reversed. It is also possible to incorporate an antioxidant, a preservative, a volume sensor, etc.
Tillsatsnivån för nämnda icke-toxiska salter till den farmaceutiska'kompositionen för rektal administrering är van- ligen 0,5-20 vikt-% räknat på hela beredningen, företrädesvis 'i - 15 vikt-Så och, för ännu bättre resultat, 3 - 10 vikt-äs. &;lisatsnivån för'nämnda icke-toxiska salt till basen är 0,5 - .., .. 4: vikt-%, företrädesvis 1"- 20 vikt-% och speciellt 2 - 13 10 15 _20 25 30 'ss 447 447 6 vikt-%.The level of addition of said non-toxic salts to the pharmaceutical composition for rectal administration is usually 0.5-20% by weight based on the whole preparation, preferably in - 15% by weight and, for even better results, 3 - 10% by weight. weight-ace. The concentration level of said non-toxic salt to the base is 0.5 - .., .. 4:% by weight, preferably 1 "- 20% by weight and especially 2 - 13 10 15 - 20 25 30's 447 447 6% by weight.
Vid framställning av en farmaceutisk komposition med an- vändning av en bas för rektala beredningar innehållande nämnda icke-toxiska salt sätts den aktiva substansen till basen och -- sedan efter behov kan andra beståndsdelar såsom ett antioxi- dationsmedel även tillsättas. Det är därför tillrâdligt att kontrollera tillsatsnivån för nämnda icke-toxiska salt till basen genom att i förväg bestämma den totala tillsatsnivån för den farmakologiskt aktiva substansen och andra bestånds- delar.'I så fall bör anpassningen göras på sådant sätt att koncentrationen för nämnda icke~toxiska salt i hela beredningen (konventionell-bas + farmakologiskt aktiv substans + andra beståndsdelar + nämnda icke-toxiska salt) kommer att vara inom området 0,5 - 20 vikt-%, företrädesvis 1 - 15 vikt-% och speciellt 3 - 10 vikt-%.In the preparation of a pharmaceutical composition using a base for rectal preparations containing said non-toxic salt, the active substance is added to the base and - then as needed, other ingredients such as an antioxidant may also be added. It is therefore advisable to check the level of addition of said non-toxic salt to the base by determining in advance the total level of addition of the pharmacologically active substance and other constituents. In that case the adjustment should be made in such a way that the concentration of said non-toxic toxic salt throughout the preparation (conventional base + pharmacologically active substance + other constituents + said non-toxic salt) will be in the range 0.5 - 20% by weight, preferably 1 - 15% by weight and especially 3 - 10% by weight -%.
Om den farmakologiskt aktiva substansen exempelvis är ett antibiotikum såsom en 13 -laktamförening (såsom penicilliner, cefäbosporiner, etc.) tillsättes den vanligen i proportionen 20 - 500 mg och företrädesvis 60 - 250 mg per g av hela bered- ningen. När det gäller insulin, etc. tillsätts den vanligen i proportionen 1 - 80 enheter och företrädesvis 4'- 40 enheter per g av hela beredningen. I I enlighet med den farmaceutiska kompositionen enligt uppfinningen är doseringen av ett antibiotikum, när ett I5 -laktam-antibiotikum används som den farmakologiskt aktiva substansen, från 125 mg till 2 g (styrka) per dos för vuxna och för insulin 1 - 100 enheter per dos för vuxna. Partikelstorle- ~ ken för de icke-toxiska salterna och den farmakologiskt aktiva substansen är företrädesvis inte större än 100 mesh.For example, if the pharmacologically active substance is an antibiotic such as a β-lactam compound (such as penicillins, cephalosporins, etc.), it is usually added in a proportion of 20-500 mg and preferably 60-250 mg per g of the whole formulation. In the case of insulin, etc., it is usually added in the proportion of 1 to 80 units and preferably 4 to 40 units per g of the whole preparation. In accordance with the pharmaceutical composition of the invention, the dosage of an antibiotic, when an I5-lactam antibiotic is used as the pharmacologically active substance, is from 125 mg to 2 g (strength) per dose for adults and for insulin 1 to 100 units per dose. for adults. The particle size of the non-toxic salts and the pharmacologically active substance is preferably not more than 100 mesh.
Fettsyrorna med 8 -_12 kolatomer är allmänt kända före- ningar och kan erhållas genom i och för sig kända förfaranden såsom hydrolys av naturolja eller de allmänna processerna för framställning av karboxylsyror.The fatty acids having 8-12 carbon atoms are generally known compounds and can be obtained by methods known per se such as hydrolysis of natural oil or the general processes for the production of carboxylic acids.
De icke-toxiska salterna av sådana fettsyror är också all- mänt kända och kan exempelvis framställas genom att låta en 447 447 alkalímetall- eller en organisk bas verka på sådana fettsyror.The non-toxic salts of such fatty acids are also well known and can be prepared, for example, by allowing a 447,447 alkali metal or an organic base to act on such fatty acids.
Leucinsyra och dess icke-toxiska salter är också allmänt kända.Leucic acid and its non-toxic salts are also well known.
EXEMPEL 1 8,25 g Witepsol®H-15 (frân Dynamite Nobel) smältes vid en temperatur, som inte överstiger 40°C,och 0,50 g natrium- kaprinat passerande 100 mesh tillsättes och fördelas jämnt qe- nom omrörning. Sedan fördelas 1,25 g (styrka) natriumampicillin (härefter betecknat AM-Ila) passerande 100 mesh jämnt däri.EXAMPLE 1 8.25 g of Witepsol® H-15 (from Dynamite Nobel) are melted at a temperature not exceeding 40 ° C, and 0.50 g of sodium caprinate exceeding 100 mesh are added and evenly distributed by stirring. Then 1.25 g (strength) of sodium ampicillin (hereinafter referred to as AM-IIa) passing 100 mesh is evenly distributed therein.
Blandningen gjuts i suppositoriebehållare med ett gram per be- hållare för att framställa ett rektalsuppositorium.The mixture is poured into suppository containers at one gram per container to produce a rectal suppository.
EXEMPEL 2 Rektalsuppositorier med de sammansättningar som anges i Tabell 1 framställdes i enlighet med tillvägagångssättet i exempel 1. I Tabell 1 anger "Na" natriumsalt.EXAMPLE 2 Rectal suppositories having the compositions set forth in Table 1 were prepared according to the procedure of Example 1. In Table 1, "Na" indicates sodium salt.
TABELL 1 Farmakologiskt aktiv Bas Nr' syra substans 1 Kaprinsfgra-Na 5% All-Na ® 2 Laurinsyra-Na 5% 125 mg (styrka) Witepsol H-15 3 Myristinsyra-bïa 5% (13,3 %) 817 mg (81,7 %) 4 l-arginixkaprinat AM-Na Witepsol® H-15 10% 125 mg (styrka) 767 mg (76,7%) (13-.3 %) l-lys irmkaprinat (Il Kaprinsyra-Na 5% l-arginirmaprinat 5% Oefazolin-Na 125 Ing (styrka) (1 3 , 1 %) Witepsol ®H-1 5 319 mg (81,9 %) 8 Kaprinsvra-Na 5% Cefalotin-Na 125 mg (styrka) Witepsol® H-1 5 818 mg (81,8 %) (13 ,2%) 'I Kz-lprínsf/ra-Na 5% AM-Nei 0.D.O * 125 mg (styrka) 817 mg (81,7 2:) (13,3%) * Triglvcerid med kedja av medellängd 447 447 Absorotionen av de i exemplen 1 och 2 framställda rektal- suppositorierna i blodomloppet bestämdes från plasmakoncentra- tionerna (/uq styrka/ml) av farmakologiskt aktiv substans.TABLE 1 Pharmacologically active Base No. acid substance 1 Capric acid-Na 5% All-Na ® 2 Lauric acid-Na 5% 125 mg (strength) Witepsol H-15 3 Myristic acid-bia 5% (13.3%) 817 mg (81 .7%) 4 l-arginine caprinate AM-Na Witepsol® H-15 10% 125 mg (strength) 767 mg (76.7%) (13-.3%) 1-lysine caprinate (Il Capric acid-Na 5% l -arginirmaprinate 5% Oefazolin-Na 125 Ing (strength) (1 3, 1%) Witepsol ®H-1 5 319 mg (81.9%) 8 Capric acid-Na 5% Cefalotin-Na 125 mg (strength) Witepsol® H -1 5 818 mg (81.8%) (13, 2%) 13.3%) * Medium chain chain triglyceride 447 447 The absorption of the rectal suppositories prepared in Examples 1 and 2 was determined from the plasma concentrations (/ uq strength / ml) of pharmacologically active substance.
Resultaten visas i Tabell 2.The results are shown in Table 2.
Bestämningsmetod: Från anus av en hund som fastats 24 h administrerades kom- positionen till ett djup av omkring 3 cm.Determination method: From the anus of a dog fasted for 24 hours, the composition was administered to a depth of about 3 cm.
För att mäta blodnivåer togs blodprov från karotisvenen med bestämda tidsmellanrum och plasmaprov beredda med rutin- metoder analyserades med avseende på aktivitetstiter med den biologiska bestämninqsmetoden.To measure blood levels, blood samples were taken from the carotid vein at regular intervals and plasma samples prepared by routine methods were analyzed for activity titers by the biological determination method.
Sålunda, i enlighet med japansk antibiotikastandard, an- ndes Sarcina lutea och Bacillus subtilis som analysorqa~ nismcr för penicilliner resp. cefalosporiner och be- " . . . o stämningarna utfordes med pappersskivemetoden (odling vid 37 C i 15 - 20 H).Thus, in accordance with the Japanese antibiotic standard, Sarcina lutea and Bacillus subtilis were used as analyzers for penicillins and penicillins, respectively. cephalosporins and the moods are challenged by the paper disc method (culturing at 37 ° C for 15-20 H).
TABELL 2 KONCENTRATION AV FARMAKOLOGISKT AKTIVA SUBSTANSER I PLASMA (HUND) PROV Koncentration i plasma(/uq styrka/ml) Åfi 10 20 40 60 90 min. min. min. min. min.TABLE 2 CONCENTRATION OF PHARMACOLOGICAL ACTIVE SUBSTANCES IN PLASMA (DOG) SAMPLE Concentration in plasma (/ uq strength / ml) Å fi 10 20 40 60 90 min. my. my. my. my.
Exempel 1 3,1 2,2 1,6 1,1 0,5 Exempel 2 ; Nr. 1 8,0 6,5 2,7 1,4 0,6 " Nr. 2 5,1 2,5 1,3 0,8 0,3 " Nr. 3 0,5 1,5 0,3 0,1 0 " Nr. 4 10,9 8,6 6,2 2,9 1,7 " Nr 5 9,2 7,0 2,9 1,6 0,7 " Nr. 6 14,1 14,6 11,5 3,6 5,0 “ Nr. 7 13,0 10,4 5,4 4,9 3,2 " Nr. 8 13,4 7,7 4,3 1,4 0,3 " Nr. 9 8,2 3,8 4,2 2,1 0,8 (kontroll) 4_q AVI-Na 125 mq (styrka) 0 0 0 0 0 (13,3 %) Witepsol H-15 867 mg Éf-Wra- 447 447 EXEMPEL 3 Rektalsuppositorier med de sammansättningar som anges i prov~spalten i Tabell 3 framställdes i enlighet med tillväga- qånqssättet i exempel 1. Dessa suppositorier administrerades till friska vuxna män och utsöndringen med urinen av de farma- kologiskt aktiva substanserna bestämdes. Resultaten visas i Tabell 3.Example 1 3.1 2.2 1.6 1.1 0.5 Example 2; Nr. 1 8.0 6.5 2.7 1.4 0.6 "No. 2 5.1 2.5 1.3 0.8 0.3" No. 3 0.5 1.5 0.3 0.1 0 "No. 4 10.9 8.6 6.2 2.9 1.7" No. 5 9.2 7.0 2.9 1.6 0, 7 "No. 6 14.1 14.6 11.5 3.6 5.0" No. 7 13.0 10.4 5.4 4.9 3.2 "No. 8 13.4 7.7 4.3 1.4 0.3 "No. 9 8.2 3.8 4.2 2.1 0.8 (control) 4_q AVI-Na 125 mq (strength) 0 0 0 0 0 (13.3%) Witepsol H-15 867 mg Éf-Wra 447 447 EXAMPLE 3 Rectal suppositories with the compositions listed in the sample column of Table 3 were prepared according to the procedure of Example 1. These suppositories were administered to healthy adult men and the urinary excretion of the pharmacologically active substances were determined, the results are shown in Table 3.
För att mäta utsöndringen med urinen tillvaratogs urin- prov vid bestämda tidpunkter efter administreringen, späddes och undersöktes genom den procedur som beskrivits i exempel 2. värdena för utsöndringen med urinen i Tabell 3 är procen- tuella med den administrerade dosen som bas. 447 447 10 we mww mf|mmmvHowm@»Ha «.mm Q «.« o.Pm wm pmaflwmmxssflmpmz Amxnwuwv me mwr cfiwwflmmwu m P cwmøHnwwHmn_mHmß f.m~ C w_@ m.N~ wav ßmnfl~mmx=fim>H| ~\ Mmmm »pa »mm wmnws mrfmnmvflommwpfiz m.«F O m_@ ~_«~ Mm umnflflmmxasfiuvmz fimxnmumv we omm o o o o I mzløfluofimmwu @.fN w_o ~.~ m.w, pm pßgømfiasflgumz f_wm m_~ Q.« w_Nm wof = = w P nwmnfinwwuwn mflmz «_@~ <.P @.« @_«~ mm = = “How ppm www wwnms m.@P N.c @.f «.@ W, umnflnmmxsøfiuumz mT¿~^vHomßmpfiz @.mP O æ.@ @.Nf wm umflwummxasfluumz .mMH>»mV ma mm, >.f O ~_O m." 1 mzlsfiflflfioflmam ^z@|cV~H«poa s@|« p«-~ awloï ¶m~>m wmß _ mcmumpsw >H»xß _ uxwflmofloxmšumm Amoø wv wzfimnznwaszwmø >omm Amxmflcflmšv nmmcwumflflm m>fluMm wxmfimofloxæëumm >m mcfluwmmmuøcflnb m Aåmmáë 447 447 11 e\° wa www m,|m^mvHomm@»fis4 Amxnæuwv ms mww mzlcflufimmmwu w~mm m.ßN ms www mf|m^mvHøwmw@Hz ^mx~>»mV ms mmf mzlflowmßmñmwo 0\0 umflflnmmxñnflnumz me www m~|m^mvHommw»fis ^mxu>»wv wa mm? mz|~øNw»wwu NMHÜM HÉÜHHUMZ GW Mmflflnmmxšsfluumz m P dmmcflflwwuwn namn muwm »um Hmm wmømñ mf|mA%uHOmQwßfl3 ^mxu>uw. me mm? flzlfl-SHHONNMNU ^s@|@VpHwuoa Smlw swlm mnßm mcmnmßflm >fluMm man . uxwflmofloxmšumm Amofl W.To measure the excretion with the urine, urine samples were collected at specific times after administration, diluted and examined by the procedure described in Example 2. The values for the excretion with the urine in Table 3 are percentages with the administered dose as the base. 447 447 10 we mww mf | mmmvHowm @ »Ha« .mm Q «.« O.Pm wm pma fl wmmxss fl mpmz Amxnwuwv me mwr c fi ww fl mmwu m P cwmøHnwwHmn_mHmß f.m ~ C w_ @ m.N ~ wav mmx = ßmß ~ \ Mmmm »pa» mm wmnws mrfmnmv fl ommwp fi z m. «FO m_ @ ~ _« ~ Mm umn flfl mmxas fi uvmz fi mxnmumv we omm oooo I mzlø fl uo fi mmwu @ .fN w_o ~. ~ Wm_ Q_ ~ mw, pm p. nwmn fi nwwuwn m fl mz «_ @ ~ <.P @.« @_ «~ mm = =“ How ppm www wwnms m. @ P Nc @ .f «. @ W, umn fl nmmxsø fi uumz mT¿ ~ ^ vHomßmp fi z @ .mP O æ. @ @ .Nf wm um fl wummxas fl uumz .mMH> »mV ma mm,> .f O ~ _O m." 1 mzls fiflflfi o fl mam ^ z @ | cV ~ H «poa s @ |« p «- ~ awloï ¶m ~> m wmß _ mcmumpsw > H "XSS _ uxw al mo al oxmšumm Amoo wv wz fi mnznwaszwmø> iff Amxm al c al mSV nmmcwum flfl etc.> al UMM wxm fi mo al oxæëumm> m mc al uwmmmuøc al nb m Aåmmáë 447 447 11 e \ ° wa www m | m mvHomm @» f s4 Amxnæuwv ms MWW mzlc fl u fi mmmwu w ~ mm m.ßN ms www mf | m ^ mvHøwmw @ Hz ^ mx ~> »mV ms mmf mzl fl owmßmñmwo 0 \ 0 um flfl nmmxñn fl numz me www m ~ | m ^ mvHommw» fi s ^ mxu> »wv wa mm? mz | ~ øNw» wwu MHm UMm HÉmHMM Üm HÉm P dmmc flfl wwuwn name muwm »um Hmm wmømñ mf | mA% uHOmQwß fl3 ^ mxu> uw. Me mm? Fl zl fl- SHHONNMNU ^ s @ | @VpHwuoa Smlw swlm mnßm mcmnmß fl m> fl um wm man man.
U2HmQZ@wBDZHmD >OMm 447 447 12 o\° ^mMu>umv ms Nfm m m flm @ How mflflš mä mmf mZlfiflflHfiOflGmQH5w N.wN Éxnwumv ma Éw .:-w@ mä mmf MZIHOUGMEMMQO Hommwufls o\° Amxnmumv wa oww m Tm av Hommmnñs wa mm? ~z|=fiwoH:m«mu ßmxuhumv ma wrw - m flm @ HOmQwMflB wa mm? mz Bflxmuomwo m.ow f~m m~m :SP m umnflummxšøfluvmz .mufiafiï wa m S ..._ Tm nmu Hommmfiz mä mm? øwßlßm 3313 »ämfioa swiv svlm mH>m man mcmumnsm >flvxm uxmflmofloxmšumm Bow i ozfiåznmamzwma >OMm 447 447 wa m E m Tm Hommwufiz WE mm MZ EflNOHSmmU CN) we m å m Tm Qv Hommwfläs cßvzfiw. wa mï MZ GHuHMOwwU 13 WE www m Tu mnvflowmwuflz Amxnæumv mä mmv MZ fiflHHflOmX0HOfiQ m.m~ (ÅO ma .åw m Tm mm Hommmfläz mä mmw flflflflfloflxoåm iài: »Époe .u _- : _. .n 2 umcfinmmxšøfinumz mu>m mcmumnflm >fluxm uxmflmofloxmâumm UZHZQZQWBDZMXD 447 447 14 ma omm ___. mrnmflwñvflommwuäs .Qm.mN I ^Qm~N ^Qo.mN Amxuæumv wš ww»mQmH5>mHM ~ ~ ~ o Ömufiuflänwwv WE OmN ^m>.>m Aøa P .mm m .mm om M m = = mz øflflflfluflmsm WE www m Tm @ Howmwuäz I . 0 . m Dfluumz ^mxuwumV må mmf N.wm N.m o mm w m umcau mxë 1 mnæmcmHs>mHM WE www ïï NJ N13 0.3 w m flfiøfisšnupmz mïm@flommmfi.z _ .m o.of m_mN p m vmflhnmmxëøflnwmz Amxnmumv må mmf M.Wm m.m o_mf m_mm M m = = *¥mmmo@ ms Km m Tm mw Hommmuäs _ ~ a v Gfiummxëflfluumz Amxnæumv mä mm? m_@ O m F O m “ m w mz ,mmf|@ .. . mcmuwnnm >fluxm Emfâïmßoß åè åTN šfo nä? än . »xmflmofloxßeumm Bow w ozäazownhšâzo >Omm 447 447 .flfimmäßfiufißßfl ...mZ: HUÜÉÜ m. HAUQME H .mu>wGøHø>mfiM >m møflnwøwmßønflnb An .mz øfifiaflofiøäm >m mcfluvcmmuøøflun Än uammäflflHum:Hw|mn>mH>xønumx|N|cw|N|ux0 fic.N.<@oHM>uflßmNmlvnmxolmloxolwlfiamuwš ...__ -.,.__:.._._...,....._....__,.._. . . _ f.f-__....,_.._~_. -.._ I W n... ..._-f ß |fio..flvuä|m1flowmupwuïm 7139.? fmnmuwxoflvwsnß|mowflsmufiwom Aïøwwwxohflšni: ååíongmxåuå- S? .m8 i, 1:- ma www mffmnmvfiowmwuflz ^no_mN 1 ^nc~m ^n@_~N .mMH>umV ma mwf o.NN 0., c.« @.>f M m pmunßflssfimumz Amxuænmv ms emm Am Am Am .ß nflfififiofixoam Anmfšvflmpoa Éè šïm åao mïw man . mzfimßsw >ÜLE uxm«m0H0xmEumm w| Amon wv ozHmoznmæ:zH;: >omm 447 447 16 EXEMPEL 4 Rektalsuppositorier med de sammansättningar som anges i prov~spalten i Tabell 4 framställdes i enlighet med tillväga- gångssättet i exempel 1.U2HmQZ @ wBDZHmD> OMm 447 447 12 o \ ° ^ mMu> umv ms Nfm mm flm @ How m flfl š mä mmf mZl fiflfl H fi O fl GmQH5w N.wN Éxnwumv ma Éw. wa mm? ~ z | = fi woH: m «mu ßmxuhumv ma wrw - m flm @ HOmQwM fl B wa mm? mz B fl xmuomwo m.ow f ~ m m ~ m: SP m umn fl ummxšø fl uvmz .mu fi a fi ï wa m S ..._ Tm nmu Hommm fi z mä mm? øwßlßm 3313 »äm fi oa swiv svlm mH> m man mcmumnsm> fl vxm uxm fl mo fl oxmšumm Bow i oz fi åznmamzwma> OMm 447 447 wa m E m Tm Hommwu fi z WE mm MZ E fl NOHSmmU T Q Qs h h mm m m m. wa mï MZ GHuHMOwwU 13 WE www m Tu mnv fl owmwu fl z Amxnæumv mä mmv MZ fifl HH fl OmX0HO fi Q mm ~ (ÅO ma .åw m Tm mm Hommm fl äz mä mmw flflflflfl o fl xoåm iài: »um> m m. uxm fl mo fl oxmâumm UZHZQZQWBDZMXD 447 447 14 ma omm ___. mrnm fl wñv fl ommwuäs .Qm.mN I ^ Qm ~ N ^ Qo.mN Amxuæumv wš ww »mQmH5> mHM ~ ~ ~ m Ömm fi>. om M m = = mz ø flflflfl u fl msm WE www m Tm @ Howmwuäz I. 0. m D fl uumz ^ mxuwumV må mmf N.wm Nm o mm wm umcau mxë 1 mnæmcmHs> mHM WE www ïï NJ N13 0.3 wm flfi ø fi sšnupmz mï. .m o.of m_mN pm vm fl hnmmxëø fl nwmz Amxnmumv må mmf M.Wm mm o_mf m_mm M m = = * ¥ mmmo @ ms Km m Tm mw Hommmuäs _ ~ av G fi ummxë flfl uumz Amxnæumv mä mm? m_ @ O m FO m “ | @ ... mcmuwnnm> fl uxm Emfâïmßoß åè åTN šfo nä? än. »xm fl mo fl oxßeumm Bow w ozäazownhšâzo> Omm 447 447 .flfi mmäß fi u fi ßß fl ... mZ: HUÜÉÜ m. > m mc fl uvcmmuøø fl un Än uammä flfl Hum: Hw | mn> mH> xønumx | N | cw | N | ux0 fi c.N. <@ oHM> u fl ßmNmlvnmxolmloxolwl fi amuwš ... __ -., .__: .._._..., ....._....__, .._. . . _ f.f -__...., _.._ ~ _. -.._ I W n ... ..._- f ß | fi o .. fl vuä | m1 fl owmupwuïm 7139.? fmnmuwxo fl vwsnß | mow fl smu fi wom Aïøwwwxoh fl šni: ååíongmxåuå- S? .m8 i, 1: - ma www mffmnmv fi owmwu fl z ^ no_mN 1 ^ nc ~ m ^ n @ _ ~ N .mMH> umV ma mwf o.NN 0., c. «@.> f M m pmunß fl ss fi mumz Amxuænmv ms emm Am Am Am .ß n flfififi o fi xoam Anmfšv fl mpoa Éè šïm åao mïw man. mz fi mßsw> ÜLE uxm «m0H0xmEumm w | Amon wv ozHmoznmæ: zH ;:> omm 447 447 16 EXAMPLE 4 Rectal suppositories with the compositions listed in the sample column of Table 4 were prepared according to the procedure of Example 1.
Dessa rektalsuppositorier administrerades till kaniner och tidsförloppet för blodglukosnivån följdes mot kontroller, där rektalsupposítorier, som inte innehöll någon av syrorna, administrerades. Resultaten anges i Tabell 4.These rectal suppositories were administered to rabbits and the time course of the blood glucose level was monitored against controls, where rectal suppositories, which did not contain any of the acids, were administered. The results are given in Table 4.
Bestämningsmetod: Varje rektalsuppositorium administrerades till ett djup av 2 cm från anus hos en kanin, som fastats 24 h. För att mäta blodglukosnivån togs blodprov från aurikulärvenen vid bestämda tidpunkter och analyserades med glukosoxidasmetoden.Determination method: Each rectal suppository was administered to a depth of 2 cm from the anus of a rabbit fasted for 24 hours. To measure the blood glucose level, blood samples were taken from the auricular vein at specific times and analyzed by the glucose oxidase method.
'I 447 447 17 ms m.@@m _ m~|mnUHowoøpflz »wow mma wwof wmef door .o.H NF lllllllll GflH5wßH Aflfiønvmøxv Aw mv ma m.@wm wfcf wrof wßø wmß wcc. wa om mF|mnvHomøw~Hs ßuwmnfivflwfl .D.H w m QHHZWGH .www ms om wow wøm www wow .wcer pmusmflssflflpmz = N ma m.mwm Aww. mrammmvflowawßfiz wa om .ø.H NP P www wmm www www wear umnfiwmmxfiøfluumz øfiHøwuH Q N ßm_f s c._ n m_c s C mwnm mmm . cHHøm:H .wz <>Hzwomnflwno4m >omm Tnfififlvfiv fiOflnwühämflflflåflmfiflfifiwflfl HQMMQ WNÖMHCWOMDMUUOHÉ w ÄQWMÉF 447 447 18 EXEMPEL 5 Rektalsuppositorier med de sammansättningar som anges i prov-spalten i Tabell 5 framställdes i enlighet med det till- vägagångssätt som beskrivits i exempel 1.'I 447 447 17 ms m. @@ m _ m ~ | mnUHowoøp fl z »wow mma wwof wmef door .o.H NF lllllllll G fl H5wßH A flfi ønvmøxv Aw mv ma m. @ Wm wfcf wrof wßø wmß wcc. wa om mF | mnvHomøw ~ Hs ßuwmn fi v fl w fl .D.H w m QHHZWGH .www ms om wow wøm www wow .wcer pmusm fl ss flfl pmz = N ma m.mwm Aww. mrammmv fl owawß fi z wa om .ø.H NP P www wmm www www wear umn fi wmmx fi ø fl uumz ø fi HøwuH Q N ßm_f s c._ n m_c s C mwnm mmm. cHHøm: H .wz <> Hzwomn fl wno4m> omm Tn fififl v fi v fi O fl nwühäm flflfl å fl m fiflfifi w flfl HQMMQ WNÖMHCWOMDMUUOHÉ w ÄQWMÉF 447 447 18 EXAMPLE 5 Sample compilations set out as examples.
Dessa rektalsuppositorier administrerades till kaniner och utsöndrinqen med urinen av de farmakologiskt aktiva sub- stanserna bestämdes. Resultaten visas i Tabell 5.These rectal suppositories were administered to rabbits and the urinary excretion of the pharmacologically active substances was determined. The results are shown in Table 5.
Bestämningsmetod: För att mäta utsöndringen med urinen tillvaratogs urin- prov efter administrering vid bestämda tidpunkter, späddes och analyserades med avseende på aktivitetstiter med bio- logisk analysmetod.Determination method: To measure the excretion with the urine, urine samples were collected after administration at specific times, diluted and analyzed with respect to activity titers with biological analysis method.
Sålunda,i enlighet med japansk antibiotikastandard, användes Escherichia coli och Bacillus subtilis, som analys- organismer för peptid (kolistin) resp. aminoglykosid-anti- biotika (gentamicin, dibekacin och kanamycin) och analyserna utfördes med pappersskivemetoden (odling vid 37°C under 15 ~ 20 h). 447 447 19 o.mm m P m Tmßw Howmwufis o_Q_ w.mf m.@m wm = = .mxumuwv ms cv Gflowñmcmm m P mf|m Howmwuflz «_mm w_m~ w.mf m.fm wm = = ^mxnw@m. ma « nflomxmnfln m F m Ta @Hommwfiz Q.Nm @_m @.f_ @_~m wm = = Amxuwuwv wa ow cfivfišmuflww w P m .hm @ Howmwfiz Fm _ ~.m w.o~ m_>w wm umcfiummxssfiuumz Amxuwpmv ma ON M cflpmflfiom ^§@|Ovuflm~o@ §@|« n«|N :N10 @»>m mun . wømumnøm >H»xm uxmflmøaøxmäuuh Ämow wv wzHmmznweszHza >oxm æfl AGHQMMV Mwmflmumflfiw m>flwMm nMmHwOflOMmEMmw >m @GfiHUfi@mu5GflHD m flflmmflë 447 447 20 EXEMg§Q_§ 2,36 g Witepsol(:)H-15 smältes vid en temperatur ej över- stigande 40°C och 0,125 g natriumkaprinat passerande 100 mesh tillsattes och fördelades jämnt däri. Sedan fördelades 15 mg D-3-merkapto-2-metylpropanoyl-L-prolin (SQ 14,225) jämnt.Thus, in accordance with Japanese antibiotic standards, Escherichia coli and Bacillus subtilis were used as assay organisms for peptide (colistin) and aminoglycoside antibiotics (gentamicin, dibecacin and kanamycin) and the analyzes were performed by the paper disc method (culture at 37 ° C for 15 ~ 20 hours). 447 447 19 o.mm m P m Tmßw Howmwu fi s o_Q_ w.mf m. @ M wm = = .mxumuwv ms cv G fl owñmcmm m P mf | m Howmwu fl z «_mm w_m ~ w.mf m.fm wm = = ^ mxnw @ m . ma «n fl omxmn fl n m F m Ta @Hommw fi z Q.Nm @_m @ .f_ @ _ ~ m wm = = Amxuwuwv wa ow c fi v fi šmu fl ww w P m .hm @ Howmw fi z Fm _ ~ .m wo ~ m_> w wm umc fi umm Onxx M c fl pm flfi om ^ § @ | Ovu fl m ~ o @ § @ | «n« | N: N10 @ »> m mun. wømumnøm> H »xm uxm fl møaøxmäuuh Ämow wv wzHmmznweszHza> oxm æ fl AGHQMMV Mwm fl mum flfi w m> fl wMm nMmHwO fl OMmEMmw> m @G fi HU fi @ mu5G fl 20 rising 40 ° C and 0.125 g of sodium caprinate passing 100 mesh were added and evenly distributed therein. Then, 15 mg of D-3-mercapto-2-methylpropanoyl-L-proline (SQ 14,225) was evenly distributed.
Blandningen göts i en suppositoriebehållare för att framstäl- la ett rektalsuppositorium.The mixture was poured into a suppository container to produce a rectal suppository.
Tre grupper (fem råttor per grupp) av spontant hyperten- *siva råttor (10-14 veckor gamla hanar av Wister-stam), nedan betecknade SHR, sattes upp. Varje råtta i den första gruppen gavs ett rektalsu positorium (natriumkaprinat 5 mg, SQ 14,225 0,6 mq, Witepsol H-15 94,4 mg) framställt enligt ovan. Varje 1 ;1 i den andra gruppen (kontroll) injicerades subkutant med 5 ml/kg av endast koksaltlösning och till varje råtta i den tredje gruppen (kontroll) administrerades oralt 0,6 mg SQ .4,225 i form av en vattenlösning. Förändringar i medelblod- trycket för de tre grupperna med tiden bestämdes i enlighet med det sätt som beskrivits i J. Pharmacol. Exp. Ther. 205, 281-288, 1073.Three groups (five rats per group) of spontaneously hypertensive * rats (10-14 week old males of Wister strain), hereinafter referred to as SHR, were set up. Each rat in the first group was given a rectal suppository (sodium caprinate 5 mg, SQ 14.225 0.6 mq, Witepsol H-15 94.4 mg) prepared as above. Each 1: 1 in the second group (control) was injected subcutaneously with 5 ml / kg of saline only and to each rat in the third group (control) 0.6 mg of SQ .4.225 in the form of an aqueous solution was orally administered. Changes in mean blood pressure for the three groups over time were determined according to the procedure described in J. Pharmacol. Exp. Ther. 205, 281-288, 1073.
Resultaten visas i Tabell 6. 447 447 21 >_Nw« w.mwf m.mwf f.wmw w.wæf æ~vwr c~wæF c.mw~ m_Næ~ w.wwP .o.w mx\Ha m wcficwmflwflmwxox ^HHo~»øox.The results are shown in Table 6. 447 447 21> _Nw «w.mwf m.mwf f.wmw w.wæf æ ~ vwr c ~ wæF c.mw ~ m_Næ ~ w.wwP .ow mx \ Ha m wc fi cwm fl w fl mwxox ^ HHo ~» øox.
Amncv ~.mm~ w~ßwP f.wwf c.ww~ @.cwr N~mwf c.@@~ m_~æf _@.«wf m.Nwf ßmuG..0.m usfi©\mE m.o m-_«~ om Aflfiouucoxv m.mw~ w.wm« w~wmf w~cwP m.ßm~ w.mm~ -mæ~ o_wwf m.ow~ ñmunv uflmuxmn nflfiU\mE w.o mmN.«f Gm w f“ of Ammasv xuwßwofimflwøwz Anmëñfivv QHB m JJWm4F _ . _ . w 447 447 22 Ešêfíšêltl 2,225 g Witepsol(š>H-15 smältes vid en temperatur ej över- stigande 40°C och 0,125 g natriumkaprinat passerande 100 mesh tillsattes och fördelades jämnt. Sedan fördelades 0,15 g SQ 20,831 jämnt. Blandningen göts i en suppositoriebehållare för att framställa ett rektalsuppositorium.Amncv ~ .mm ~ w ~ ßwP f.wwf c.ww ~ @ .cwr N ~ mwf c. @@ ~ m_ ~ æf _ @. «Wf m.Nwf ßmuG..0.m us fi © \ mE mo m- _ «~ Om A flfi ouucoxv m.mw ~ w.wm« w ~ wmf w ~ cwP m.ßm ~ w.mm ~ -mæ ~ o_wwf m.ow ~ ñmunv u fl muxmn n flfi U \ mE wo mmN. «F Gm wf“ of Ammasv xuwßwo fi m fl wøwz Anmëñ fi vv QHB m JJWm4F _. _. w 447 447 22 Ešêfíšêltl 2,225 g Witepsol (š> H-15 was melted at a temperature not exceeding 40 ° C and 0.125 g sodium caprinate passing 100 mesh was added and evenly distributed. Then 0.15 g SQ 20,831 was evenly distributed. The mixture was poured into a suppository container for making a rectal suppository.
Tre grupper (fem rätter per grupp) av SHR sattes upp. Till varje råtta i den första gruppen administrerades ett rektal~ suppositorium (natriumkaprinat 5 mg, SQ 2Q881 6 mg, Witepsoléj H-15 89 mg) framställt enligt ovan. Varje råtta i den andra gruppen (kontroll) gavs genom subkutan injektion 5 ml/kg av endast koksaltlösning och till varje råtta i den tredje grup- ,;n (kontroll) admjnistrerades oralt 6 mg SQ 20,881 i form av en vattenlösning. Förändringar i medelblodtycket för de tre grupperna med tiden bestämdes på det sätt som beskrivits i J. Pharmacol. Exp. Ther. Egg, 281-288, 1978.Three groups (five dishes per group) of SHR were set up. To each rat in the first group was administered a rectal suppository (sodium caprinate 5 mg, SQ 2Q881 6 mg, Witepsoléj H-15 89 mg) prepared as above. Each rat in the second group (control) was given by subcutaneous injection 5 ml / kg of saline only and to each rat in the third group (control) was administered orally 6 mg of SQ 20,881 as an aqueous solution. Changes in mean blood pressure for the three groups over time were determined as described in J. Pharmacol. Exp. Ther. Egg, 281-288, 1978.
Resultaten visas i Tabell 7. 447 447 Amnnv .o.m wx\Ha m m.~w~ m.wæ« >.~æ~ m.oæ_ «_fæ~ ~.mwF m.mæ~ v.ww~ w.Nw~ w.~æf @_wæf mcflcmmfluflmwxox Åfiflouufloxv ^mucv .u.m uflfiw\mE m m.mm~ o.fwf m.wm~ N~mm~ m.mm~ m.mm« o~mw~ æ.wwF m.oæf m_Næf w.~w« fæw.om Om ^~Ho~@=ox_ ^mnsv flfiflumwu ~_mw~ m_Nw_ w.owF m.o@. >.«w_ æ_>mP @.>m_ -@mf m.mæ~ «_«æ« m.mw~ ~uflw\ms w fwm~cN Gm mf fif Nr ofi m m w N W Q N: W; Auwæaflß. a 1% . ^m:EEv uumwöøflmfluöüz ß J4mmt- :JLThe results are shown in Table 7. 447 447 Amnnv .om wx \ Ha m m. ~ W ~ m.wæ «>. ~ Æ ~ m.oæ_« _fæ ~ ~ .mwF m.mæ ~ v.ww ~ w.Nw ~ w. ~ æf @ _wæf mc fl cmm fl u fl mwxox Å fifl ouu fl oxv ^ mucv .um u flfi w \ mE m m.mm ~ o.fwf m.wm ~ N ~ mm ~ m.mm ~ m.mm «o ~ mw ~ æ.wwF m.oæf m_Næf w. ~ w «fæw.om Om ^ ~ Ho ~ @ = ox_ ^ mnsv flfifl umwu ~ _mw ~ m_Nw_ w.owF mo @. >. «W_ æ_> mP @.> M_ - @ mf m.mæ ~« _ «æ« m.mw ~ ~ u fl w \ ms w fwm ~ cN Gm mf fi f Nr o fi m m w N W Q N: W; Auwæa fl ß. a 1%. ^ m: EEv uumwöø fl m fl uöüz ß J4mmt-: JL
Claims (8)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55035128A JPS5857407B2 (en) | 1980-03-19 | 1980-03-19 | Base for rectal administration |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE8007820L SE8007820L (en) | 1981-09-20 |
| SE447447B true SE447447B (en) | 1986-11-17 |
Family
ID=12433287
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8007820A SE447447B (en) | 1980-03-19 | 1980-11-06 | ADJUVANCING COMPOSITION TO PROMOTE ABSORPTION OF PHARMACOLOGICALLY ACTIVE SUBSTANCES CONTAINING NON-TOXIC SALTS OF FAT ACIDS WITH 8-12 COLATOMES AND NON-TOXIC SALTS OF LEUCIC ACID |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5857407B2 (en) |
| AU (1) | AU537260B2 (en) |
| BE (1) | BE885941A (en) |
| CH (1) | CH645808A5 (en) |
| IT (1) | IT1134202B (en) |
| SE (1) | SE447447B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
| US6846801B1 (en) | 1993-06-24 | 2005-01-25 | Astrazeneca Ab | Systemic administration of a therapeutic preparation |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4134831C2 (en) * | 1991-10-22 | 1995-05-18 | Mannesmann Ag | Arrangement for determining a coefficient of friction information |
| ITMI20070084A1 (en) * | 2007-01-22 | 2008-07-23 | Carlo Ghisalberti | LIPID BASED VAGINAL ANTISEPTIC DEVICES |
| CN109790259B (en) | 2016-09-30 | 2021-12-07 | 东丽株式会社 | Copolymer and medical material using the same |
-
1980
- 1980-03-19 JP JP55035128A patent/JPS5857407B2/en not_active Expired
- 1980-10-24 AU AU63686/80A patent/AU537260B2/en not_active Expired
- 1980-10-30 BE BE0/202645A patent/BE885941A/en not_active IP Right Cessation
- 1980-11-06 SE SE8007820A patent/SE447447B/en not_active IP Right Cessation
- 1980-11-06 CH CH825580A patent/CH645808A5/en not_active IP Right Cessation
- 1980-11-07 IT IT25850/80A patent/IT1134202B/en active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
| US6846801B1 (en) | 1993-06-24 | 2005-01-25 | Astrazeneca Ab | Systemic administration of a therapeutic preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| AU537260B2 (en) | 1984-06-14 |
| IT8025850A0 (en) | 1980-11-07 |
| CH645808A5 (en) | 1984-10-31 |
| BE885941A (en) | 1981-02-16 |
| IT1134202B (en) | 1986-08-13 |
| SE8007820L (en) | 1981-09-20 |
| AU6368680A (en) | 1981-09-24 |
| JPS56131526A (en) | 1981-10-15 |
| JPS5857407B2 (en) | 1983-12-20 |
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